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Clin Orthop Relat Res. Sep 2008; 466(9): 2114–2130.
Published online Jun 18, 2008. doi:  10.1007/s11999-008-0335-z
PMCID: PMC2492997

Osteosarcoma Development and Stem Cell Differentiation

Ni Tang, MD, PhD,1,2 Wen-Xin Song, MD,2 Jinyong Luo, MD,1,2 Rex C. Haydon, MD, PhD,2 and Tong-Chuan He, MD, PhDcorresponding author1,2


Osteosarcoma is the most common nonhematologic malignancy of bone in children and adults. The peak incidence occurs in the second decade of life, with a smaller peak after age 50. Osteosarcoma typically arises around the growth plate of long bones. Most osteosarcoma tumors are of high grade and tend to develop pulmonary metastases. Despite clinical improvements, patients with metastatic or recurrent diseases have a poor prognosis. Here, we reviewed the current understanding of human osteosarcoma, with an emphasis on potential links between defective osteogenic differentiation and bone tumorigenesis. Existing data indicate osteosarcoma tumors display a broad range of genetic and molecular alterations, including the gains, losses, or arrangements of chromosomal regions, inactivation of tumor suppressor genes, and the deregulation of major signaling pathways. However, except for p53 and/or RB mutations, most alterations are not constantly detected in the majority of osteosarcoma tumors. With a rapid expansion of our knowledge about stem cell biology, emerging evidence suggests osteosarcoma should be regarded as a differentiation disease caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells. Understanding the molecular pathogenesis of human osteosarcoma could ultimately lead to the development of diagnostic and prognostic markers, as well as targeted therapeutics for osteosarcoma patients.


Osteosarcoma (OS) is the most frequent primary bone sarcoma, comprising approximately 20% of all bone tumors and about 5% of pediatric tumors overall [34, 67, 73, 75, 77, 94, 127, 136, 146, 210, 252, 259]. In fact, OS is the fifth most common malignancy among individuals aged 15 to 19 years, and the second most common in adolescence after lymphoma. OS has a bimodal age distribution, with the first peak in the second decade of life and a second peak in elderly adults [146, 210]. Higher incidences in boys and in African-American children have been reported [146, 210]. The most common locations in young adults are areas with rapid bone growth, including distal femur, proximal tibia, and proximal humerus. Nevertheless, OS is relatively rare, and less than 1000 new cases are diagnosed each year in the United States, accounting for less than 2% of all new cancer cases in the U.S. [146, 210].

Although OS development is associated with several genetic predisposition conditions, most OS tumors are sporadic without familial patterns [67, 73, 77, 94, 146, 210, 252, 259]. Our current understanding of OS etiology is rather limited. Exposure to chemical beryllium oxide [51], orthopaedic prostheses [101], and the FBJ virus [51] causes OS in animal models, but their role in human OS is unknown. SV40 viral DNA has been detected in up to 50% of OS tumors [24, 125, 161], while it is unclear whether SV40 plays any role in OS tumorigenesis [51, 62]. Radiation exposure is a well-documented risk factor for OS [51, 88, 147, 239, 256], but the interval between radiation exposure and tumor appearance is long, and hence it is likely irrelevant to the development of most conventional OS tumors. Nevertheless, radiation could be responsible for the development of secondary OS postradiation therapy of certain primary tumors.

Despite the relative low incidence of OS, more than 20,000 articles describing the pathogenic and clinical aspects of OS have been published thus far. As summarized in this survey, OS displays a broad range of genetic and epigenetic alterations, and yet no consensus changes have been identified in all OS tumors [34, 67, 73, 75, 77, 94, 127, 136, 146, 210, 252, 259]. With the rapid expansion of our knowledge about stem cell biology and cancer stem cells [204, 217, 260, 278], increasing evidence suggests OS may be considered a differentiation disease [75, 231]. Terminal differentiation of osteoblasts, which are derived from multipotent mesenchymal stem cells, is a well-orchestrated process and controlled by a cascade of regulatory signaling [36, 38, 39, 75, 82, 96, 114, 129, 136, 171, 173, 187, 270]. Pathologic and molecular features of most if not all OS tumors strongly suggest OS may be caused by genetic and epigenetic disruptions of osteoblast differentiation pathway [75, 231]. Promoting differentiation and/or circumventing differentiation defects may be exploited as an efficacious adjuvant therapy for OS since current chemotherapies mostly target the proliferative aspects of OS tumors [75, 76, 188].

In this survey, we briefly review currently identified genetic alterations that may be associated with osteosarcoma pathogenesis, and then focus on recent findings that suggest potential links between defective osteogenic differentiation of mesenchymal stem cells and osteosarcoma development. We believe this line of investigation will provide insight into the pathogenesis of osteosarcoma.

Search Strategies and Criteria

We performed PubMed searches of the literature relevant to the subject with the following keywords utilized individually or in combination: osteosarcoma (20,168 references), osteosarcoma pathogenesis (8232 references), osteosarcoma genetics (3587 references), osteosarcoma mutation (1232 references), osteosarcoma biology (238 references), osteosarcoma stem cell (669 references), osteosarcoma stem cell differentiation (99 references), and osteosarcoma lung metastasis (894 references), as of March 2008. Publications in languages other than English, pertinent review articles, and book chapters were not excluded in our searches. However, we mostly reviewed the English abstracts of the articles published in other languages and only utilized the articles that added any information to this review. Whenever information overlapped, we referenced the most recent articles built on conclusions or reports of previous articles. Our searches of articles published in the English language revealed considerable overlap in articles identified under the different search terms, and we carefully reviewed the articles for pertinence to our review article. In this review, we primarily focused on relevant publications within the past 10 years, while not excluding older but commonly referenced and highly regarded prior publications. We suspect many of the osteosarcoma cases described in the literature represent high-grade osteosarcomas.

Clinical Aspects of Human OS

Most OS patients present with pain and swelling in the affected regions after trauma or vigorous physical activities [146]. The diagnosis of OS is usually made by radiographic appearance and location of tumor lesions and a biopsy for pathologic confirmation [146]. OS can present radiographically as a lytic, sclerotic, or mixed lytic-sclerotic lesion [146]. Up to 20% of OS patients present with radiographically detectable lung metastases, whereas 80% of patients with localized OS develop metastases after surgical resection alone [146]. Death from OS is usually the result of progressive pulmonary metastasis with respiratory failure [146].

OS has a broad spectrum of histologic appearances with common characteristics containing highly proliferative malignant mesenchymal stem cells and the production of osteoid and/or bone by tumor cells [62, 146]. Histologically, OS can be divided into several subtypes. Conventional osteoblastic OS makes up about 70%, whereas chondroblastic and fibroblastic OS tumors are the next most common at 10% each [62, 73, 102, 231]. Other OS types include anaplastic, telangiectatic, giant cell-rich, and small cell OS [102]. Conventional OS is a primary intramedullary high-grade sarcoma. Current clinical management of OS includes pre- and postoperative chemotherapy and surgical resection [62]. Only about 20% of OS patients can be cured without chemotherapy [62, 102, 146]. Chemotherapy agents include doxorubicin, cisplatin, ifosfamide, and methotrexate [62, 102, 127, 146]. Surgical removal of the primary tumor requires a wide-margin resection, followed by limb salvage reconstruction [62, 102, 127, 146].

OS prognostic indicators include extent of disease at diagnosis, size and location of the tumor, response to chemotherapy, and surgical remission [62, 102, 127, 146]. For those OS patients who present without detectable metastases, approximately 70% of them can achieve long-term survival [62, 102, 127, 146]. The remaining 30% will relapse, mostly within 5 years [62, 102, 127, 146]. Pulmonary metastasis is the most common form of distant spread. The average survival after a recurrence is less than 1 year [62, 102, 127, 146]. Removal of a surgically resectable recurrence or pulmonary metastasis improves survival [62, 102, 127, 146]. Thus, a major challenge in clinical management of OS is to identify poor responders to chemotherapy and/or to detect early metastatic lesions.

Chromosomal Abnormalities in Human OS

Unlike other sarcomas, such as synovial sarcoma, alveolar rhabdomyosarcoma, and Ewing’s sarcoma, no specific translocations or genetic abnormalities have been identified in OS [34, 67, 73, 75, 77, 94, 127, 136, 146, 210, 252, 259]. Nevertheless, nearly 70% of OS tumors display a multitude of cytogenetic abnormalities [146, 210]. The ploidy number in OS has ranged from haploidy to near-hexaploidy. Chromosomal regions of 1p11–p13, 1q11–q12, 1q21–q22, 11p14–p15, 14p11–p13, 15p11–p13, 17p, and 19q13 are most commonly involved in structural abnormalities [146, 210]. Gain of chromosome 1 and loss of chromosomes 9, 10, 13, and 17 are most common overall. Less frequently involved chromosomal regions were 13q14 (locus of RB1), 12p12–pter (locus of KRAS), 6q11–q4, and 8p23 [146, 210].

A combination of several detection modalities has provided a more accurate assessment of the complex cytogenetic aberrations in OS [146, 210]. The most frequently detected amplifications include chromosomal regions 6p12–p21 (28%), 17p11.2 (32%), and 12q13–q14 (8%) [210]. Several other recurrent chromosomal losses (2q, 3p, 9, 10p, 12q, 13q, 14q, 15q, 16, 17p, and 18q) and chromosomal gains (Xp, Xq, 5q, 6p, 8q, 17p, and 20q) were also identified, as well as several recurrent breakpoint clusters and nonrecurrent reciprocal translocations [210]. These findings further highlight the complexity and the instability of the genetic makeup of OS tumors.

Genetic Alterations of Tumor Suppression Genes in Human OS

Retinoblastoma Tumor Suppressor

Individuals affected by hereditary retinoblastoma (RB) heterozygous for a germline inactivation of RB1 have an approximately 1000 times higher incidence of OS. RB1 maps to 13q14 [1, 111]. Genetic alterations of RB1 have been found in up to 70% of sporadic OS cases [2, 4, 12, 13, 164, 215, 235, 248, 267]. Loss of heterozygosity (LOH) of RB1 locus is present in 60% to 70% of OS tumors [12, 48, 271], whereas structural rearrangements and point mutations occur less commonly (30% and 10%, respectively) [2, 4, 12, 13, 164, 215, 235, 248, 267]. Furthermore, LOH at the RB1 locus has been proposed as a poor prognostic factor in OS [146, 210].

RB is an important regulator of G1/S cell cycle progression [178]. During G1/S transition, RB becomes phosphorylated, resulting in the activation of E2F factors that bind to the dephosphorylated RB protein and promote DNA synthesis and G1 to S transition [178]. CDK4 in complex with cyclin D1 phosphorylates RB. Thus, amplification or overexpression of these genes results in functional inactivation of the RB pathway. The CDKs are regulated by a series of inhibitory proteins, including p16INK4a, as a negative regulator of cell cycle progression (see below). Loss of p16INK4a expression occurs in osteogenic sarcomas lacking RB1 alterations [179].

p53 Tumor Suppressor

The tumor suppressor gene TP53 is located at 17p13, a region frequently identified as abnormal in OS [29, 210]. TP53 encodes a transcription factor and regulates genes involved in cell cycle, DNA damage response, and apoptosis [40, 69, 87, 126]. Alterations in TP53 observed in OS tumors consisted of point mutations (20%–30%, mostly missense mutations), gross gene rearrangements (10%–20%), and allelic loss (75%–80%) [3, 20, 28, 119, 152, 162, 163, 169, 170, 184, 186, 199, 206, 214, 221, 227, 236, 237, 241, 249, 271]. The association of TP53 with OS is further supported by the high risk of OS in patients with the Li-Fraumeni syndrome, an autosomal dominant disorder characterized by a germline mutation of TP53 [128, 144, 145, 194, 223]. Germline mutations of TP53 have been identified in a small percentage (3%) of sporadic OS cases [112, 156, 236, 237]. However, TP53 mutation status is seemingly not associated with the stages of OS tumor and/or metastasis [60]. Nevertheless, the mutation status of TP53, and to a lesser extent of RB1, could serve as a valuable indicator for predicting chemoresistance of OS [64].

p16INK4a and p14ARF CDK Inhibitors

INK4A (also known as CDKN2A), localized to 9p21, encodes p16INK4a, a tumor suppressor that functions in part through the inhibition of CDK4 (see below) [198]. The p16INK4a protein can impose a sustained G1 arrest [123, 198]. In 87 OS specimens from 79 patients, INK4A changes were observed in five of 55 cases examined (four deletions and one rearrangement), whereas no INK4A exon 2-point mutations or methylation were detected [94, 140, 162, 210, 257]. CDK4 gene amplification occurred in six of 67 tumors, but none of those with INK4A alterations [94, 210]. The absence of expression of p16INK4a correlated with decreased survival in pediatric OS patients [94, 210].

INK4A also encodes p14ARF through bicistronic transcription involving the use of an alternative reading frame [198]. The p14 protein is structurally and functionally unrelated to p16INK4a [66, 123]. Whereas p16INK4a indirectly regulates RB1 function, p14 regulates TP53 function by binding MDM2 (see below) and sequestering it in the nucleolus, thereby preventing it from shuttling p53 to the cytoplasm for degradation [192, 279]. INK4A is deleted in approximately 10% of OS, and almost all deletions would be expected to knock out expression of p14ARF as well [133]. Because loss of p14ARF should release MDM2 from this negative regulatory mechanism, deletion of INK4A represents another mechanism of functional TP53 inactivation. As the alternative products of INK4A, p14ARF and p16INK4a, interact negatively with MDM2 and CDK4, deletions of the INK4A gene would be functionally equivalent to 12q13 amplification of both MDM2 and CDK4 [94, 146, 210, 252]. As a result, either of two singular genetic events (ie, INK4A deletion or 12q13 amplification) can inactivate two separate critical pathways of cell cycle control [94, 146, 210, 252].

Activation of Oncogenes in Human OS

The c-MYC product is involved in regulating cell growth and DNA replication [32, 177]. Seven to 12 percent of OS tumors have MYC amplification [9, 10, 120, 193]. This genetic alteration may be more common in Pagetic OS (see below) [210]. At the expression level, MYC expression in OS was elevated in nine of 21 (42%) patients who relapsed and in four of 17 (23%) patients who remained disease-free [53].

FOS forms heterodimeric transcription complexes with specific JUN proteins that regulate target genes involved in cell growth, differentiation, transformation, and bone metabolism [208, 255]. When the viral homolog v-FOS is injected into rodents, OS formation is induced [208, 255]. Transgenic mice overexpressing FOS in bone develop OS [208, 255]. In one report [266], 61% of OS tumors expressed high levels of FOS. The highest levels of FOS (and of JUN) expression have been reported in conventional OS [50]. FOS was expressed in nine of 21 (42%) patients who subsequently developed metastases [50, 53, 193]. Further, FOS was more frequently expressed in high-grade than in low-grade lesions [210].

MDM2, located at 12q13, encodes a protein that negatively modulates TP53 function by binding the p53 protein and physically blocking the region of p53 responsible for transcriptional activation of specific genes and targets p53 for degradation [29, 69, 87, 126, 247]. Amplification leading to MDM2 overexpression functionally suppresses p53 even in the presence of wild-type p53 protein [30, 124, 184, 185]. The 12q13 region, containing MDM2 and CDK4, is amplified in 5% to 10% of OS [132, 167, 184, 185]. However, some amplicons in this region (12q13–q14) do not include MDM2 [49]. Although MDM2 amplification has been related to progression and metastases in OS [119, 174], MDM2 amplification and TP53 mutations have not correlated with response to chemotherapy or survival [274].

Although CDK4 gene amplification has been detected in a low percentage of OS cases [93, 141], CDK4 proteins are highly expressed in 65% of low-grade OS [200]. CDK4 forms a complex with cyclin D1 and phosphorylates RB, thus releasing the E2F transcription factor from its interaction with RB [33, 179]. It has been suggested higher CDK4 levels secondary to amplification may stoichiometrically favor RB phosphorylation, thereby impairing cell cycle control [43, 107, 140, 213]. High levels of CDK4 may also drive 12q13–q15 amplification independently of MDM2 because discontinuity of the 12q13 amplicons has been identified [15, 43, 93, 257].

High levels of cyclin D1 (CCND1) have been detected in 22% of OS, and CCND1 amplification has been reported in 4% of OS [140, 257]. Furthermore, the absence of cyclin D1 expression is a powerful prognostic factor because it is associated with a metastatic phenotype [166].

ERBB2 (also known as HER2/neu and c-erbB-2) encodes a protein structurally homologous to the EGF receptor without a known ligand. At the time of initial biopsy, 20 of 47 OS (42.6%) displayed high levels of ERBB2 expression, relative to adjacent normal tissues [63]. However, the actual role of ERBB2 expression in OS development remains unclear. One study [281] found, in patients with high-grade OS without metastatic disease at presentation, increased expression of ERBB2 in tumor cells was associated with an increased probability of event-free and overall survival [281], while other studies demonstrated cytoplasmic staining of ERBB2 in pretreatment OS correlated with an increased risk of pulmonary metastases and OS cells positive for ERBB2 may represent a chemoresistant aggressive subpopulation of OS [281].

Deregulation of Major Signaling Pathways in Human OS

Wnts are a family of highly conserved, secreted proteins that play an important role in development and tumorigenesis [8, 22, 56, 58, 61, 110, 131, 134, 176, 182, 183, 197, 203, 246, 262, 264]. Many Wnts and their receptors are expressed in early bone progenitors [58, 61, 110, 134, 183]. Aberrant activation of Wnt signaling is associated with many common human cancers [8, 56, 134, 137, 203, 246]. Elevated cytoplasmic and/or nuclear localization of β-catenin, a critical mediator of the canonical Wnt pathway, has been detected in the majority of OS tumors and may correlate with OS metastasis [74, 90]. Sporadic mutations of β-catenin have also been identified [89]. OS expressing high levels of Wnt coreceptor LRP5 is less differentiated and is associated with decreased patient survival [80]. In addition, ectopic expression of the Wnt agonist DKK3 suppressed invasion and motility of OS line SAOS2 [81].

TGFβ/BMP family members play important roles in regulating cell growth and development [135, 149151, 282]. In OS tumors, expression of TGFβ1 and TGFβ3 is higher than that of TGFβ2 [113]. TGFβ3 expression strongly related to disease progression [113]. Also, although increased expression of TGFβ2 and β3 and VEGF was correlated with OS grade, only VEGF expression was correlated with survival [92]. BMPs and their receptors (BMPRs) regulate bone and skeletal development [135, 282]. Mutations in BMPs or BMPRs lead to skeletal defects, familial primary pulmonary hypertension, and neoplasias [280]. Numerous BMPs and/or BMPRs are highly expressed in OS tumors [91, 143, 258]. Overexpression of the BMPR-II may be related to poor prognosis in malignant and metastatic OS tumors [59, 275].

MET encodes the receptor for hepatocyte growth factor (HGF/scatter factor), a cytokine that stimulates cell proliferation and motility [46, 172, 207, 216]. MET/HGF is therefore believed to play a role in stromal-epithelial interaction. Approximately 60% of OS tumors expressed MET receptor at high levels [46, 216], while some OS samples demonstrated both HGF and MET expression [46]. Thus, the activation of MET/HGF pathway may contribute to the aggressive behavior of OS tumors [14, 21, 46, 207].

GLI, originally identified as an oncogene amplified in malignant glioma, plays a role in transducing the sonic hedgehog (Shh) signal [168]. Shh is involved in anterior-posterior patterning of the limbs, and alterations in GLI1 expression may play a role in OS development [94]. GLI1 is located at 12q13.3–q14.1 and is a zinc finger transcription factor. GLI was coamplified with CDK4 in two of six OS samples [257]. An increased expression of GLI was detected in many sarcomas including seven of eight OS tumors, especially in undifferentiated tumors [205, 224].

FGFR2 plays an important role in bone and skeletal development, and inherited mutations of FGFR2 underlie skeletal dysplasias [261]. LOH of FGFR2 at 10q26 has been detected in high-grade OS, while mutations were not found in FGFR2 [160]. IGFs are produced by osteoblasts and act through their receptors to activate proliferation and differentiation. OS cells overexpress IGF1R. Additional investigations are needed to determine whether these pathways contribute to the malignant phenotype of OS [139].

Other Genetic and/or Molecular Changes in Human OS

Paget Disease of Bone

Paget disease of bone is a heritable bone disorder characterized by rapid bone remodeling leading to abnormal bone formation. Approximately 1% of patients with Paget disease of bone develop OS [157]. Patients with Paget disease of bone account for a substantial fraction of OS occurring after the age of 60 years. Genetic linkage of Paget disease has been demonstrated to involve 18q21.1–q22 [86, 269]. Of interest is the demonstration of a possible role of the FOS gene in the pathogenesis of Paget disease [11], as well as RANK (also known as TNFRSF11A) and OPG (also known as TNFRSF11B) [68, 157, 222], although the bona fide Paget disease gene(s) remain to be identified.

Mutations of RECQ Helicases

RECQ helicases are conserved proteins that share a highly homologous DNA helicase domain, and mutations in three of the five RECQ helicases are associated with cancer predisposition syndromes, namely Rothmund-Thomson syndrome, Bloom syndrome, and Werner syndrome [252]. Rothmund-Thomson syndrome is an autosomal recessive disorder with an increased risk for OS. In one cohort of 41 patients with Rothmund-Thomson syndrome, 13 (32%) developed OS, tending to develop at a younger age (median age, 9 years) [254]. The presence of RECQL4 mutations is correlated with the risk for developing OS [253].

Bloom syndrome and Werner syndrome have some overlapping clinical features, and both exhibit predispositions to developing cancers [78]. Patients with Bloom syndrome have mutations in the BLM gene and are predisposed to all the types of cancers at a much younger age and at a higher frequency [54]. Patients with Werner syndrome have mutations in the WRN gene and are predisposed to developing OS and other tumors [65]. Of the three OS predisposition syndromes, Rothmund-Thomson syndrome appears to have the highest and most specific risk for OS tumor [252]. Thus, inactivation of the helicase pathways may contribute to OS development.

Telomerase and Telomeres in OS

Telomerase (TERT) activity is undetectable in normal cells, benign lesions, and low-grade sarcomas [272] and is present in only a portion of OS [5, 212, 242]. TERT activity in OS tumors exhibited an inverse correlation with occurrence of pulmonary metastases in patients treated with chemotherapy [211]. Alternative lengthening of telomeres in OS may be equivalent to TERT activity [5]. Of 62 OS patients, a subset of cases lacked both TERT activity and evidence of alternative lengthening of telomeres, which was associated with a favorable prognosis [242].

Activation of Matrix Metalloproteinases (MMPs)

MMPs are zinc-dependent endopeptidases that degrade extracellular matrix proteins. MMPs are controlled by both proenzymes and inhibition of tissue inhibitor of MMPs (TIMPs). MMP2 and MMP9 were overexpressed in OS cells and associated with the ability of the cells to metastasize [18]. Increased expression of membrane-type MMP1 has been correlated with poor prognosis in OS patients [240]. Upregulation of TIMP1 is associated with poor clinical outcome for OS. Binding of TIMP-1 to an unknown receptor system reportedly triggers Ras/Raf1/FAK signaling in OS. Thus, TIMP1 may have a dual effect on tumor progression [47, 84].

Neurofibromatosis-2 (NF2)/Merlin

NF2 encodes Merlin, an ezrin-radixin-moesin (ERM)-related protein that functions as a tumor suppressor [153, 154]. NF2 null mice die in early embryogenesis, whereas NF2 heterozygous mice are viable but develop a variety of highly metastatic tumors, including OS and hepatocellular carcinoma, with long latencies [155]. Merlin mediates contact inhibition of growth through signals from the extracellular matrix. At high cell density, Merlin becomes hypophosphorylated and inhibits cell growth in response to hyaluronate through specific interaction with the cytoplasmic tail of CD44 [55, 109, 118, 218]. Well-dedifferentiated OS tumors have a higher level of CD44 [94]. Merlin may control the stability of the adherens junction by its interaction with the actin cytoskeleton. Loss of this function may lead to tumorigenesis and metastasis [106, 121]. The N-terminal region of Merlin increases p53 stability by inhibiting the MDM2-mediated p53 degradation. Thus, loss of Merlin may also destabilize p53 [108].

Additional Genetic Changes

The budding uninhibited by benzimidazole 3 (BUB3) was identified in a region of LOH at 10q26 in 20 high-grade OS tumors, although no mutations of BUB3 were observed in OS. BUB3 plays a role in chromosome homeostasis and is a component of the spindle assembly checkpoint complex [23], alterations of which could underlie the aneuploidy that is characteristic of OS [160]. Interestingly, BUB3 is a target of E2F [6]. Primase polypeptide 1 (PRIM1), located at 12q13, is amplified in nine of 22 OS tumors [276].

MDM2 and CDK4 are considered the most important amplification targets in 12q13–q15 [202], but the region also contains numerous genes, including CHOP (ie, DDIT3), SAS (sarcoma amplified sequence) [159], OS-4 [226], OS-9 [225], PRIM1 [276], and other as yet poorly characterized genes [44]. Amplification of SAS was reported in 36% of OS [180] and was linked with increased CDK4 expression [268]. Other suspected oncogenes include MAPK7 and peripheral myelin protein (PMP22/GAS3), both located at 17p11.2. MAPK7 was amplified in 10 of 19 OS samples [243]. Frequent amplification of PMP22 is observed in high-grade OS [244]. HMGIC gene (also known as HMGA2, localized to 12q14–q15) was rearranged by fusing with the keratin sulfate proteoglycan lumican gene LUM in an OS line [115]. HMGIC gene was also amplified and rearranged in two primary OS [16].

Allelic loss at 4q32–q34 was identified in 63% of OS [220]. High frequencies of allelic loss have been detected at 3q26 [79, 117], 13q, 17p, and 18q, suggesting other tumor suppressor genes may exist at 3q and 18q [271]. Expression of DCC (deleted in colon cancer), located on 18q21, decreases in OS [85]. Two potential OS suppressor gene loci were demonstrated at 6q14 (imbalance in 77% of cases) and 15q21 (58% of cases) [175].

Genome-wide Approaches to Identifications of OS-associated Genes

Microarray-based expression profiling analysis has become an increasingly common practice to identify genes associated with OS pathogenesis [103]. One such study has shown, among the 100 most up- and downregulated genes, 35 are affected in all three OS lines, with eight genes showing an increase and 27 genes a reduction in the expression level compared with normal human osteoblasts [265]. These findings have provided a proof-of-principle of genome-wide approaches to unraveling the pathogenesis of OS.

OS Metastasis-associated Genes

Ezrin, a member of the ERM proteins, has been identified as a metastasis-related gene that is differentially expressed in murine OS lines with differential metastatic potential [104106]. Ezrin is involved in intracellular signal transduction regulating cell migration and metastasis [251] and is expressed in a variety of cancers, some of which are associated with poor outcome [142, 148]. In a study of 19 patients with OS, the disease-free interval of OS patients with high ezrin expression was substantially shorter than that in patients with low ezrin expression, and the risk of metastatic relapse was 80% greater in the former group [106].

Expression of S100A6 was reported in 84% of analyzed OS specimens [138]. There is a trend toward decreased clinically evident metastasis with increased S100A6 staining. Overexpression of S100A6 in OS cells decreases cell motility and anchorage-independent growth [138]. These findings suggest, while S100A6 is commonly overexpressed in OS, loss of its expression may correlate with a metastatic phenotype. A cluster of 16 types of S100 genes is located on 1q21, which is frequently amplified or rearranged [25, 35, 37, 71, 158, 190, 209]. S100 proteins constitute a group of nearly 20 proteins that contain well-conserved EF-hand calcium-binding domains [209]. Several S100 proteins have been associated with human cancers [25, 35, 37, 71, 158, 190, 209].

Annexin 2 (AnxA2) was downregulated in metastatic samples [57]. AnxA2 belongs to a large family of diverse proteins characterized by conserved annexin repeat domains and the ability to bind negatively charged phospholipids in a calcium-dependent manner [7]. AnxA2 was downregulated in a subset of human OS metastases and metastatic lines [45, 165]. The actual role of AnxA2 in suppressing OS metastasis remains to be elucidated.

Chemokine stromal cell-derived factor 1 (SDF-1) belongs to cytokinelike proteins that, through binding to their CXCR receptors, play a role in cytoskeleton rearrangement, adhesion to endothelial cells, and directional migration [19]. CXCR4/SDF-1 is important in tumor progression [130, 228]. Migration and adhesion of OS cells were promoted by SDF-1 treatment, whereas the development of pulmonary metastasis after injection of OS cells in a mouse model could be prevented by the administration of T134 peptide, an inhibitor of CXCR4 [191].

Possible Links Between Defective Osteogenic Differentiation and Bone Tumorigenesis

Human OS tumors exhibit osteoblast-like features, although the differentiation status of OS tumors can be observed within a broad range, from highly differentiated to poorly differentiated or undifferentiated phenotypes [75]. However, potential cancer stem cells responsible for OS development have yet to be identified. Understanding the molecular mechanism underlying osteogenic differentiation would help to unravel the molecular pathogenesis of human OS. Osteogenesis results from a well-coordinated sequence of events involving epithelial mesenchymal interaction, condensation, and differentiation (Fig. 1A). Several major signaling pathways, such Wnt, BMP, FGF, and hedgehog signaling, play an important role in regulating osteogenic differentiation [58, 134136, 203, 204]. At the transcription level, several transcriptional factors have been identified as important regulators of osteogenic lineage commitment and terminal differentiation. These transcriptional factors include Runx2, Osterix, ATF4, and TAZ [17, 31, 36, 41, 95, 97100, 189, 229, 230, 250, 263, 273]. Among these factors, Runx2 plays an important role and serves as a hub to direct progenitors to osteogenic lineage [38, 39, 82, 96, 114, 129, 171, 173, 187, 270].

Fig. 1A B
(A) Osteogenic differentiation is a well-coordinated process. Mesenchymal stem cells (MSCs) can give rise to several lineages, such as myocytes, adipocytes, chondrocytes, and osteocytes, with appropriate stimuli, presumably by activating proper lineage-specific ...

Runx2 is a member of the Runx class of transcription factors that contain a highly conserved 128 amino acid motif conferring DNA binding, protein-protein interactions, and ATP binding activities [38, 39, 82, 96, 114, 129, 171, 173, 187, 270]. Runx2−/− die shortly after birth and demonstrated a cartilaginous skeleton with complete absence of ossification. Despite the cartilaginous phenotype in the Runx2-null mice, histologic analysis demonstrated delayed chondrocyte maturation suggesting the importance of Runx2 in chondrogenesis and osteogenesis. Additionally, when Runx2 is overexpressed in chondrocytes via the chondrocyte-specific type II collagen promoter, it results in ectopic chondrocyte hypertrophy and endochondral ossification, thereby demonstrating the importance of Runx2 in controlling differentiation of both chondrocytes and osteoblasts [38, 39, 82, 96, 114, 129, 171, 173, 187, 270]. Runx2 transcriptional activity is regulated by numerous transcriptional co-activators and corepressors, including its interaction with Rb protein (see below).

OS can be regarded as a differentiation disease that is caused by genetic and epigenetic disruptions of osteoblast terminal differentiation (Fig. 1B). This model is supported by the following facts: First, OS tumors exhibit the characteristics of undifferentiated osteoblasts [26, 75, 83, 181, 195, 196, 219, 233, 277]. Second, differentiation-promoting agents (eg, PPARγ agonists and 9-cis-retinoic acid) induce osteoblast differentiation [75, 76]. Third, RB coactivates Runx2 through direct physical interactions at sites of active transcription, and loss of function of RB attenuates terminal osteoblast differentiation in vitro [232]. RB plays essential roles in many cellular processes including mesenchymal differentiation [70, 72, 116, 245]. Fourth, Runx2 coordinates terminal cell cycle exit through induction of p27KIP [1], which in turn is required for normal bone development and is lost in dedifferentiated human OS [233]. Lastly, osteogenic stimuli, such as osteogenic BMPs, failed to promote the terminal differentiation of most OS cells and rather enhanced OS tumor growth, further highlighting the existence of possible differentiation defects in OS cells [75]. Furthermore, in Ewing’s sarcoma (ESW), EWS/ETS fusion proteins block differentiation along osteogenic and adipogenic lineages of marrow stromal cells [238]. In fact, expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells results in EWS/FLI-1-dependent, Ewing’s sarcoma-like tumors [27]. Conversely, upon EWS-FLI1 silencing, some of the ESW cell lines can differentiate along the adipogenic or osteogenic lineages when stimulated with appropriate differentiation cocktails [234]. Taken together, these emerging data strongly suggest osteosarcomogenesis may be resulted from defects in osteoblast differentiation pathway.


Osteosarcomas are a clinically and molecularly heterogeneous group of malignancies characterized by varying degrees of mesenchymal differentiation. The genetic and epigenetic alterations described above may represent a cross-sectional endpoint view of OS. However, defining their roles in OS development has been hampered by the complexity of the genetic changes and the rarity of OS samples. Although osteosarcoma tumors display a broad range of genetic and molecular alterations, most alterations are not frequently detected in the majority of osteosarcoma tumors. With a rapid expansion of our knowledge about stem cell biology, emerging evidence suggests osteosarcoma may be regarded as a differentiation disease caused by genetic and epigenetic changes that interrupt osteoblast differentiation from mesenchymal stem cells.

In this survey, we first reviewed the current genetic alterations and molecular biology of OS, and then focused on the possible relationship between osteogenic differentiation and bone tumorigenesis. By searching PubMed with various keywords, we found over 20,000 publications relevant to the topic. Although we only conducted the search using a single database, PubMed represents one of the most extensive databases for biomedical sciences. We believe most of the relevant and important findings related to OS have been included in this single database but cannot exclude other information that might be found in other databases (e.g., EMBASE).

It is conceivable that, at least for a subset of osteosarcomas, cancer-initiating cells may share features of a committed osteoprogenitor. Tumorigenesis may involve disruption of mechanisms, appropriately constrain the initiation of proliferation by tumor stem cells, or allow persistent expression of stem cell-like features in apparently partially committed cells. The similarities between stem cell properties and those of transformed cells are striking as both cell types possess unlimited self-renewal, express telomerase, and are undifferentiated as defined by the absence of lineage-restricted markers. In fact, a small subpopulation of self-renewing OS cells are capable of forming suspended spherical cells and colonies [55]. These OS cells as well as tissue specimens express activated STAT3 and the marker genes of pluripotent embryonic stem (ES) cells, Oct 3/4 and Nanog [55]. In support of this notion, OS is frequently observed in adolescence, a stage of intensive skeletal growth entailing increased osteoblast activity. Stem cells are more resistant to mutagenic events than somatic cells, in part due to enhanced apoptotic responses to genotoxic stress and DNA damage. The efficiency of such processes appears inversely related to the degree of terminal differentiation [231]. Thus, future investigations should be devoted to identifying the key defects in the osteoblast differentiation pathway, which is also responsible for the development of primary bone tumors.

As one of the most important factors regulate osteoblast lineage commitment and expansion, Runx2 may be deregulated and plays an important role in OS development. Runx2 levels and function are biologically linked to a cell growth-related G(1) transition in osteoblastic cells [52]. Runx2 and histone deacetylase 3-mediated repression is believed to allow high expression of bone sialoprotein-a bone matrix glycoprotein whose expression coincides with terminal osteoblastic differentiation and the onset of mineralization-in differentiating human osteoblast cells [122]. Runx2 is hyperphosphorylated by CDK1/cyclin B during mitosis, and dynamically converted into a hypophosphorylated form by PP1/PP2A-dependent dephosphorylation after mitosis to support the postmitotic regulation of Runx2 target genes [201]. A more recent study indicates Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis and Bax as a direct target of Runx2, suggesting Runx2 may act as a proapoptotic factor in osteosarcoma cells [42].

Another important factor that may play an important role in osteogenic differentiation and bone tumorigenesis is pRb. The cell cycle regulatory pathway regulated by pRb is inactivated in almost all human cancers, but individual tumor types seem to target specific components to achieve this effect. As described in Results, pRb itself is frequently inactivated in OS, and inherited heterozygous loss of the RB gene confers approximately a 1000-fold greater incidence of OS than the general population. Several lines of evidence implicate pRb in osteogenesis as pRb coactivates Runx2 through direct physical interactions at sites of active transcription, and loss of function of pRb attenuates terminal osteoblast differentiation in vitro [231]. Runx2 coordinates terminal cell cycle exit through induction of the CDK2 inhibitor p27KIP1, which in turn is required for normal bone development in vitro and in vivo, and is lost in dedifferentiated human osteosarcomas [231]. It is also possible pRb influences osteoblast differentiation through other mechanisms involving chromatin structure. Thus, it would be important to investigate how the deregulation of pRb and/or Runx2 functions may lead to the development of bone sarcomas.

Understanding the molecular pathogenesis of human osteosarcoma could ultimately lead to the development of diagnostic and prognostic markers, as well as targeted therapeutics for osteosarcoma patients. Dissecting the molecular mechanisms that control osteoblast differentiation is important not only to understand normal skeletogenesis and to pinpoint potential defects responsible for OS development but also to improve the clinical management of human OS. Although pre- and postoperative chemotherapies have improved the 5-year survival rate of OS patients, recurrent and/or metastatic OS tumors are more aggressive and usually resistant to conventional cancer therapies. In a broader sense, most current chemotherapies and/or radiation therapies target the rapidly proliferative tumor cells, with little consideration of promoting tumor cell differentiation. It is conceivable a combined therapeutic approach targeting both proliferation and differentiation phases of tumor cells would be more efficacious and less prone to inducing chemoresistance [75, 76, 217, 278]. Thus, identification of the critical differentiation defects in OS tumors may lead to a rational design of therapeutic strategies that induce terminal differentiation of OS cells through alternative differentiation pathways and/or bypassing the differentiation defects.

The potentially important role of genetic and epigenetic events in both osteogenesis and bone tumorigenesis is now recognized. Our current knowledge of transcriptional regulation of osteoblast differentiation will provide important insights into the potential defects in osteogenic differentiation of OS cells. Future research should be directed towards identifying these differentiation defects in OS cells. This knowledge may help us develop efficacious differentiation therapies for OS by exploiting noncell autonomous signals to promote differentiation state.


We apologize to the investigators whose original work could not be cited due to space constraints.


One or more of the authors have received funding from the American Cancer Society (TCH), The Brinson Foundation (RCH, TCH), the Orthopaedic Research and Education Foundation (RCH), and the National Institutes of Health (RCH, TCH).


1. Abramson DH, Ellsworth RM, Kitchin FD, Tung G. Second nonocular tumors in retinoblastoma survivors. Are they radiation-induced? Ophthalmology. 1984;91:1351–1355. [PubMed]
2. Alonso J, Garcia-Miguel P, Abelairas J, Mendiola M, Pestana A. A microsatellite fluorescent method for linkage analysis in familial retinoblastoma and deletion detection at the RB1 locus in retinoblastoma and osteosarcoma. Diagn Mol Pathol. 2001;10:9–14. [PubMed]
3. Andreassen A, Oyjord T, Hovig E, Holm R, Florenes VA, Nesland JM, Myklebost O, Hoie J, Bruland OS, Borresen AL, et al. p53 abnormalities in different subtypes of human sarcomas. Cancer Res. 1993;53:468–471. [PubMed]
4. Araki N, Uchida A, Kimura T, Yoshikawa H, Aoki Y, Ueda T, Takai S, Miki T, Ono K. Involvement of the retinoblastoma gene in primary osteosarcomas and other bone and soft-tissue tumors. Clin Orthop Relat Res. 1991;270:271–277. [PubMed]
5. Aue G, Muralidhar B, Schwartz HS, Butler MG. Telomerase activity in skeletal sarcomas. Ann Surg Oncol. 1998;5:627–634. [PubMed]
6. Baek WK, Park JW, Lim JH, Suh SI, Suh MH, Gabrielson E, Kwon TK. Molecular cloning and characterization of the human budding uninhibited by benomyl (BUB3) promoter. Gene. 2002;295:117–123. [PubMed]
7. Balch C, Dedman JR. Annexins II and V inhibit cell migration. Exp Cell Res. 1997;237:259–263. [PubMed]
8. Barker N, Clevers H. Catenins, Wnt signaling and cancer. Bioessays. 2000;22:961–965. [PubMed]
9. Barrios C, Castresana JS, Kreicbergs A. Clinicopathologic correlations and short-term prognosis in musculoskeletal sarcoma with c-myc oncogene amplification. Am J Clin Oncol. 1994;17:273–276. [PubMed]
10. Barrios C, Castresana JS, Ruiz J, Kreicbergs A. Amplification of c-myc oncogene and absence of c-Ha-ras point mutation in human bone sarcoma. J Orthop Res. 1993;11:556–563. [PubMed]
11. Beedles KE, Sharpe PT, Wagner EF, Grigoriadis AE. A putative role for c-Fos in the pathophysiology of Paget’s disease. J Bone Miner Res. 1999;14 Suppl 2:21–28. [PubMed]
12. Belchis DA, Meece CA, Benko FA, Rogan PK, Williams RA, Gocke CD. Loss of heterozygosity and microsatellite instability at the retinoblastoma locus in osteosarcomas. Diagn Mol Pathol. 1996;5:214–219. [PubMed]
13. Benassi MS, Molendini L, Gamberi G, Ragazzini P, Sollazzo MR, Merli M, Asp J, Magagnoli G, Balladelli A, Bertoni F, Picci P. Alteration of pRb/p16/cdk4 regulation in human osteosarcoma. Int J Cancer. 1999;84:489–493. [PubMed]
14. Benini S, Baldini N, Manara MC, Chano T, Serra M, Rizzi S, Lollini PL, Picci P, Scotlandi K. Redundancy of autocrine loops in human osteosarcoma cells. Int J Cancer. 1999;80:581–588. [PubMed]
15. Berner JM, Forus A, Elkahloun A, Meltzer PS, Fodstad O, Myklebost O. Separate amplified regions encompassing CDK4 and MDM2 in human sarcomas. Genes Chromosomes Cancer. 1996;17:254–259. [PubMed]
16. Berner JM, Meza-Zepeda LA, Kools PF, Forus A, Schoenmakers EF, Van de Ven WJ, Fodstad O, Myklebost O. HMGIC, the gene for an architectural transcription factor, is amplified and rearranged in a subset of human sarcomas. Oncogene. 1997;14:2935–2941. [PubMed]
17. Bialek P, Kern B, Yang X, Schrock M, Sosic D, Hong N, Wu H, Yu K, Ornitz DM, Olson EN, Justice MJ, Karsenty G. A twist code determines the onset of osteoblast differentiation. Dev Cell. 2004;6:423–435. [PubMed]
18. Bjornland K, Flatmark K, Pettersen S, Aaasen AO, Fodstad O, Maelandsmo GM. Matrix metalloproteinases participate in osteosarcoma invasion. J Surg Res. 2005;127:151–156. [PubMed]
19. Bleul CC, Fuhlbrigge RC, Casasnovas JM, Aiuti A, Springer TA. A highly efficacious lymphocyte chemoattractant, stromal cell-derived factor 1 (SDF-1). J Exp Med. 1996;184:1101–1109. [PMC free article] [PubMed]
20. Bodey B, Groger AM, Bodey B Jr., Siegel SE, Kaiser HE. Immunohistochemical detection of p53 protein overexpression in primary human osteosarcomas. Anticancer Res. 1997;17:493–498. [PubMed]
21. Burrow S, Andrulis IL, Pollak M, Bell RS. Expression of insulin-like growth factor receptor, IGF-1, and IGF-2 in primary and metastatic osteosarcoma. J Surg Oncol. 1998;69:21–27. [PubMed]
22. Cadigan KM, Nusse R. Wnt signaling: a common theme in animal development. Genes Dev. 1997;11:3286–3305. [PubMed]
23. Cahill DP, Kinzler KW, Vogelstein B, Lengauer C. Genetic instability and darwinian selection in tumours. Trends Cell Biol. 1999;9:M57–60. [PubMed]
24. Carbone M, Rizzo P, Procopio A, Giuliano M, Pass HI, Gebhardt MC, Mangham C, Hansen M, Malkin DF, Bushart G, Pompetti F, Picci P, Levine AS, Bergsagel JD, Garcea RL. SV40-like sequences in human bone tumors. Oncogene. 1996;13:527–535. [PubMed]
25. Carlsson H, Petersson S, Enerback C. Cluster analysis of S100 gene expression and genes correlating to psoriasin (S100A7) expression at different stages of breast cancer development. Int J Oncol. 2005;27:1473–1481. [PubMed]
26. Carpio L, Gladu J, Goltzman D, Rabbani SA. Induction of osteoblast differentiation indexes by PTHrP in MG-63 cells involves multiple signaling pathways. Am J Physiol Endocrinol Metab. 2001;281:E489–499. [PubMed]
27. Castillero-Trejo Y, Eliazer S, Xiang L, Richardson JA, Ilaria RL Jr. Expression of the EWS/FLI-1 oncogene in murine primary bone-derived cells Results in EWS/FLI-1-dependent, ewing sarcoma-like tumors. Cancer Res. 2005;65:8698–8705. [PubMed]
28. Castresana JS, Rubio MP, Gomez L, Kreicbergs A, Zetterberg A, Barrios C. Detection of TP53 gene mutations in human sarcomas. Eur J Cancer. 1995;31A:735–738. [PubMed]
29. Chandar N, Billig B, McMaster J, Novak J. Inactivation of p53 gene in human and murine osteosarcoma cells. Br J Cancer. 1992;65:208–214. [PMC free article] [PubMed]
30. Chen CY, Oliner JD, Zhan Q, Fornace AJ Jr., Vogelstein B, Kastan MB. Interactions between p53 and MDM2 in a mammalian cell cycle checkpoint pathway. Proc Natl Acad Sci USA. 1994;91:2684–2688. [PMC free article] [PubMed]
31. Chien KR, Karsenty G. Longevity and lineages: toward the integrative biology of degenerative diseases in heart, muscle, and bone. Cell. 2005;120:533–544. [PubMed]
32. Cole MD, McMahon SB. The Myc oncoprotein: a critical evaluation of transactivation and target gene regulation. Oncogene. 1999;18:2916–2924. [PubMed]
33. Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995;147:545–560. [PMC free article] [PubMed]
34. Cormier JN, Pollock RE. Soft tissue sarcomas. CA Cancer J Clin. 2004;54:94–109. [PubMed]
35. Deichmann M, Benner A, Bock M, Jackel A, Uhl K, Waldmann V, Naher H. S100-Beta, melanoma-inhibiting activity, and lactate dehydrogenase discriminate progressive from nonprogressive American Joint Committee on Cancer stage IV melanoma. J Clin Oncol. 1999;17:1891–1896. [PubMed]
36. Deng ZL, Sharff KA, Tang N, Song WX, Luo JXL, Chen J, Bennett E, Reid R. Manning D, Xue A, Montag AG, Luu HH, Haydon RC, He T-C. Regulation of osteogenic differentiation during skeletal development. Frontiers in Biosci. 2008;13:2001–2021. [PubMed]
37. Diederichs S, Bulk E, Steffen B, Ji P, Tickenbrock L, Lang K, Zanker KS, Metzger R, Schneider PM, Gerke V, Thomas M, Berdel WE, Serve H, Muller-Tidow C. S100 family members and trypsinogens are predictors of distant metastasis and survival in early-stage non-small cell lung cancer. Cancer Res. 2004;64:5564–5569. [PubMed]
38. Ducy P, Starbuck M, Priemel M, Shen J, Pinero G, Geoffroy V, Amling M, Karsenty G. A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development. Genes Dev. 1999;13:1025–1036. [PMC free article] [PubMed]
39. Ducy P, Zhang R, Geoffroy V, Ridall AL, Karsenty G. Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation. Cell. 1997;89:747–754. [PubMed]
40. el-Deiry WS. Regulation of p53 downstream genes. Semin Cancer Biol. 1998;8:345–357. [PubMed]
41. Elefteriou F, Benson MD, Sowa H, Starbuck M, Liu X, Ron D, Parada LF, Karsenty G. ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae. Cell Metab. 2006;4:441–451. [PMC free article] [PubMed]
42. Eliseev RA, Dong YF, Sampson E, Zuscik MJ, Schwarz EM, O’Keefe RJ, Rosier RN, Drissi MH. Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis. Oncogene. [Epub ahead of print]. Jan 28 2008. [PubMed]
43. Elkahloun AG, Bittner M, Hoskins K, Gemmill R, Meltzer PS. Molecular cytogenetic characterization and physical mapping of 12q13–15 amplification in human cancers. Genes Chromosomes Cancer. 1996;17:205–214. [PubMed]
44. Elkahloun AG, Krizman DB, Wang Z, Hofmann TA, Roe B, Meltzer PS. Transcript mapping in a 46-kb sequenced region at the core of 12q13.3 amplification in human cancers. Genomics. 1997;42:295–301. [PubMed]
45. Emoto K, Sawada H, Yamada Y, Fujimoto H, Takahama Y, Ueno M, Takayama T, Uchida H, Kamada K, Naito A, Hirao S, Nakajima Y. Annexin II overexpression is correlated with poor prognosis in human gastric carcinoma. Anticancer Res. 2001;21:1339–1345. [PubMed]
46. Ferracini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, Cremona O, Campanacci M, Comoglio PM. The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene. 1995;10:739–749. [PubMed]
47. Ferrari C, Benassi S, Ponticelli F, Gamberi G, Ragazzini P, Pazzaglia L, Balladelli A, Bertoni F, Picci P. Role of MMP-9 and its tissue inhibitor TIMP-1 in human osteosarcoma: findings in 42 patients followed for 1–16 years. Acta Orthop Scand. 2004;75:487–491. [PubMed]
48. Feugeas O, Guriec N, Babin-Boilletot A, Marcellin L, Simon P, Babin S, Thyss A, Hofman P, Terrier P, Kalifa C, Brunat-Mentigny M, Patricot LM, Oberling F. Loss of heterozygosity of the RB gene is a poor prognostic factor in patients with osteosarcoma. J Clin Oncol. 1996;14:467–472. [PubMed]
49. Forus A, Florenes VA, Maelandsmo GM, Meltzer PS, Fodstad O, Myklebost O. Mapping of amplification units in the q13–14 region of chromosome 12 in human sarcomas: some amplica do not include MDM2. Cell Growth Differ. 1993;4:1065–1070. [PubMed]
50. Franchi A, Calzolari A, Zampi G. Immunohistochemical detection of c-fos and c-jun expression in osseous and cartilaginous tumours of the skeleton. Virchows Arch. 1998;432:515–519. [PubMed]
51. Fuchs B, Pritchard DJ. Etiology of osteosarcoma. Clin Orthop Relat Res. 2002;397:40–52. [PubMed]
52. Galindo M, Pratap J, Young DW, Hovhannisyan H, Im HJ, Choi JY, Lian JB, Stein JL, Stein GS, van Wijnen AJ. The bone-specific expression of Runx2 oscillates during the cell cycle to support a G1-related antiproliferative function in osteoblasts. J Biol Chem. 2005;280:20274–20285. [PMC free article] [PubMed]
53. Gamberi G, Benassi MS, Bohling T, Ragazzini P, Molendini L, Sollazzo MR, Pompetti F, Merli M, Magagnoli G, Balladelli A, Picci P. C-myc and c-fos in human osteosarcoma: prognostic value of mRNA and protein expression. Oncology. 1998;55:556–563. [PubMed]
54. German J. Bloom syndrome: a mendelian prototype of somatic mutational disease. Medicine (Baltimore). 1993;72:393–406. [PubMed]
55. Gibbs CP, Kukekov VG, Reith JD, Tchigrinova O, Suslov ON, Scott EW, Ghivizzani SC, Ignatova TN, Steindler DA. Stem-like cells in bone sarcomas: implications for tumorigenesis. Neoplasia. 2005;7:967–976. [PMC free article] [PubMed]
56. Giles RH, van Es JH, Clevers H. Caught up in a Wnt storm: Wnt signaling in cancer. Biochim Biophys Acta. 2003;1653:1–24. [PubMed]
57. Gillette JM, Chan DC, Nielsen-Preiss SM. Annexin 2 expression is reduced in human osteosarcoma metastases. J Cell Biochem. 2004;92:820–832. [PubMed]
58. Glass DA 2nd, Karsenty G. In vivo analysis of Wnt signaling in bone. Endocrinology. 2007;148:2630–2634. [PubMed]
59. Gobbi G, Sangiorgi L, Lenzi L, Casadei R, Canaider S, Strippoli P, Lucarelli E, Ghedini I, Donati D, Fabbri N, Warzecha J, Yeoung C, Helman LJ, Picci P, Carinci P. Seven BMPs and all their receptors are simultaneously expressed in osteosarcoma cells. Int J Oncol. 2002;20:143–147. [PubMed]
60. Gokgoz N, Wunder JS, Mousses S, Eskandarian S, Bell RS, Andrulis IL. Comparison of p53 mutations in patients with localized osteosarcoma and metastatic osteosarcoma. Cancer. 2001;92:2181–2189. [PubMed]
61. Gordon MD, Nusse R. Wnt signaling: multiple pathways, multiple receptors, and multiple transcription factors. J Biol Chem. 2006;281:22429–22433. [PubMed]
62. Gorlick R, Anderson P, Andrulis I, Arndt C, Beardsley GP, Bernstein M, Bridge J, Cheung NK, Dome JS, Ebb D, Gardner T, Gebhardt M, Grier H, Hansen M, Healey J, Helman L, Hock J, Houghton J, Houghton P, Huvos A, Khanna C, Kieran M, Kleinerman E, Ladanyi M, Lau C, Malkin D, Marina N, Meltzer P, Meyers P, Schofield D, Schwartz C, Smith MA, Toretsky J, Tsokos M, Wexler L, Wigginton J, Withrow S, Schoenfeldt M, Anderson B. Biology of childhood osteogenic sarcoma and potential targets for therapeutic development: meeting summary. Clin Cancer Res. 2003;9:5442–5453. [PubMed]
63. Gorlick R, Huvos AG, Heller G, Aledo A, Beardsley GP, Healey JH, Meyers PA. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J Clin Oncol. 1999;17:2781–2788. [PubMed]
64. Goto A, Kanda H, Ishikawa Y, Matsumoto S, Kawaguchi N, Machinami R, Kato Y, Kitagawa T. Association of loss of heterozygosity at the p53 locus with chemoresistance in osteosarcomas. Jpn J Cancer Res. 1998;89:539–547. [PubMed]
65. Goto M, Miller RW, Ishikawa Y, Sugano H. Excess of rare cancers in Werner syndrome (adult progeria). Cancer Epidemiol Biomarkers Prev. 1996;5:239–246. [PubMed]
66. Haber DA. Splicing into senescence: the curious case of p16 and p19ARF. Cell. 1997;91:555–558. [PubMed]
67. Hansen MF. Genetic and molecular aspects of osteosarcoma. J Musculoskelet Neuronal Interact. 2002;2:554–560. [PubMed]
68. Hansen MF, Cavenee WK. Genetics of cancer predisposition. Cancer Res. 1987;47:5518–5527. [PubMed]
69. Hansen R, Oren M. p53; from inductive signal to cellular effect. Curr Opin Genet Dev. 1997;7:46–51. [PubMed]
70. Harbour JW, Dean DC. The Rb/E2F pathway: expanding roles and emerging paradigms. Genes Dev. 2000;14:2393–2409. [PubMed]
71. Harpio R, Einarsson R. S100 proteins as cancer biomarkers with focus on S100B in malignant melanoma. Clin Biochem. 2004;37:512–518. [PubMed]
72. Hatakeyama M, Weinberg RA. The role of RB in cell cycle control. Prog Cell Cycle Res. 1995;1:9–19. [PubMed]
73. Hayden JB, Hoang BH. Osteosarcoma: basic science and clinical implications. Orthop Clin North Am. 2006;37:1–7. [PubMed]
74. Haydon RC, Deyrup A, Ishikawa A, Heck R, Jiang W, Zhou L, Feng T, King D, Cheng H, Breyer B, Peabody T, Simon MA, Montag AG, He TC. Cytoplasmic and/or nuclear accumulation of the beta-catenin protein is a frequent event in human osteosarcoma. Int J Cancer. 2002;102:338–342. [PMC free article] [PubMed]
75. Haydon RC, Luu HH, He TC. Osteosarcoma and osteoblastic differentiation: a new perspective on oncogenesis. Clin Orthop Relat Res. 2007;454:237–246. [PubMed]
76. Haydon RC, Zhou L, Feng T, Breyer B, Cheng H, Jiang W, Ishikawa A, Peabody T, Montag A, Simon MA, He TC. Nuclear receptor agonists as potential differentiation therapy agents for human osteosarcoma. Clin Cancer Res. 2002;8:1288–1294. [PubMed]
77. Helman LJ, Meltzer P. Mechanisms of sarcoma development. Nat Rev Cancer. 2003;3:685–694. [PubMed]
78. Hickson ID. RecQ helicases: caretakers of the genome. Nat Rev Cancer. 2003;3:169–178. [PubMed]
79. Himelstein BP. Osteosarcoma and other bone cancers. Curr Opin Oncol. 1998;10:326–333. [PubMed]
80. Hoang BH, Kubo T, Healey JH, Sowers R, Mazza B, Yang R, Huvos AG, Meyers PA, Gorlick R. Expression of LDL receptor-related protein 5 (LRP5) as a novel marker for disease progression in high-grade osteosarcoma. Int J Cancer. 2004;109:106–111. [PubMed]
81. Hoang BH, Kubo T, Healey JH, Yang R, Nathan SS, Kolb EA, Mazza B, Meyers PA, Gorlick R. Dickkopf 3 inhibits invasion and motility of Saos-2 osteosarcoma cells by modulating the Wnt-beta-catenin pathway. Cancer Res. 2004;64:2734–2739. [PubMed]
82. Hong JH, Hwang ES, McManus MT, Amsterdam A, Tian Y, Kalmukova R, Mueller E, Benjamin T, Spiegelman BM, Sharp PA, Hopkins N, Yaffe MB. TAZ, a transcriptional modulator of mesenchymal stem cell differentiation. Science. 2005;309:1074–1078. [PubMed]
83. Hong SH, Kadosawa T, Nozaki K, Mochizuki M, Matsunaga S, Nishimura R, Sasaki N. In vitro retinoid-induced growth inhibition and morphologic differentiation of canine osteosarcoma cells. Am J Vet Res. 2000;61:69–73. [PubMed]
84. Hornebeck W, Lambert E, Petitfrere E, Bernard P. Beneficial and detrimental influences of tissue inhibitor of metalloproteinase-1 (TIMP-1) in tumor progression. Biochimie. 2005;87:377–383. [PubMed]
85. Horstmann MA, Posl M, Scholz RB, Anderegg B, Simon P, Baumgaertl K, Delling G, Kabisch H. Frequent reduction or loss of DCC gene expression in human osteosarcoma. Br J Cancer. 1997;75:1309–1317. [PMC free article] [PubMed]
86. Hughes AE, Ralston SH, Marken J, Bell C, MacPherson H, Wallace RG, van Hul W, Whyte MP, Nakatsuka K, Hovy L, Anderson DM. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet. 2000;24:45–48. [PubMed]
87. Hung J, Anderson R. p53: functions, mutations and sarcomas. Acta Orthop Scand Suppl. 1997;273:68–73. [PubMed]
88. Huvos AG, Woodard HQ, Cahan WG, Higinbotham NL, Stewart FW, Butler A, Bretsky SS. Postradiation osteogenic sarcoma of bone and soft tissues. A clinicopathologic study of 66 patients. Cancer. 1985;55:1244–1255. [PubMed]
89. Iwao K, Miyoshi Y, Nawa G, Yoshikawa H, Ochi T, Nakamura Y. Frequent beta-catenin abnormalities in bone and soft-tissue tumors. Jpn J Cancer Res. 1999;90:205–209. [PubMed]
90. Iwaya K, Ogawa H, Kuroda M, Izumi M, Ishida T, Mukai K. Cytoplasmic and/or nuclear staining of beta-catenin is associated with lung metastasis. Clin Exp Metastasis. 2003;20:525–529. [PubMed]
91. Jin Y, Yang LJ. Immunohistochemical analysis of bone morphogenetic protein (BMP) in osteosarcoma. J Oral Pathol Med. 1990;19:152–154. [PubMed]
92. Jung ST, Moon ES, Seo HY, Kim JS, Kim GJ, Kim YK. Expression and significance of TGF-beta isoform and VEGF in osteosarcoma. Orthopedics. 2005;28:755–760. [PubMed]
93. Kanoe H, Nakayama T, Murakami H, Hosaka T, Yamamoto H, Nakashima Y, Tsuboyama T, Nakamura T, Sasaki MS, Toguchida J. Amplification of the CDK4 gene in sarcomas: tumor specificity and relationship with the RB gene mutation. Anticancer Res. 1998;18:2317–2321. [PubMed]
94. Kansara M, Thomas DM. Molecular pathogenesis of osteosarcoma. DNA Cell Biol. 2007;26:1–18. [PubMed]
95. Karsenty G. Bone formation and factors affecting this process. Matrix Biol. 2000;19:85–89. [PubMed]
96. Karsenty G. Role of Cbfa1 in osteoblast differentiation and function. Semin Cell Dev Biol. 2000;11:343–346. [PubMed]
97. Karsenty G. Central control of bone formation. Adv Nephrol Necker Hosp. 2001;31:119–133. [PubMed]
98. Karsenty G. Genetic control of skeletal development. Novartis Found Symp. 2001;232:6–17; discussion 17–22. [PubMed]
99. Karsenty G. The complexities of skeletal biology. Nature. 2003;423:316–318. [PubMed]
100. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2:389–406. [PubMed]
101. Keel SB, Jaffe KA, Petur Nielsen G, Rosenberg AE. Orthopaedic implant-related sarcoma: a study of twelve cases. Mod Pathol. 2001;14:969–977. [PubMed]
102. Kempf-Bielack B, Bielack SS, Jurgens H, Branscheid D, Berdel WE, Exner GU, Gobel U, Helmke K, Jundt G, Kabisch H, Kevric M, Klingebiel T, Kotz R, Maas R, Schwarz R, Semik M, Treuner J, Zoubek A, Winkler K. Osteosarcoma relapse after combined modality therapy: an analysis of unselected patients in the Cooperative Osteosarcoma Study Group (COSS). J Clin Oncol. 2005;23:559–568. [PubMed]
103. Khan J, Wei JS, Ringner M, Saal LH, Ladanyi M, Westermann F, Berthold F, Schwab M, Antonescu CR, Peterson C, Meltzer PS. Classification and diagnostic prediction of cancers using gene expression profiling and artificial neural networks. Nat Med. 2001;7:673–679. [PMC free article] [PubMed]
104. Khanna C, Khan J, Nguyen P, Prehn J, Caylor J, Yeung C, Trepel J, Meltzer P, Helman L. Metastasis-associated differences in gene expression in a murine model of osteosarcoma. Cancer Res. 2001;61:3750–3759. [PubMed]
105. Khanna C, Prehn J, Yeung C, Caylor J, Tsokos M, Helman L. An orthotopic model of murine osteosarcoma with clonally related variants differing in pulmonary metastatic potential. Clin Exp Metastasis. 2000;18:261–271. [PubMed]
106. Khanna C, Wan X, Bose S, Cassaday R, Olomu O, Mendoza A, Yeung C, Gorlick R, Hewitt SM, Helman LJ. The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis. Nat Med. 2004;10:182–186. [PubMed]
107. Khatib ZA, Matsushime H, Valentine M, Shapiro DN, Sherr CJ, Look AT. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 1993;53:5535–5541. [PubMed]
108. Kim H, Kwak NJ, Lee JY, Choi BH, Lim Y, Ko YJ, Kim YH, Huh PW, Lee KH, Rha HK, Wang YP. Merlin neutralizes the inhibitory effect of Mdm2 on p53. J Biol Chem. 2004;279:7812–7818. [PubMed]
109. Kim HS, Park YB, Oh JH, Jeong J, Kim CJ, Lee SH. Expression of CD44 isoforms correlates with the metastatic potential of osteosarcoma. Clin Orthop Relat Res. 2002;396:184–190. [PubMed]
110. Kim JB, Leucht P, Lam K, Luppen C, Ten Berge D, Nusse R, Helms JA. Bone regeneration is regulated by wnt signaling. J Bone Miner Res. 2007;22:1913–1923. [PubMed]
111. Kitchin FD, Ellsworth RM. Pleiotropic effects of the gene for retinoblastoma. J Med Genet. 1974;11:244–246. [PMC free article] [PubMed]
112. Kleihues P, Schauble B, zur Hausen A, Esteve J, Ohgaki H. Tumors associated with p53 germline mutations: a synopsis of 91 families. Am J Pathol. 1997;150:1–13. [PMC free article] [PubMed]
113. Kloen P, Gebhardt MC, Perez-Atayde A, Rosenberg AE, Springfield DS, Gold LI, Mankin HJ. Expression of transforming growth factor-beta (TGF-beta) isoforms in osteosarcomas: TGF-beta3 is related to disease progression. Cancer. 1997;80:2230–2239. [PubMed]
114. Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K, Shimizu Y, Bronson RT, Gao YH, Inada M, Sato M, Okamoto R, Kitamura Y, Yoshiki S, Kishimoto T. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997;89:755–764. [PubMed]
115. Kools PF, Van de Ven WJ. Amplification of a rearranged form of the high-mobility group protein gene HMGIC in OsA-CI osteosarcoma cells. Cancer Genet Cytogenet. 1996;91:1–7. [PubMed]
116. Korenjak M, Brehm A. E2F-Rb complexes regulating transcription of genes important for differentiation and development. Curr Opin Genet Dev. 2005;15:520–527. [PubMed]
117. Kruzelock RP, Murphy EC, Strong LC, Naylor SL, Hansen MF. Localization of a novel tumor suppressor locus on human chromosome 3q important in osteosarcoma tumorigenesis. Cancer Res. 1997;57:106–109. [PubMed]
118. Kuryu M, Ozaki T, Nishida K, Shibahara M, Kawai A, Inoue H. Expression of CD44 variants in osteosarcoma. J Cancer Res Clin Oncol. 1999;125:646–652. [PubMed]
119. Ladanyi M, Cha C, Lewis R, Jhanwar SC, Huvos AG, Healey JH. MDM2 gene amplification in metastatic osteosarcoma. Cancer Res. 1993;53:16–18. [PubMed]
120. Ladanyi M, Park CK, Lewis R, Jhanwar SC, Healey JH, Huvos AG. Sporadic amplification of the MYC gene in human osteosarcomas. Diagn Mol Pathol. 1993;2:163–167. [PubMed]
121. Lallemand D, Curto M, Saotome I, Giovannini M, McClatchey AI. NF2 deficiency promotes tumorigenesis and metastasis by destabilizing adherens junctions. Genes Dev. 2003;17:1090–1100. [PMC free article] [PubMed]
122. Lamour V, Detry C, Sanchez C, Henrotin Y, Castronovo V, Bellahcene A. Runx2- and histone deacetylase 3-mediated repression is relieved in differentiating human osteoblast cells to allow high bone sialoprotein expression. J Biol Chem. 2007;282:36240–36249. [PubMed]
123. Larsen CJ. p16INK4a: a gene with a dual capacity to encode unrelated proteins that inhibit cell cycle progression. Oncogene. 1996;12:2041–2044. [PubMed]
124. Leach FS, Tokino T, Meltzer P, Burrell M, Oliner JD, Smith S, Hill DE, Sidransky D, Kinzler KW, Vogelstein B. p53 Mutation and MDM2 amplification in human soft tissue sarcomas. Cancer Res. 1993;53(10 Suppl):2231–2234. [PubMed]
125. Lednicky JA, Stewart AR, Jenkins JJ 3rd, Finegold MJ, Butel JS. SV40 DNA in human osteosarcomas shows sequence variation among T-antigen genes. Int J Cancer. 1997;72:791–800. [PubMed]
126. Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–331. [PubMed]
127. Lewis VO. What’s new in musculoskeletal oncology. J Bone Joint Surg Am. 2007;89:1399–1407. [PubMed]
128. Li FP, Fraumeni JF Jr, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW. A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988;48:5358–5362. [PubMed]
129. Lian JB, Stein GS, Javed A, van Wijnen AJ, Stein JL, Montecino M, Hassan MQ, Gaur T, Lengner CJ, Young DW. Networks and hubs for the transcriptional control of osteoblastogenesis. Rev Endocr Metab Disord. 2006;7:1–16. [PubMed]
130. Libura J, Drukala J, Majka M, Tomescu O, Navenot JM, Kucia M, Marquez L, Peiper SC, Barr FG, Janowska-Wieczorek A, Ratajczak MZ. CXCR4-SDF-1 signaling is active in rhabdomyosarcoma cells and regulates locomotion, chemotaxis, and adhesion. Blood. 2002;100:2597–2606. [PubMed]
131. Logan CY, Nusse R. The Wnt signaling pathway in development and disease. Annu Rev Cell Dev Biol. 2004;20:781–810. [PubMed]
132. Lonardo F, Ueda T, Huvos AG, Healey J, Ladanyi M. p53 and MDM2 alterations in osteosarcomas: correlation with clinicopathologic features and proliferative rate. Cancer. 1997;79:1541–1547. [PubMed]
133. Lopez-Guerrero JA, Lopez-Gines C, Pellin A, Carda C, Llombart-Bosch A. Deregulation of the G1 to S-phase cell cycle checkpoint is involved in the pathogenesis of human osteosarcoma. Diagn Mol Pathol. 2004;13:81–91. [PubMed]
134. Luo J, Chen J, Deng ZL, Luo X, Song WX, Sharff KA, Tang N, Haydon RC, Luu HH, He TC. Wnt signaling and human diseases: what are the therapeutic implications? Lab Invest. 2007;87:97–103. [PubMed]
135. Luo J, Sun MH, Kang Q, Peng Y, Jiang W, Luu HH, Luo Q, Park JY, Li Y, Haydon RC, He TC. Gene therapy for bone regeneration. Curr Gene Ther. 2005;5:167–179. [PubMed]
136. Luu HH, Song WX, Luo X, Manning D, Luo J, Deng ZL, Sharff KA, Montag AG, Haydon RC, He TC. Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res. 2007;25:665–677. [PubMed]
137. Luu HH, Zhang R, Haydon RC, Rayburn E, Kang Q, Si W, Park JK, Wang H, Peng Y, Jiang W, He TC. Wnt/beta-catenin signaling pathway as a novel cancer drug target. Curr Cancer Drug Targets. 2004;4:653–671. [PubMed]
138. Luu HH, Zhou L, Haydon RC, Deyrup AT, Montag AG, Huo D, Heck R, Heizmann CW, Peabody TD, Simon MA, He TC. Increased expression of S100A6 is associated with decreased metastasis and inhibition of cell migration and anchorage independent growth in human osteosarcoma. Cancer Lett. 2005;229:135–148. [PubMed]
139. MacEwen EG, Pastor J, Kutzke J, Tsan R, Kurzman ID, Thamm DH, Wilson M, Radinsky R. IGF-1 receptor contributes to the malignant phenotype in human and canine osteosarcoma. J Cell Biochem. 2004;92:77–91. [PubMed]
140. Maelandsmo GM, Berner JM, Florenes VA, Forus A, Hovig E, Fodstad O, Myklebost O. Homozygous deletion frequency and expression levels of the CDKN2 gene in human sarcomas–relationship to amplification and mRNA levels of CDK4 and CCND1. Br J Cancer. 1995;72:393–398. [PMC free article] [PubMed]
141. Maitra A, Roberts H, Weinberg AG, Geradts J. Loss of p16(INK4a) expression correlates with decreased survival in pediatric osteosarcomas. Int J Cancer. 2001;95:34–38. [PubMed]
142. Makitie T, Carpen O, Vaheri A, Kivela T. Ezrin as a prognostic indicator and its relationship to tumor characteristics in uveal malignant melanoma. Invest Ophthalmol Vis Sci. 2001;42:2442–2449. [PubMed]
143. Maliakal JC, Asahina I, Hauschka PV, Sampath TK. Osteogenic protein-1 (BMP-7) inhibits cell proliferation and stimulates the expression of markers characteristic of osteoblast phenotype in rat osteosarcoma (17/2.8) cells. Growth Factors. 1994;11:227–234. [PubMed]
144. Malkin D, Jolly KW, Barbier N, Look AT, Friend SH, Gebhardt MC, Andersen TI, Borresen AL, Li FP, Garber J, et al. Germline mutations of the p53 tumor-suppressor gene in children and young adults with second malignant neoplasms. N Engl J Med. 1992;326:1309–1315. [PubMed]
145. Malkin D, Li FP, Strong LC, Fraumeni JF Jr, Nelson CE, Kim DH, Kassel J, Gryka MA, Bischoff FZ, Tainsky MA, et al. Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990;250:1233–1238. [PubMed]
146. Marina N, Gebhardt M, Teot L, Gorlick R. Biology and therapeutic advances for pediatric osteosarcoma. Oncologist. 2004;9:422–441. [PubMed]
147. Mark RJ, Poen J, Tran LM, Fu YS, Selch MT, Parker RG. Postirradiation sarcomas. A single-institution study and review of the literature. Cancer. 1994;73:2653–2662. [PubMed]
148. Martin TA, Harrison G, Mansel RE, Jiang WG. The role of the CD44/ezrin complex in cancer metastasis. Crit Rev Oncol Hematol. 2003;46:165–186. [PubMed]
149. Massague J. TGF-beta signal transduction. Annu Rev Biochem. 1998;67:753–791. [PubMed]
150. Massague J, Chen YG. Controlling TGF-beta signaling. Genes Dev. 2000;14:627–644. [PubMed]
151. Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. Embo J. 2000;19:1745–1754. [PMC free article] [PubMed]
152. Masuda H, Miller C, Koeffler HP, Battifora H, Cline MJ. Rearrangement of the p53 gene in human osteogenic sarcomas. Proc Natl Acad Sci USA. 1987;84:7716–7719. [PMC free article] [PubMed]
153. McClatchey AI. Neurofibromatosis type II: mouse models reveal broad roles in tumorigenesis and metastasis. Mol Med Today. 2000;6:252–253. [PubMed]
154. McClatchey AI, Giovannini M. Membrane organization and tumorigenesis–the NF2 tumor suppressor, Merlin. Genes Dev. 2005;19:2265–2277. [PubMed]
155. McClatchey AI, Saotome I, Mercer K, Crowley D, Gusella JF, Bronson RT, Jacks T. Mice heterozygous for a mutation at the Nf2 tumor suppressor locus develop a range of highly metastatic tumors. Genes Dev. 1998;12:1121–1133. [PMC free article] [PubMed]
156. McIntyre JF, Smith-Sorensen B, Friend SH, Kassell J, Borresen AL, Yan YX, Russo C, Sato J, Barbier N, Miser J, et al. Germline mutations of the p53 tumor suppressor gene in children with osteosarcoma. J Clin Oncol. 1994;12:925–930. [PubMed]
157. McNairn JD, Damron TA, Landas SK, Ambrose JL, Shrimpton AE. Inheritance of osteosarcoma and Paget’s disease of bone: a familial loss of heterozygosity study. J Mol Diagn. 2001;3:171–177. [PMC free article] [PubMed]
158. Melo-Junior MR, Filho JL, Cavalcanti CL, Patu VJ, Beltrao EI, Carvalho LB. Detection of S100 protein from prostatic cancer patients using anti-S100 protein antibody immobilized on POS-PVA discs. Biotechnol Bioeng. 2007;97:182–187. [PubMed]
159. Meltzer PS, Jankowski SA, Dal Cin P, Sandberg AA, Paz IB, Coccia MA. Identification and cloning of a novel amplified DNA sequence in human malignant fibrous histiocytoma derived from a region of chromosome 12 frequently rearranged in soft tissue tumors. Cell Growth Differ. 1991;2:495–501. [PubMed]
160. Mendoza S, David H, Gaylord GM, Miller CW. Allelic loss at 10q26 in osteosarcoma in the region of the BUB3 and FGFR2 genes. Cancer Genet Cytogenet. 2005;158:142–147. [PubMed]
161. Mendoza SM, Konishi T, Miller CW. Integration of SV40 in human osteosarcoma DNA. Oncogene. 1998;17:2457–2462. [PubMed]
162. Miller CW, Aslo A, Campbell MJ, Kawamata N, Lampkin BC, Koeffler HP. Alterations of the p15, p16,and p18 genes in osteosarcoma. Cancer Genet Cytogenet. 1996;86:136–142. [PubMed]
163. Miller CW, Aslo A, Tsay C, Slamon D, Ishizaki K, Toguchida J, Yamamuro T, Lampkin B, Koeffler HP. Frequency and structure of p53 rearrangements in human osteosarcoma. Cancer Res. 1990;50:7950–7954. [PubMed]
164. Miller CW, Aslo A, Won A, Tan M, Lampkin B, Koeffler HP. Alterations of the p53, Rb and MDM2 genes in osteosarcoma. J Cancer Res Clin Oncol. 1996;122:559–565. [PubMed]
165. Mintz MB, Sowers R, Brown KM, Hilmer SC, Mazza B, Huvos AG, Meyers PA, Lafleur B, McDonough WS, Henry MM, Ramsey KE, Antonescu CR, Chen W, Healey JH, Daluski A, Berens ME, Macdonald TJ, Gorlick R, Stephan DA. An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Res. 2005;65:1748–1754. [PubMed]
166. Molendini L, Benassi MS, Magagnoli G, Merli M, Sollazzo MR, Ragazzini P, Gamberi G, Ferrari C, Balladelli A, Bacchini P, Picci P. Prognostic significance of cyclin expression in human osteosarcoma. Int J Oncol. 1998;12:1007–1011. [PubMed]
167. Momand J, Jung D, Wilczynski S, Niland J. The MDM2 gene amplification database. Nucleic Acids Res. 1998;26:3453–3459. [PMC free article] [PubMed]
168. Motoyama J, Liu J, Mo R, Ding Q, Post M, Hui CC. Essential function of Gli2 and Gli3 in the formation of lung, trachea and oesophagus. Nat Genet. 1998;20:54–57. [PubMed]
169. Mousses S, McAuley L, Bell RS, Kandel R, Andrulis IL. Molecular and immunohistochemical identification of p53 alterations in bone and soft tissue sarcomas. Mod Pathol. 1996;9:1–6. [PubMed]
170. Mulligan LM, Matlashewski GJ, Scrable HJ, Cavenee WK. Mechanisms of p53 loss in human sarcomas. Proc Natl Acad Sci USA. 1990;87:5863–5867. [PMC free article] [PubMed]
171. Mundlos S, Otto F, Mundlos C, Mulliken JB, Aylsworth AS, Albright S, Lindhout D, Cole WG, Henn W, Knoll JH, Owen MJ, Mertelsmann R, Zabel BU, Olsen BR. Mutations involving the transcription factor CBFA1 cause cleidocranial dysplasia. Cell. 1997;89:773–779. [PubMed]
172. Naka T, Iwamoto Y, Shinohara N, Ushijima M, Chuman H, Tsuneyoshi M. Expression of c-met proto-oncogene product (c-MET) in benign and malignant bone tumors. Mod Pathol. 1997;10:832–838. [PubMed]
173. Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR, de Crombrugghe B. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell. 2002;108:17–29. [PubMed]
174. Nakayama T, Toguchida J, Wadayama B, Kanoe H, Kotoura Y, Sasaki MS. MDM2 gene amplification in bone and soft-tissue tumors: association with tumor progression in differentiated adipose-tissue tumors. Int J Cancer. 1995;64:342–346. [PubMed]
175. Nathrath MH, Kuosaite V, Rosemann M, Kremer M, Poremba C, Wakana S, Yanagi M, Nathrath WB, Hofler H, Imai K, Atkinson MJ. Two novel tumor suppressor gene loci on chromosome 6q and 15q in human osteosarcoma identified through comparative study of allelic imbalances in mouse and man. Oncogene. 2002;21:5975–5980. [PubMed]
176. Nelson WJ, Nusse R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science. 2004;303:1483–1487. [PMC free article] [PubMed]
177. Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene. 1999;18:3004–3016. [PubMed]
178. Nevins JR, Leone G, DeGregori J, Jakoi L. Role of the Rb/E2F pathway in cell growth control. J Cell Physiol. 1997;173:233–236. [PubMed]
179. Nielsen GP, Burns KL, Rosenberg AE, Louis DN. CDKN2A gene deletions and loss of p16 expression occur in osteosarcomas that lack RB alterations. Am J Pathol. 1998;153:159–163. [PMC free article] [PubMed]
180. Noble-Topham SE, Burrow SR, Eppert K, Kandel RA, Meltzer PS, Bell RS, Andrulis IL. SAS is amplified predominantly in surface osteosarcoma. J Orthop Res. 1996;14:700–705. [PubMed]
181. Nozaki K, Kadosawa T, Nishimura R, Mochizuki M, Takahashi K, Sasaki N. 1,25-Dihydroxyvitamin D3, recombinant human transforming growth factor-beta 1, and recombinant human bone morphogenetic protein-2 induce in vitro differentiation of canine osteosarcoma cells. J Vet Med Sci. 1999;61:649–656. [PubMed]
182. Nusse R. The Wnt gene family in tumorigenesis and in normal development. J Steroid Biochem Mol Biol. 1992;43:9–12. [PubMed]
183. Nusse R. Wnt signaling in disease and in development. Cell Res. 2005;15:28–32. [PubMed]
184. Oliner JD, Kinzler KW, Meltzer PS, George DL, Vogelstein B. Amplification of a gene encoding a p53-associated protein in human sarcomas. Nature. 1992;358:80–83. [PubMed]
185. Oliner JD, Pietenpol JA, Thiagalingam S, Gyuris J, Kinzler KW, Vogelstein B. Oncoprotein MDM2 conceals the activation domain of tumour suppressor p53. Nature. 1993;362:857–860. [PubMed]
186. Oliveira P, Nogueira M, Pinto A, Almeida MO. Analysis of p53 expression in osteosarcoma of the jaw: correlation with clinicopathologic and DNA ploidy findings. Hum Pathol. 1997;28:1361–1365. [PubMed]
187. Otto F, Thornell AP, Crompton T, Denzel A, Gilmour KC, Rosewell IR, Stamp GW, Beddington RS, Mundlos S, Olsen BR, Selby PB, Owen MJ. Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development. Cell. 1997;89:765–771. [PubMed]
188. Park BH, Breyer B, He TC. Peroxisome proliferator-activated receptors: roles in tumorigenesis and chemoprevention in human cancer. Curr Opin Oncol. 2001;13:78–83. [PubMed]
189. Patel MS, Karsenty G. Regulation of bone formation and vision by LRP5. N Engl J Med. 2002;346:1572–1574. [PubMed]
190. Pedrocchi M, Schafer BW, Mueller H, Eppenberger U, Heizmann CW. Expression of Ca(2+)-binding proteins of the S100 family in malignant human breast-cancer cell lines and biopsy samples. Int J Cancer. 1994;57:684–690. [PubMed]
191. Perissinotto E, Cavalloni G, Leone F, Fonsato V, Mitola S, Grignani G, Surrenti N, Sangiolo D, Bussolino F, Piacibello W, Aglietta M. Involvement of chemokine receptor 4/stromal cell-derived factor 1 system during osteosarcoma tumor progression. Clin Cancer Res. 2005;11(2 Pt 1):490–497. [PubMed]
192. Pomerantz J, Schreiber-Agus N, Liegeois NJ, Silverman A, Alland L, Chin L, Potes J, Chen K, Orlow I, Lee HW, Cordon-Cardo C, DePinho RA. The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53. Cell. 1998;92:713–723. [PubMed]
193. Pompetti F, Rizzo P, Simon RM, Freidlin B, Mew DJ, Pass HI, Picci P, Levine AS, Carbone M. Oncogene alterations in primary, recurrent, and metastatic human bone tumors. J Cell Biochem. 1996;63:37–50. [PubMed]
194. Porter DE, Holden ST, Steel CM, Cohen BB, Wallace MR, Reid R. A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families. J Bone Joint Surg Br. 1992;74:883–886. [PubMed]
195. Postiglione L, Di Domenico G, Giordano-Lanza G, Ladogana P, Turano M, Castaldo C, Di Meglio F, Cocozza S, Montagnani S. Effect of human granulocyte macrophage-colony stimulating factor on differentiation and apoptosis of the human osteosarcoma cell line SaOS-2. Eur J Histochem. 2003;47:309–316. [PubMed]
196. Postiglione L, Domenico GD, Montagnani S, Spigna GD, Salzano S, Castaldo C, Ramaglia L, Sbordone L, Rossi G. Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces the osteoblastic differentiation of the human osteosarcoma cell line SaOS-2. Calcif Tissue Int. 2003;72:85–97. [PubMed]
197. Povelones M, Nusse R. Wnt signalling sees spots. Nat Cell Biol. 2002;4:E249–250. [PubMed]
198. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83:993–1000. [PubMed]
199. Radig K, Schneider-Stock R, Haeckel C, Neumann W, Roessner A. p53 gene mutations in osteosarcomas of low-grade malignancy. Hum Pathol. 1998;29:1310–1316. [PubMed]
200. Ragazzini P, Gamberi G, Benassi MS, Orlando C, Sestini R, Ferrari C, Molendini L, Sollazzo MR, Merli M, Magagnoli G, Bertoni F, Bohling T, Pazzagli M, Picci P. Analysis of SAS gene and CDK4 and MDM2 proteins in low-grade osteosarcoma. Cancer Detect Prev. 1999;23:129–136. [PubMed]
201. Rajgopal A, Young DW, Mujeeb KA, Stein JL, Lian JB, van Wijnen AJ, Stein GS. Mitotic control of RUNX2 phosphorylation by both CDK1/cyclin B kinase and PP1/PP2A phosphatase in osteoblastic cells. J Cell Biochem. 2007;100:1509–1517. [PubMed]
202. Reifenberger G, Reifenberger J, Ichimura K, Meltzer PS, Collins VP. Amplification of multiple genes from chromosomal region 12q13–14 in human malignant gliomas: preliminary mapping of the amplicons shows preferential involvement of CDK4, SAS, and MDM2. Cancer Res. 1994;54:4299–4303. [PubMed]
203. Reya T, Clevers H. Wnt signalling in stem cells and cancer. Nature. 2005;434:843–850. [PubMed]
204. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–111. [PubMed]
205. Roberts WM, Douglass EC, Peiper SC, Houghton PJ, Look AT. Amplification of the gli gene in childhood sarcomas. Cancer Res. 1989;49:5407–5413. [PubMed]
206. Romano JW, Ehrhart JC, Duthu A, Kim CM, Appella E, May P. Identification and characterization of a p53 gene mutation in a human osteosarcoma cell line. Oncogene. 1989;4:1483–1488. [PubMed]
207. Rong S, Jeffers M, Resau JH, Tsarfaty I, Oskarsson M, Vande Woude GF. Met expression and sarcoma tumorigenicity. Cancer Res. 1993;53:5355–5360. [PubMed]
208. Ruther U, Komitowski D, Schubert FR, Wagner EF. c-fos expression induces bone tumors in transgenic mice. Oncogene. 1989;4:861–865. [PubMed]
209. Salama I, Malone PS, Mihaimeed F, Jones JL. A review of the S100 proteins in cancer. Eur J Surg Oncol. [Epub Jun 13 2007]. 2008;34:357–364. [PubMed]
210. Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: osteosarcoma and related tumors. Cancer Genet Cytogenet. 2003;145:1–30. [PubMed]
211. Sangiorgi L, Gobbi GA, Lucarelli E, Sartorio SM, Mordenti M, Ghedini I, Maini V, Scrimieri F, Reggiani M, Bertoja AZ, Benassi MS, Picci P. Presence of telomerase activity in different musculoskeletal tumor histotypes and correlation with aggressiveness. Int J Cancer. 20 2001;95:156–161. [PubMed]
212. Scheel C, Schaefer KL, Jauch A, Keller M, Wai D, Brinkschmidt C, van Valen F, Boecker W, Dockhorn-Dworniczak B, Poremba C. Alternative lengthening of telomeres is associated with chromosomal instability in osteosarcomas. Oncogene. 2001;20:3835–3844. [PubMed]
213. Schmidt EE, Ichimura K, Reifenberger G, Collins VP. CDKN2 (p16/MTS1) gene deletion or CDK4 amplification occurs in the majority of glioblastomas. Cancer Res. 1994;54:6321–6324. [PubMed]
214. Schneider-Stock R, Radig K, Oda Y, Mellin W, Rys J, Niezabitowski A, Roessner A. p53 gene mutations in soft-tissue sarcomas–correlations with p53 immunohistochemistry and DNA ploidy. J Cancer Res Clin Oncol. 1997;123:211–218. [PubMed]
215. Scholz RB, Kabisch H, Weber B, Roser K, Delling G, Winkler K. Studies of the RB1 gene and the p53 gene in human osteosarcomas. Pediatr Hematol Oncol. 1992;9:125–137. [PubMed]
216. Scotlandi K, Baldini N, Oliviero M, Di Renzo MF, Martano M, Serra M, Manara MC, Comoglio PM, Ferracini R. Expression of Met/hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors. Am J Pathol. 1996;149:1209–1219. [PMC free article] [PubMed]
217. Sell S. Stem cell origin of cancer and differentiation therapy. Crit Rev Oncol Hematol. 2004;51:1–28. [PubMed]
218. Shiratori H, Koshino T, Uesugi M, Nitto H, Saito T. Acceleration of lung metastasis by up-regulation of CD44 expression in osteosarcoma-derived cell transplanted mice. Cancer Lett. 2001;170:177–182. [PubMed]
219. Siggelkow H, Schenck M, Rohde M, Viereck V, Tauber S, Atkinson MJ, Hufner M. Prolonged culture of HOS 58 human osteosarcoma cells with 1,25-(OH)2-D3, TGF-beta, and dexamethasone reveals physiological regulation of alkaline phosphatase, dissociated osteocalcin gene expression, and protein synthesis and lack of mineralization. J Cell Biochem. 2002;85:279–294. [PubMed]
220. Simons A, Schepens M, Forus A, Godager L, van Asseldonk M, Myklebost O, van Kessel AG. A novel chromosomal region of allelic loss, 4q32-q34, in human osteosarcomas revealed by representational difference analysis. Genes Chromosomes Cancer. 1999;26:115–124. [PubMed]
221. Smith-Sorensen B, Gebhardt MC, Kloen P, McIntyre J, Aguilar F, Cerutti P, Borresen AL. Screening for TP53 mutations in osteosarcomas using constant denaturant gel electrophoresis (CDGE). Hum Mutat. 1993;2:274–285. [PubMed]
222. Sparks AB, Peterson SN, Bell C, Loftus BJ, Hocking L, Cahill DP, Frassica FJ, Streeten EA, Levine MA, Fraser CM, Adams MD, Broder S, Venter JC, Kinzler KW, Vogelstein B, Ralston SH. Mutation screening of the TNFRSF11A gene encoding receptor activator of NF kappa B (RANK) in familial and sporadic Paget’s disease of bone and osteosarcoma. Calcif Tissue Int. 2001;68:151–155. [PubMed]
223. Srivastava S, Zou ZQ, Pirollo K, Blattner W, Chang EH. Germ-line transmission of a mutated p53 gene in a cancer-prone family with Li-Fraumeni syndrome. Nature. 1990;348:747–749. [PubMed]
224. Stein U, Eder C, Karsten U, Haensch W, Walther W, Schlag PM. GLI gene expression in bone and soft tissue sarcomas of adult patients correlates with tumor grade. Cancer Res. 1999;59:1890–1895. [PubMed]
225. Su YA, Hutter CM, Trent JM, Meltzer PS. Complete sequence analysis of a gene (OS-9) ubiquitously expressed in human tissues and amplified in sarcomas. Mol Carcinog. 1996;15:270–275. [PubMed]
226. Su YA, Lee MM, Hutter CM, Meltzer PS. Characterization of a highly conserved gene (OS4) amplified with CDK4 in human sarcomas. Oncogene. 1997;15:1289–1294. [PubMed]
227. Sztan M, Papai Z, Szendroi M, Looij M, Olah E. Allelic losses from chromosome 17 in human osteosarcomas. Pathol Oncol Res. 1997;3:115–120. [PubMed]
228. Taichman RS, Cooper C, Keller ET, Pienta KJ, Taichman NS, McCauley LK. Use of the stromal cell-derived factor-1/CXCR4 pathway in prostate cancer metastasis to bone. Cancer Res. 2002;62:1832–1837. [PubMed]
229. Takeda S, Elefteriou F, Karsenty G. Common endocrine control of body weight, reproduction, and bone mass. Annu Rev Nutr. 2003;23:403–411. [PubMed]
230. Takeda S, Karsenty G. Central control of bone formation. J Bone Miner Metab. 2001;19:195–198. [PubMed]
231. Thomas D, Kansara M. Epigenetic modifications in osteogenic differentiation and transformation. J Cell Biochem. 2006;98:757–769. [PubMed]
232. Thomas DM, Carty SA, Piscopo DM, Lee JS, Wang WF, Forrester WC, Hinds PW. The retinoblastoma protein acts as a transcriptional coactivator required for osteogenic differentiation. Mol Cell. 2001;8:303–316. [PubMed]
233. Thomas DM, Johnson SA, Sims NA, Trivett MK, Slavin JL, Rubin BP, Waring P, McArthur GA, Walkley CR, Holloway AJ, Diyagama D, Grim JE, Clurman BE, Bowtell DD, Lee JS, Gutierrez GM, Piscopo DM, Carty SA, Hinds PW. Terminal osteoblast differentiation, mediated by runx2 and p27KIP1, is disrupted in osteosarcoma. J Cell Biol. 2004;167:925–934. [PMC free article] [PubMed]
234. Tirode F, Laud-Duval K, Prieur A, Delorme B, Charbord P, Delattre O. Mesenchymal stem cell features of Ewing tumors. Cancer Cell. 2007;11:421–429. [PubMed]
235. Toguchida J, Ishizaki K, Sasaki MS, Ikenaga M, Sugimoto M, Kotoura Y, Yamamuro T. Chromosomal reorganization for the expression of recessive mutation of retinoblastoma susceptibility gene in the development of osteosarcoma. Cancer Res. 1988;48:3939–3943. [PubMed]
236. Toguchida J, Yamaguchi T, Dayton SH, Beauchamp RL, Herrera GE, Ishizaki K, Yamamuro T, Meyers PA, Little JB, Sasaki MS, et al. Prevalence and spectrum of germline mutations of the p53 gene among patients with sarcoma. N Engl J Med. 1992;326:1301–1308. [PubMed]
237. Toguchida J, Yamaguchi T, Ritchie B, Beauchamp RL, Dayton SH, Herrera GE, Yamamuro T, Kotoura Y, Sasaki MS, Little JB, et al. Mutation spectrum of the p53 gene in bone and soft tissue sarcomas. Cancer Res. 1992;52:6194–6199. [PubMed]
238. Torchia EC, Jaishankar S, Baker SJ. Ewing tumor fusion proteins block the differentiation of pluripotent marrow stromal cells. Cancer Res. 2003;63:3464–3468. [PubMed]
239. Tucker MA, D’Angio GJ, Boice JD Jr, Strong LC, Li FP, Stovall M, Stone BJ, Green DM, Lombardi F, Newton W, et al. Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med. 1987;317:588–593. [PubMed]
240. Uchibori M, Nishida Y, Nagasaka T, Yamada Y, Nakanishi K, Ishiguro N. Increased expression of membrane-type matrix metalloproteinase-1 is correlated with poor prognosis in patients with osteosarcoma. Int J Oncol. 2006;28:33–42. [PubMed]
241. Ueda Y, Dockhorn-Dworniczak B, Blasius S, Mellin W, Wuisman P, Bocker W, Roessner A. Analysis of mutant P53 protein in osteosarcomas and other malignant and benign lesions of bone. J Cancer Res Clin Oncol. 1993;119:172–178. [PubMed]
242. Ulaner GA, Huang HY, Otero J, Zhao Z, Ben-Porat L, Satagopan JM, Gorlick R, Meyers P, Healey JH, Huvos AG, Hoffman AR, Ladanyi M. Absence of a telomere maintenance mechanism as a favorable prognostic factor in patients with osteosarcoma. Cancer Res. 2003;63:1759–1763. [PubMed]
243. van Dartel M, Cornelissen PW, Redeker S, Tarkkanen M, Knuutila S, Hogendoorn PC, Westerveld A, Gomes I, Bras J, Hulsebos TJ. Amplification of 17p11.2 approximately p12, including PMP22, TOP3A, and MAPK7, in high-grade osteosarcoma. Cancer Genet Cytogenet. 2002;139:91–96. [PubMed]
244. van Dartel M, Hulsebos TJ. Characterization of PMP22 expression in osteosarcoma. Cancer Genet Cytogenet. 2004;152:113–118. [PubMed]
245. van Deursen JM. Rb loss causes cancer by driving mitosis mad. Cancer Cell. 2007;11:1–3. [PubMed]
246. van Es JH, Barker N, Clevers H. You Wnt some, you lose some: oncogenes in the Wnt signaling pathway. Curr Opin Genet Dev. 2003;13:28–33. [PubMed]
247. Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310. [PubMed]
248. Wadayama B, Toguchida J, Shimizu T, Ishizaki K, Sasaki MS, Kotoura Y, Yamamuro T. Mutation spectrum of the retinoblastoma gene in osteosarcomas. Cancer Res. 1994;54:3042–3048. [PubMed]
249. Wadayama B, Toguchida J, Yamaguchi T, Sasaki MS, Yamamuro T. p53 expression and its relationship to DNA alterations in bone and soft tissue sarcomas. Br J Cancer. 1993;68:1134–1139. [PMC free article] [PubMed]
250. Wagner EF, Karsenty G. Genetic control of skeletal development. Curr Opin Genet Dev. 2001;11:527–532. [PubMed]
251. Wan X, Mendoza A, Khanna C, Helman LJ. Rapamycin inhibits ezrin-mediated metastatic behavior in a murine model of osteosarcoma. Cancer Res. 2005;65:2406–2411. [PubMed]
252. Wang LL. Biology of osteogenic sarcoma. Cancer J. 2005;11:294–305. [PubMed]
253. Wang LL, Gannavarapu A, Kozinetz CA, Levy ML, Lewis RA, Chintagumpala MM, Ruiz-Maldanado R, Contreras-Ruiz J, Cunniff C, Erickson RP, Lev D, Rogers M, Zackai EH, Plon SE. Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome. J Natl Cancer Inst. 2003;95:669–674. [PubMed]
254. Wang LL, Levy ML, Lewis RA, Chintagumpala MM, Lev D, Rogers M, Plon SE. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients. Am J Med Genet. 2001;102:11–17. [PubMed]
255. Wang ZQ, Liang J, Schellander K, Wagner EF, Grigoriadis AE. c-fos-induced osteosarcoma formation in transgenic mice: cooperativity with c-jun and the role of endogenous c-fos. Cancer Res. 1995;55:6244–6251. [PubMed]
256. Weatherby RP, Dahlin DC, Ivins JC. Postradiation sarcoma of bone: review of 78 Mayo Clinic cases. Mayo Clin Proc. 1981;56:294–306. [PubMed]
257. Wei G, Lonardo F, Ueda T, Kim T, Huvos AG, Healey JH, Ladanyi M. CDK4 gene amplification in osteosarcoma: reciprocal relationship with INK4A gene alterations and mapping of 12q13 amplicons. Int J Cancer. 1999;80:199–204. [PubMed]
258. Weiss KR, Cooper GM, Jadlowiec JA, McGough RL 3rd, Huard J. VEGF and BMP expression in mouse osteosarcoma cells. Clin Orthop Relat Res. 2006;450:111–117. [PubMed]
259. Whelan JS. Osteosarcoma. Eur J Cancer. 1997;33:1611–1618; discussion 1618–1619. [PubMed]
260. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res. 2006;66:1883–1890; discussion 1895–1886. [PubMed]
261. Wilkie AO, Patey SJ, Kan SH, van den Ouweland AM, Hamel BC. FGFs, their receptors, and human limb malformations: clinical and molecular correlations. Am J Med Genet. 2002;112:266–278. [PubMed]
262. Willert K, Nusse R. Beta-catenin: a key mediator of Wnt signaling. Curr Opin Genet Dev. 1998;8:95–102. [PubMed]
263. Winslow MM, Pan M, Starbuck M, Gallo EM, Deng L, Karsenty G, Crabtree GR. Calcineurin/NFAT signaling in osteoblasts regulates bone mass. Dev Cell. 2006;10:771–782. [PubMed]
264. Wodarz A, Nusse R. Mechanisms of Wnt signaling in development. Annu Rev Cell Dev Biol. 1998;14:59–88. [PubMed]
265. Wolf M, El-Rifai W, Tarkkanen M, Kononen J, Serra M, Eriksen EF, Elomaa I, Kallioniemi A, Kallioniemi OP, Knuutila S. Novel findings in gene expression detected in human osteosarcoma by cDNA microarray. Cancer Genet Cytogenet. 2000;123:128–132. [PubMed]
266. Wu JX, Carpenter PM, Gresens C, Keh R, Niman H, Morris JW, Mercola D. The proto-oncogene c-fos is over-expressed in the majority of human osteosarcomas. Oncogene. 1990;5:989–1000. [PubMed]
267. Wunder JS, Czitrom AA, Kandel R, Andrulis IL. Analysis of alterations in the retinoblastoma gene and tumor grade in bone and soft-tissue sarcomas. J Natl Cancer Inst. 1991;83:194–200. [PubMed]
268. Wunder JS, Eppert K, Burrow SR, Gokgoz N, Bell RS, Andrulis IL. Co-amplification and overexpression of CDK4, SAS and MDM2 occurs frequently in human parosteal osteosarcomas. Oncogene. 1999;18:783–788. [PubMed]
269. Wuyts W, Van Wesenbeeck L, Morales-Piga A, Ralston S, Hocking L, Vanhoenacker F, Westhovens R, Verbruggen L, Anderson D, Hughes A, Van Hul W. Evaluation of the role of RANK and OPG genes in Paget’s disease of bone. Bone. 2001;28:104–107. [PubMed]
270. Yamaguchi A, Komori T, Suda T. Regulation of osteoblast differentiation mediated by bone morphogenetic proteins, hedgehogs, and Cbfa1. Endocr Rev. 2000;21:393–411. [PubMed]
271. Yamaguchi T, Toguchida J, Yamamuro T, Kotoura Y, Takada N, Kawaguchi N, Kaneko Y, Nakamura Y, Sasaki MS, Ishizaki K. Allelotype analysis in osteosarcomas: frequent allele loss on 3q, 13q, 17p, and 18q. Cancer Res. 1992;52:2419–2423. [PubMed]
272. Yan P, Coindre JM, Benhattar J, Bosman FT, Guillou L. Telomerase activity and human telomerase reverse transcriptase mRNA expression in soft tissue tumors: correlation with grade, histology, and proliferative activity. Cancer Res. 1999;59:3166–3170. [PubMed]
273. Yang X, Karsenty G. ATF4, the osteoblast accumulation of which is determined post-translationally, can induce osteoblast-specific gene expression in non-osteoblastic cells. J Biol Chem. 2004;279:47109–47114. [PubMed]
274. Yokoyama R, Schneider-Stock R, Radig K, Wex T, Roessner A. Clinicopathologic implications of MDM2, p53 and K-ras gene alterations in osteosarcomas: MDM2 amplification and p53 mutations found in progressive tumors. Pathol Res Pract. 1998;194:615–621. [PubMed]
275. Yoshikawa H, Nakase T, Myoui A, Ueda T. Bone morphogenetic proteins in bone tumors. J Orthop Sci. 2004;9:334–340. [PubMed]
276. Yotov WV, Hamel H, Rivard GE, Champagne MA, Russo PA, Leclerc JM, Bernstein ML, Levy E. Amplifications of DNA primase 1 (PRIM1) in human osteosarcoma. Genes Chromosomes Cancer. 1999;26:62–69. [PubMed]
277. Zenmyo M, Komiya S, Hamada T, Hiraoka K, Kato S, Fujii T, Yano H, Irie K, Nagata K. Transcriptional activation of p21 by vitamin D(3) or vitamin K(2) leads to differentiation of p53-deficient MG-63 osteosarcoma cells. Hum Pathol. 2001;32:410–416. [PubMed]
278. Zhang M, Rosen JM. Stem cells in the etiology and treatment of cancer. Curr Opin Genet Dev. 2006;16:60–64. [PubMed]
279. Zhang Y, Xiong Y, Yarbrough WG. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell. 1998;92:725–734. [PubMed]
280. Zhao GQ. Consequences of knocking out BMP signaling in the mouse. Genesis. 2003;35:43–56. [PubMed]
281. Zhou H, Randall RL, Brothman AR, Maxwell T, Coffin CM, Goldsby RE. Her-2/neu expression in osteosarcoma increases risk of lung metastasis and can be associated with gene amplification. J Pediatr Hematol Oncol. 2003;25:27–32. [PubMed]
282. Zou H, Choe KM, Lu Y, Massague J, Niswander L. BMP signaling and vertebrate limb development. Cold Spring Harb Symp Quant Biol. 1997;62:269–272. [PubMed]

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