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Lancet. Author manuscript; available in PMC 2008 May 19.
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PMCID: PMC2214903

Metastasis: recent discoveries and novel treatment strategies


Most cancer deaths are due to the development of metastases, hence the most important improvements in morbidity and mortality will result from prevention (or elimination) of such disseminated disease. Some would argue that treatments directed against metastasis are too late because cells have already escaped from the primary tumour. Such an assertion runs contrary to the significant but (for many common adult cancers) fairly modest improvements in survival following the use of adjuvant radiation and chemotherapy designed to eliminate disseminated cells after surgical removal of the primary tumour. Nonetheless, the debate raises important issues concerning the accurate early identification of clonogenic, metastatic cells, the discovery of novel, tractable targets for therapy, and the monitoring of minimal residual disease. We focus on recent findings regarding intrinsic and extrinsic molecular mechanisms controlling metastasis that determine how, when, and where cancers metastasise, and their implications for patient management in the 21st century.


Metastasis is the culmination of neoplastic progression. In their classic review, Hanahan and Weinberg describe six hallmarks of cancer.1 Besides immortality, abnormal growth regulation, self-sufficient growth, evasion of apoptosis, and sustained angiogenesis, invasion and metastasis are identified as distinguishing characteristics. However, although invasion through the basement membrane is the hallmark that objectively defines malignancy, not all neoplasms are invasive (eg, ductal carcinoma in situ of the breast and prostatic intraepithelial neoplasia), although they can progress towards malignancy. Similarly, the ability to metastasise is not an inherent property of all neoplastic cells. Some tumours are highly aggressive, forming secondary lesions with high frequency (eg, small cell carcinoma of the lung, melanoma, pancreatic carcinoma) whereas others rarely metastasise to distant sites despite being locally invasive (eg, basal cell carcinomas of the skin, glioblastoma multiforme).

Metastasis is generally described in terms of haematogenous (bloodborne) dissemination. However, secondary tumours can arise via spread through lymphatics (lymph node metastasis is a common feature of many carcinomas) or across body cavities (eg, ovarian carcinomas mainly establish secondary tumours by dissemination within the abdomen, rarely forming metastases via haematogenous spread). Cells can even migrate along the spaces between the endothelium and basement membrane or along neurons, as is the case in pancreatic carcinomas. The molecular and cellular mechanisms underlying these different proclivities are the topic of constant debate2 and intense research efforts because they have important implications for our ability to predict, identify, and eradicate life-threatening metastatic disease.

Search strategy and selection criteria

We tried to identify all relevant studies irrespective of language. We searched PubMed, Medline, and Current Contents with a combination of the following terms: “metastasis”, “invasion”, “dissemination”, “chemokine”, “gene”, “protease”, “angiogenesis”, “lymphangiogenesis”, “signalling pathways”, “stroma”, “hypoxia”, “stem cell”, “host”, “gene signature”, “cell adhesion”, “extracellular matrix”, “microenvironment”, and “cancer therapy”. Studies were selected on the basis of recent contributions to the understanding of the cellular and molecular basis of cancer metastasis. Most searches covered 2000–07, but earlier papers were also included. Further references were selected from the bibliographies of cited papers.

Basic mechanisms of metastasis

Progression towards an invasive phenotype

The process of metastasis begins before cells migrate from a primary tumour mass. Among the earliest characteristics of transformed cells are genetic and phenotypic instability. Cancer cells are more prone to mutation and phenotypic drift than their normal counterparts.3-5 Genetic instability, coupled with a Darwinian type of selection—survival of the fittest—results in populations resistant to normal homoeostatic growth controls, immune attack, and environmental restraints.6 The rate of progression varies and, within any neoplastic mass, subpopulations can be isolated with different malignant potential (figure 1). Thus, not all tumours are metastatic, nor are all cells within so-called metastatic tumours capable of metastasising.7-9 Even cells isolated from large metastases show substantial heterogeneity when assessed experimentally,10 raising questions as to whether cells might transiently acquire metastatic potential.6

Figure 1
How and when is metastatic potential determined?

Recent evidence suggests that tumour cells might begin conditioning distant tissues for colonisation by establishing a so-called pre-metastatic niche.11 As yet unknown factors mobilise haematopoetic stem cells to tissues, remodel the matrix, and modify stromal cells and the growth factor milieu such that tumour cells are attracted to or have increased predilection for growth at these sites.12 In a transgenic mouse colon carcinoma model, CD34+ immature myeloid cells expressing the chemokine receptor CCR1 were recruited from the bone marrow to the edges of local primary lesions and stimulated local invasion by tumour cells expressing the ligand CCL9.13 Importantly, genetic instability, generation of variants, and establishment of premetastatic niches represent intrinsic tumour cell and microenvironmental changes that take place before cancer cell dissemination.

Epithelial-mesenchymal transition

Neoplastic cells might acquire the ability to metastasise by dedifferentiation to a more motile mesenchymal cell phenotype, a process called epithelial-mesenchymal transition (EMT).14,15 Once established in a new environment, metastatic cells might then revert back to a non-metastatic phenotype, via a mesenchymal-epithelial transition. Epithelial-mesenchymal transition can be induced by different stimuli, with transforming growth factor (TGF) β signalling having a key role. Other important mediators include oncogenic signalling pathways (notably phosphoinositide 3 [PI3] kinase), mitogen-activated protein (MAP) kinases, loss of E-cadherin (or a switch to N-cadherin), and activation of transcription regulators such as Twist and Snail (SNA1).16-18 Interestingly, Wnt, Notch, and Hedgehog signalling pathways (also implicated in stem cell maintenance) are linked to epithelial-mesenchymal transition.19

Cells induced to undergo epithelial-mesenchymal transition not only exhibit enhanced motility but also are resistant to apoptosis: key requirements for successful metastasis.20 However, other cancer cells might use a collective migration that is independent of an epithelial-mesenchymal transition.21 The fact that Wnt signalling can also induce collective migration in addition to epithelial-mesenchymal transition emphasises the complex interrelations and plasticity in all of these processes.22

Although a role for epithelial-mesenchymal transition during development is well accepted and can be demonstrated and manipulated in many experimental tumour models, some question whether it occurs in human cancers,23 and it is important to state explicitly that epithelial-mesenchymal transition is not synonymous with invasion or metastasis.

Resistance to apoptosis and anoikis

Dissemination requires that tumour cells detach from the matrix or cell-cell anchor(s) that control tissue architecture. Under normal circumstances, epithelial cells undergo apoptosis (programmed cell death) when adhesion to the correct substrate is disrupted.24,25 Indeed, a specialised form of apoptosis—anoikis—results when normal cells are maintained in suspension; this process is clearly a mechanism designed to protect multicellular organisms from rogue cells establishing themselves outside their correct anatomical location. Metastatic cells therefore must be resistant to anoikis and apoptosis to survive during dissemination and colonisation of ectopic sites. Many studies show that crucial apoptotic modulators are deregulated in metastases. This deregulation is accomplished by various means: activation of survival pathways (eg, PI3 kinase-Akt), upregulation of matrix metalloproteinases (which downregulate death receptors, release growth factors, and condition the extracellular matrix for invasion); overexpression of anti-apoptotic proteins (BCL-2, BCL-XL) or focal adhesion kinase (FAK), and inactivation of p53, among others.26-28 The importance of anoikis resistance in metastasis was elegantly shown in experimental studies where a functional screen for suppressors of anoikis identified the neurotrophic receptor TrkB as a key mediator. Rat intestinal epithelial cells are very sensitive to detachment-induced anoikis and are non-tumourigenic, but when transfected with TrkB, they become highly tumourigenic and metastatic via both the lymphatic and haematogenous routes, even destroying bone.29,30 TrkB is often overexpressed in human malignancies and is mutated in colon cancer.31 Its activation also induces vascular endothelial growth factor (VEGF) expression via hypoxia inducible factor (HIF) 1α, potentially assisting with establishment and angiogenesis of tumours at secondary sites.32

Angiogenesis and lymphangiogenesis

That tumour growth and progression is limited before vascularisation of the neoplastic mass is generally accepted.33 Vascularisation is achieved via neo-angiogenesis,34 co-option of existing blood vessels,35 vasculogenic mimicry (in which poorly differentiated, highly malignant tumour cells can form a primitive vascular system),36 or a combination of these processes. Newly formed leaky capillaries can also serve as conduits for disseminating cells.

Hypoxia and activated oncogenes, including RAS, EGFR, and HER2/NEU, upregulate angiogenic cytokines (eg, VEGF and interleukin 8) and proteolytic enzymes (eg, matrix metalloproteinases, urokinase plasminogen activator [uPA]) and downregulate inhibitors such as thrombospondin (TSP1) via PI3 kinase and MAP kinase signalling pathways, thus potentiating angiogenesis, tumour growth, and spread.33,37,38 Hypoxia could also directly affect tumour cell motility, invasion, and metastasis, with a key component recently identified as HIF1α-regulated lysyl oxidase (LOX).39 LOX is linked to poor prognosis in several tumour types, including breast and oral cancers. It is thought to regulate FAK activity, cell-matrix adhesion, and motility, potentially creating a niche permissive for metastatic growth at secondary sites. CXCR4, a chemokine implicated in site-selective metastasis, is also upregulated by hypoxia as well as oncogenes such as HER2, MET, and EGFR.40-42 Hypoxia regulates many other genes linked to tumour progression,43,44 recruits macrophages and other inflammatory cells,45 and can also contribute to increased genetic instability46,47 and resistance to apoptosis.48

A parallel process—lymphangiogenesis—has been invoked as a potential facilitator of lymphatic metastasis,49,50 although functional lymphatic vessels within human tumours are rare and co-option of existing lymphatic vessels could also occur.51 The major lymphangiogenic cytokines (VEGF-C and VEGF-D) and lymphangiogenesis have been linked to poor prognosis in some cancers, and more specifically with lymph node metastasis.52-54 Experimental manipulation of these cytokines modulates lymphatic metastasis in some experimental models.55-58 VEGF-A59 and other signalling systems—eg, angiopoietin:Tie, ephrin:Eph, and PDGF-BB:PDGFR—could also be involved.60 Recently, so-called zip codes have been identified on the lymphatic endothelium in tumour xenografts which, when blocked, inhibited lymphatic metastasis.61

Two questions are of particular interest: can the propensity for lymphatic metastasis be predicted from gene expression signatures, as has been claimed for other sites of metastasis? And does lymphatic dissemination predispose to distant metastasis? The role of lymphatic dissemination has recently been reviewed,62-64 and that nodal metastases could serve as a bridgehead for further dissemination in certain cancers is clear; however, direct haematogenous dissemination occurs in others. Clearly, more careful kinetic and molecular dissection of cancer spread is required to delineate the importance of tumour cells detected not only in nodes, but also in the blood and bone marrow.63,65-67

Dissemination and colonisation of secondary sites

Several million cells per gram of tumour can be shed daily into the lymphatic system or bloodstream.68 The fate of bloodborne tumour cells is somewhat controversial and experimental evidence contradictory. In some models, most circulating cells die,69,70 whereas in others, most survive and extravasate.71 Insufficient data exist to quantify the fraction of shed tumour cells that successfully seed secondary tissues, especially in human cancers. Nevertheless, all studies show that most cells entering the vasculature fail to form macroscopic foci at distant sites.

What, then, is required of a cell to successfully colonise another tissue? These abilities must co-exist within a single cell since metastases are mainly clonal.72,73 To accomplish this process, tumour cells use a variety of motility mechanisms,74,75 chemokine gradients,76 and proteinases (eg, matrix metalloproteinases, cathepsins, uPA, etc)77-80 to enter and exit the circulation. Many of the processes are also activated by endothelial cells during angiogenesis.81,82 Interestingly, Friedl and colleagues83 recently showed that the migration of tumour cells through collagen matrices still occurs in the presence of broad-spectrum proteinase inhibitor cocktails. Additionally, the intuitive assumption that these enzymes are derived from tumour cells has been challenged by the finding that most are produced by stromal cells.80,84,85

Ultimately, metastatic cells must lodge at secondary sites and re-establish adhesive connections. During haematogenous dissemination, the transit time is only seconds, thus cells are unlikely to shut down transcriptional expression of adhesion molecules as they depart the primary tumour and re-express them when they arrive at secondary sites. Cells could use alternative adhesion molecules or might selectively alter adhesion by post-translational modification of already expressed proteins, glycoproteins, lectins, or other molecules.86

Metastatic cancer cells must also evade immune effectors or co-opt immune/inflammatory cells to assist them in completing subsequent steps of the metastatic cascade, and they must resist hydrostatic sheer forces (ie, turbulence within vessels). Susceptibility to such stresses can vary widely and could contribute stochastically to metastatic inefficiency. Nonetheless, a successful metastatic cell must overcome whatever challenges to its survival are mounted.

Key issues

When and how is metastatic potential determined?

Gene expression microarrays have provided hope for the vexing issue of identifying which tumours will or will not metastasise. Chemotherapy or hormonal therapy reduces the risk of distant metastases by about a third; however, 70–80% of breast cancer patients receiving adjuvant treatment would have survived without it. Because these patient populations cannot be accurately identified, they are treated unnecessarily.87 Several research groups have used microarrays to identify so-called poor prognosis markers, molecular portraits, or death from cancer signatures that show promise for segregating patient subsets with different phenotypes, with the ultimate aim of customising treatment according to need87-93 (table 1). A recent prospective, randomised study comparing conventional clinicopathological criteria with the 70 gene signature—a set of 70 marker genes that predicts poor prognosis87—has been set up to select patients for adjuvant chemotherapy. This study is called Microarray In Node negative Disease may Avoid Chemotherapy (MINDACT; EORTC Protocol 10041-BIG 3-04).

Table 1
Examples of gene signatures for cancer progression and metastasis

Gene expression array data, in addition to providing promising prognostic and predictive tools, have also contributed to an important debate regarding the molecular basis of metastasis. The poor prognosis pattern of gene expression has been observed in primary tumours,90,93 suggesting that acquisition of metastatic competence is an early event (ie, hardwired) in tumour progression. This observation conflicts with the hypothesis that metastatic competence is due to the late emergence of specialised subclones (figure 1). How do we reconcile these two sets of observations? First, since tumours are heterogeneous, it could be that the metastasis signature is represented by the bulk population, but not by every cell within that population (ie, the expression is distributed among all the cells). Some subpopulations within the tumour could express one of the metastasis signature genes, whereas others could express larger proportions (or all) of the signature genes. Since metastases are clonal, successful cells must individually express all required properties, or be able to depend upon host support for those they lack. Second, two types of profiles have been identified by Minn and colleagues:102 a general metastagenicity set of genes (which coincidentally also potentiated primary tumour growth), superimposed upon which are (probably fewer) expression changes linked to metastasis per se, and what is more, metastasis at specific sites: organ virulence genes.102 Thus, genes relating to angiogenesis, survival, and proliferation (required for both primary and secondary tumour growth) could skew the expression profiles towards a high degree of concordance. Recently, a novel hypothesis has been proposed: that disseminating cells might return home to the primary site, increasing the population of cells in the primary tumour with metastatic molecular profiles.108 However, in other cancer types, malignant cells in bone marrow (and other sites) can show substantial genetic differences compared not only with the primary tumour, but also with each other, suggesting early (or sequential) dissemination and parallel evolution.109 Clearly there are implications from both of these (non-exclusive) mechanisms of metastasis for clinical management: in the first case, sampling the primary tumour could adequately predict the make-up of metastases, whereas if they have been generated independently, even determining the expression profile of one metastasis might not reflect that of others. Since new treatments now aim to inhibit specific underlying oncogenic pathways in cancer (eg, due to Bcr-Abl translocations, activated tyrosine kinases, mutant proteins), it will be important to be able to predict with some degree of certainty the prevalence of the target within disseminated disease sites to select patients for therapy and to assess response.

Several of the genes identified in metastasis signatures are stromal in origin,110,111 again attesting to the contribution of the host to metastasis.112 Many of these genes are concerned with remodelling of the extracellular matrix, invasion, and motility, in addition to those required for survival and proliferation. Doubt has been cast on their functional importance since there is little concordance in the genes identified in different studies.113 However, a recent editorial114 has suggested that many of the reported gene signatures are equally predictive and that combining them could be even more powerful. That the complementary functions required for successful metastasis could be fulfilled by different genes in different cancers is possible. The myriad transcriptional changes observed could be orchestrated by a few key functional regulators. For example, the wound response signature (a powerful predictor of metastasis in multiple tumour types)115 is induced by coordinated amplification of two genes, MYC and CSN5.116 Their overexpression was sufficient to induce rapid cell growth and invasiveness, but required cooperation of other genes for initial oncogenic transformation. Others have identified a metastasis expression signature similar to that of stem cells.88,117

What determines site selectivity of metastases?

Disseminated cells colonise certain tissues more commonly than others118 (figure 2). Some preferred locations can be accounted for by blood flow (eg, liver from colorectal carcinomas, vertebrae from prostate carcinomas), whereas others cannot (eg, liver from uveal melanoma, long bones from breast carcinoma).119,120 Paget explained118 this non-random distribution by suggesting that the seed (tumour cell) will only grow in an appropriate soil (tissue microenvironment). Numerous studies support this notion and several mechanisms might contribute: tumour cells could bind selectively to endothelial cells or basement membranes from certain tissues, invade more readily, or respond to organ-specific growth factors depending on the receptors expressed and signalling pathways engaged.121,122 The ERB-B/HER family of receptor tyrosine kinases: epidermal growth factor receptor (EGFR/ERB-B1, ERB-B2 [HER2], ERB-B3, and ERB-B4) are often overexpressed and, in some cases, mutated in human cancers. Upon ligand binding, they form homodimers or heterodimers and strongly activate the MAP kinase and PI3 kinase signalling pathways among others, leading to cell proliferation, motility, and invasion. MET, another receptor tyrosine kinase, and its ligand, hepatocyte growth factor, are also often upregulated in cancers. The predilection of breast cancer cells expressing ERB-B oncogenes to generate CNS metastasis123,124 could be explained by the fact that their cognate ligands (heregulins/neuregulins) are brain growth factors; similarly colon or pancreatic carcinoma cells overexpressing EGFR or MET could respond, respectively, to high levels of TGFα or hepatocyte growth factor in the liver.125,126

Figure 2
Can cancer spread to different sites be predicted?

Recently, the Massagué group used cDNA microarrays to compare lung, bone, and adrenal colonising breast carcinoma cell lines.72,102 They found that some genes expressed by tumour cells were common for metastases to all sites (eg, osteopontin), whereas others were selectively expressed if the cell lines had a predilection to growth in a given tissue (eg, CXCR4). Importantly, they found that combinations of genes were required for successful metastasis to each site; a single molecule was not sufficient. Other site-specific gene signatures have been reported in both experimental models and clinical samples (table 1).

Several clear examples of gene expression profiles relate to bone metastasis (again superimposed on a high-risk signature),72,96,102 perhaps because this site represents a more specialised and demanding environment than soft tissues. There is evidence for osteomimicry, with successful metastatic cells responding to bone-derived chemotactic and mitogenic factors and entering a vicious cycle of bone degradation and remodelling.127-129 Briefly, the vicious cycle develops when factors secreted by or expressed on tumour cells (eg, parathyroid hormone-related peptide) activate osteoblasts and osteoclasts in the bone micro-environment to produce cytokines (eg, receptor activator for nuclear factor κB ligand, RANKL); by contrast, osteoprotegerin is downregulated. Remodelling and osteolysis causes release of growth factors (eg, TGFβ and insulin-like growth factor [IGF] 1), which then stimulate tumour cell growth and motility and further release of parathyroid hormone-related peptide. Molecular profiling might help to identify patients who could benefit from bisphosphonates or other agents that interfere with bone colonisation.

Examination of bone marrow metastases identified different determinants, with evidence that this site might predict for later distant relapse.97 Early dissemination also seems to indicate seeding of cells of low metastatic potential which can remain dormant for extended periods. To survive and thrive, they need to adapt or be reinforced by later waves of better-equipped cells. Identifying which of these cells are genuine invaders is of major clinical significance.

Whether lymphatic metastasis is an active process, or merely due to the ease of access of tumour cells to lymphatic vessels and passive transport to draining nodes, is not clear. Several studies have identified gene expression profiles that predict lymphatic metastasis,101,130,131 whereas others have not.132 Interestingly, Hoang and colleagues98 suggested that the molecular signature of nodal metastasis was a composite of two patterns of gene expression: one that was similar between primary cancers and metastases, and a small subset of 27 genes that discriminated metastases, perhaps offering an elegant solution to the debate between clonal selection versus predeterminism.

What are the genes that control metastasis?

Identification of specific metastasis genes is difficult because of the need for several complementary functions that might be fulfilled by different genes in different contexts. However, several laboratories have identified more than 20 metastasis suppressors (table 2) that inhibit metastases without blocking tumour formation.133-137 The existence of such suppressors argues against metastatic potential being completely hardwired into cancer cells. Interestingly, metastasis suppressors seem to be involved in several pivotal positions that would amplify key molecular signals. Many are effective in tumour cells of multiple tissue origins, suggesting common pathways for metastasis regulation and control.

Table 2
Examples of metastasis suppressor genes and their functions133,136,138,139

Recently, the metastasis suppressor gene CD82/KAI1 has been shown to interact with a protein (DARC; Duffy antigen receptor for chemokines, also known as gp-Ly) on endothelial cells and induce senescence of tumour cells, indicating a role in preventing ectopic dissemination and growth.140 Many metastasis suppressors block growth of cells at secondary sites.136,138,139 For example, when metastasis competent C8161 human melanoma cells or their metastasis-suppressed counterparts that express neo6/C8161 or KISS1 were injected intravenously into immunocompromised mice, the parental and metastasis-suppressed cells distributed equally well throughout the body.141 The number of microscopic foci in various organs initially diminished equally; however, only the metastatic C8161 cells were subsequently able to proliferate in the lung environment to form progressive, lethal tumours. By contrast, cells expressing neo6/C8161 and C8161-KISS1 persisted for several months either as single cells or clusters of fewer than ten cells. These dormant cells could be isolated from the lungs, established in tissue culture, and were tumourigenic when transplanted at the normal position (intradermal site). From this location, they were also able to seed to the lungs but failed to develop into overt metastases. In short, cells expressing the metastasis suppressor gene were capable of completing every step of the metastatic cascade except proliferation at the secondary site.139

These observations suggest that at least some metastasis suppressors are mediators of cellular context and might regulate metastasis to some sites, but not others. However, the molecular mechanisms underlying differential growth remain ill defined. In addition to being mediators of microenvironmental signals, expression of metastasis suppressors is also subject to extracellular cues. Early analyses show that these genes (by contrast to many tumour suppressors such as p53, adenomatous polyposis coli gene [APC], and phosphatase and tensin homolog [PTEN]) are not often mutated, but more commonly controlled by epigenetic mechanisms.139,142

Microenvironmental issues: cellular context and tumour-host interactions

That metastatic potential is not simply an inherent trait of cancer cells, but is substantially modified by the microenvironment, is clear.112,143,144 The pioneering studies of Bissell and colleagues145 showed that even fully malignant breast cancer cells could be reverted to a normal phenotype by exposing them to a non-permissive stroma;145 conversely, cells could acquire malignant potential at sites of wounds or irradiated tissue.144 The extracellular matrix of secondary sites such as bone could also potentiate survival of metastatic prostate and breast carcinoma cells.146,147 Tumour cells can themselves induce a permissive environment and might even provide selective pressure for stromal cell mutations—eg, loss of functional p53148—in addition to inducing proteolytic enzymes in stromal macrophages and fibroblasts, and stimulating angiogenesis.

Two important papers provide examples of how tumours might condition their environment to sustain their development. Topczewska and colleagues149 used zebra fish as a biosensor and found that malignant melanoma cells re-programmed the phenotype of adjacent cells to ensure a biological niche in which they could thrive; this was mediated by secretion of a potent embryonic morphogen, Nodal. Inhibition of Nodal prevented invasion and reverted the cells towards a melanocytic phenotype. Kaplan and co-workers11 found that primary tumours can precondition future metastatic sites. Factors released by the primary tumour induce VEGFR1-positive bone marrow haematopoietic progenitor cells to home to specific tissue sites and form cellular clusters before arrival of the tumour cells, perhaps providing a permissive niche akin to that required by stem cells. We are now beginning to decode the language used in the cross talk between tumour cells and their environment that could lead to eventual interruption of this dialogue.

Important experimental data from Kent Hunter's group suggest that metastatic propensity might be affected by host genetic context.150 Briefly, transgenic mice of FVB/NJ strain expressing the polyoma middle T oncogene (PyMT) develop metastatic mammary tumours with a high incidence. However, when crossed with other inbred strains, metastatic potential is either enhanced or inhibited. Since all tumours are initiated by the same oncogenic event, these differences are most reasonably explained by inherited susceptibility. Indeed, Sipa1 (a Rap1GAP gene) has been identified recently as a polymorphic metastasis modifier gene in this model. Its expression level is also linked to metastasis in human prostate cancers.151 Of great interest is the fact that, in the PyMT transgenic tumour models, the 17-gene metastasis signature described by Ramaswamy and colleagues90 was evident in tumours from the high-incidence mouse strains, and furthermore, some subsets of metastasis-predictive gene expression patterns are evident in the normal tissues of these animals.150

The intriguing possibility exists that signatures that are predictive of metastasis lurk in our genomes and that constitutional genetic variation substantially modulates metastatic efficiency.152 Whether such a profile exists (or could be deciphered) in outbred human populations remains to be seen, but clearly host genetic and epigenetic environmental effects cannot be ignored. The spread of cancers apparently occurs with a frequency that is inconsistent with the necessity for additional mutational events153 and hypermethylation of suppressor genes is also a key regulator.154 Chen and colleagues155 found that a murine tumour cell line exhibited a bone-metastatic phenotype in syngeneic strain 129 mice, but this was shifted to liver metastasis in a different host strain, although the mechanisms have not been elucidated yet. Thus, although classic theory has considered the seed and the soil, we should also now recognise that host “climate” is another important determinant in metastatic growth. The various (non-exclusive) mechanisms are illustrated in a simple form in figure 1.

When is a metastasis not a metastasis?

Observations that tumour cells behave differently depending upon their microenvironment highlights the importance of clearly defining the tumour-host signalling pathways and circuitry involved, and also raises two important and practical questions: what is the clinical relevance of disseminated cells, and are single disseminated cells metastases?

The presence of single ectopic cells was not an issue until techniques capable of detecting them (or small emboli) were developed. Indeed, happenstance sections in tissues often detect disseminated neoplastic cells, but their clinical importance was negligible since they were not affecting function. This observation does not belittle the potential clinical importance of these cells, since they have accomplished most of the antecedent steps of metastasis. The potential to become cancerous is present, but when they blend innocuously, they are difficult to detect and neutralise. The challenge is to discriminate between those cells merely leaning toward such behaviour from those that are destined to become cancerous. Nonetheless, accumulating evidence suggests that the presence of tumour cells in the peripheral circulation, lymph nodes, or bone marrow are indicators of poor prognosis; however, the correlations are imperfect.66 Recent staging criteria now incorporate parameters of single cells or microscopic masses.156-158

The question as to whether isolated disseminated cells should be deemed to be metastases is still debated. In 1919, James Ewing159 referred to an uncited study by M Schmidt thus:

“From the study of lung in these cases [of cancer], Schmidt concludes that in cancers of the abdominal organs, there is frequent and repeatedly a discharge of cancer cells which lodge in the small arteries of the lungs [but fail to form metastases]”

Presently it is not known whether the persistent cells are dormant (ie, non-dividing) or of limited replicative ability. Dormancy would explain resistance to treatments that, for the most part, target proliferating cells; by contrast, a limited replicative ability would provide a potential mechanism for new mutations being passed to progeny. Failure to develop a blood supply has been suggested to be a potentially important mediator of tumour dormancy for which there is compelling experimental evidence.160 However, other mechanisms such as the action of tumour suppressor genes161 or immunological restraint162 might also have a role. Conversion to an actively proliferating population could also occur in response to changes in the host tissue (eg, injury, change in hormonal status, ageing, initiation of angiogenesis) or the development of a suitable niche.163

Failure to distinguish bona fide metastases from inert disseminated cells has important implications. Current medical practice is to eliminate all risk. Therefore, if cells have already spread, then aggressive treatments are advocated. Also, the extent and location of spread (ie, local vs circulating vs regional vs distant) determine the treatment plan. However, patients might be subjected to more cytotoxic agents than necessary since most disseminated cells fail to form secondary tumours. In addition to microarray data, several investigators have queried the relevance of circulating cells with regard to their prognostic and predictive value. This debate is valid and is the subject of prospective clinical trials.164 Interestingly, in many breast cancer patients (including several with HER2-negative primary cancers), HER2-positive circulating cancer cells were identified.165 This finding, together with the well-validated concept of micrometastases in breast cancer, could contribute to the success of the use of the anti-HER2 antibody trastuzumab in combination with adjuvant therapy after surgery.166,167

The distinction between single ectopic cells versus metastases also has ramifications for assessing efficacy in clinical trials. Does prevention of secondary outgrowths constitute a successful anti-metastatic treatment, or must all cells be eliminated? These topics have been actively debated even before the first clinical trials have begun.71,168

Molecularly targeted treatments

Classic treatments for disseminated disease—ie, radiotherapy or chemotherapy—are mainly aimed at rapidly proliferating cells via inhibition of DNA replication, DNA repair, or the cell cycle. We are now in an era of targeted treatments based on the molecular pathology of the cancer in question, and although there have been some notable successes of agents targeting oncogenic signalling pathways (eg, imatinib, trastuzumab, erlotinib, gefitinib), there is still a way to go.169-172 Nevertheless, we now have an impressive armamentarium of both small molecule inhibitors and antibodies to many oncogenic receptor tyrosine kinases, and efforts are underway to define the best way of combining these agents for maximum therapeutic benefit. The next generation of treatments will focus on supplementing these approaches by addressing new aspects of malignant behaviour.

The first anti-angiogenic agents are now being tested in the clinic, for example bevacizumab (an anti-VEGF antibody173,174), vascular disrupting agents such as combretastatin A4,175,176 and several other small molecules, antibodies and soluble decoys that target angiogenic growth factor receptors (VEGFR-2, VEGFR-3, PDGF-R, FGFR-2). Additionally, inhibitors of HIF and downstream signalling pathways show promising results.81,177 Recently, treatments combining anti-angiogenic and cytotoxic agents were shown to reduce the tumour stem cell-like fraction in glioma xenografts,178 indicating that this key population might be amenable to carefully designed therapeutic approaches.

There are also emerging strategies to reverse epigenetic events in oncogenesis—eg, aberrant histone methylation and acetylation.179,180 Several promising histone deacetylase inhibitors are in development,181,182 and it is thought that methyltransferases could also be targeted with drugs.183 However, selectively reversing inappropriate DNA hypermethylation in the promoters of tumour or metastasis suppressor genes will be very challenging.

Other exciting new targets include the endothelin (ET1) receptor and RANKL (both implicated in bone metastasis) using antagonists such as atrasentan184 and denosumab,185 respectively.

Now is the time also to consider targeting molecular pathways in lymphangiogenesis,186 anoikis,30 and the mechanisms underlying tumour-host/stromal interactions and cell motility, especially since cell motility, more so than cell proliferation, distinguishes metastatic cancers from benign lesions.81,122 These approaches will require new paradigms in trial design and patient management187-189 (table 3). Many lessons have been learned from the disappointing trials with early generation matrix metalloproteinase inhibitors.84 Contributing factors to the failures were the fact that patients with mainly late stage bulky cancers were treated and it is now clear that different matrix metalloproteinases can have both pro- and antitumour effects. The challenge now is to target specific matrix metalloproteinases while sparing those whose inhibition would be counterproductive190 and carefully to select appropriate cancer patient populations.

Table 3
Examples of current and future treatments for metastatic disease

Stem cells: are we shooting at the right cellular and molecular targets?

Complete eradication of metastases is rare. On the basis of our understanding of embryonic organ development and self-renewing adult tissues (notably the haematopoietic system), the idea is emerging that a unique population of stem cells might be responsible for generating both primary and secondary cancers, and that these cells are inherently resistant to standard treatments. These concepts were first propounded by Cohnheim in 1875191 and later explored experimentally.192,193

Adult pluripotent haematopoietic stem cells that can repopulate all of the blood cell compartments (and which, when they or their progeny become malignant, form leukaemias and lymphomas) are well described. However, the identification and characterisation of stem cells in epithelial tissues or the carcinomas that arise from them has been challenging, especially in human beings. Many cancers arise in tissues where self-renewal is essential (eg, gut, skin, bone marrow). In these tissues, a small number of stem cells, as well as maintaining their own numbers, also generate progenitor cells by asymmetric division. These progenitor cells undergo several rounds of proliferation before terminally differentiating. Only the rare stem cells are long-lived, probably as a means of limiting the accumulation of genetic damage. The default position is differentiation or death, and cancer occurs when this is overridden. The progenitor cells—in a caricature of differentiation—might be responsible for the heterogeneity evident in many cancers (and could contribute to differences in drug sensitivity and metastatic capacity). However, cytotoxic treatment could well kill the proliferating progenitor cells (reducing tumour burden) but fail to eradicate the stem cell compartment, and thus only rarely prove to be curative194-196 (figure 3).

Figure 3
Is failure to control metastasis due to residual tumour stem cells?

So what is the evidence for stem cells in adult epithelial tissues and cancer, and what are their characteristics (panel 1)? Recently, two groups succeeded in repopulating an entire mouse mammary gland from a single cell, identifying this putative stem cell with a series of surface markers.197,198 Before this, Al-Hajj and colleagues199 isolated a subpopulation of cells in human breast cancers with dramatically enhanced tumourigenic capacity when transplanted into immunodeficient mice. We do not know if cancer stem cells are derived from normal stem cells, but if so they might share one or more of their properties that would confer immortality and the ability to withstand genotoxic insults from the environment or, in the case of cancer cells, cytotoxic drugs. First, as part of their defence against damage, normal stem cells express several transporters (efflux pumps for drugs and toxins) that are the major multidrug-resistance genes in cancers.200 Additionally, stem cells have an active DNA repair capacity and exhibit resistance to apoptosis; furthermore, they are relatively quiescent, dividing rarely and leaving the expansion of the population to their progeny. All of these factors could contribute to the survival of stem cell cells able to repopulate a tumour or metastasis after cytotoxic drug treatment or radiation.201 Recently, it has been postulated that migrating stem cells, located at the tumour invasive front, exhibiting epithelial-mesenchymal transition and an activated Wnt pathway, could be responsible for colon cancer metastasis.202 Interestingly, this study, and others,74,203 have shown that motile cells are non-proliferating, again suggesting that new therapeutic modalities are required to target these dangerous cells.

Panel 1: Key properties of stem cells

  • Capacity for self-renewal and progenitor production via asymmetric cell division
  • Regulated by niche: does disruption of this host control lead to aberrant expansion of stem/progenitor cells and cancer?
  • Long-lived: time to accumulate multiple mutations
  • Ability to generate multiple lineages via downstream differentiation
  • Active telomerase expression
  • Activation of anti-apoptotic pathways (high Bcl-2 and IAP proteins)
  • Anoikis resistance: survival during dissemination?
  • Ability to migrate
  • Increased membrane transporter activity: drug resistance
  • Unique signalling pathway patterns: Wnt, Notch, Snail, Twist, Hedgehog, Bmi-1

Do stem cells express the molecules that we are currently targeting? There are conflicting reports as to whether breast cancer stem cells express the oestrogen receptor and HER2, although EGFR is reportedly present. The major signalling pathways so far identified in stem cells are often mutated in cancers but they are not, by and large, the focus of current molecular treatments.204 Potential unexploited targets include TGFβ, the Notch pathway205,206 (also implicated in angiogenesis207 and the osteomimetic properties of prostate cancers208), Wnt, Hedgehog, Snail, Twist, and Bmi-1.209-211

So, would targeting tumour stem cells damage normal stem cells? To answer this, we will need much better definition and characterisation of these two populations in a variety of tissues. However, recently Krivtsov and colleagues212 found phenotypic differences between stem cells in a mouse model of leukaemia compared with normal haemopoietic stem cells (a subset of which were also identified in human leukaemia), providing preliminary evidence that specific targeting of malignant cells might be feasible.

Conclusions and future prospects

Recent years have revealed exciting new insights into the molecular mechanisms of metastasis, although many questions remain (panel 2). We need to resolve the relative contributions of mutations in the seed cells (whether stem cells, their progeny, or both), epigenetic changes and microenvironmental influences, and not least inherited predisposition to cancer susceptibility and spread. Animal models have yielded important insights into the mechanisms of metastasis, but these must be measured against clinical reality. We need to develop more treatments that specifically target metastases, which must be tested in appropriate systems in vitro and in vivo. The design of clinical trials will be challenging: identification of patients at risk by genetic profiling and more sensitive methods of detection and quantitation of metastases are urgently required, together with early indicators of response. Prevention of metastatic outgrowth (eg, induced differentiation, stasis, or reactivation of apoptosis) is a further consideration.

Panel 2: Key unanswered questions

  • What is the relation between metastatic cancer cells and stem cells? Are there really stem cells in solid human tumours? Do current anticancer drugs kill cancer stem cells? Will there be differences between malignant and normal stem cells?
  • Are metastases the result of epithelial-mesenchymal transition? Does epithelial-mesenchymal transition contribute to progression of human cancers? Is there a transient metastatic compartment?
  • Is metastasis an inherent (selectable) property of a subset of tumour cells or an adaptive property?
  • What role does the host genotype have in determining metastatic risk?
  • What are the mechanisms of action of metastasis suppressors? Are they part of a shared pathway or are there parallel mechanisms of metastasis control?
  • What determines selective colonisation of different organs/tissues?
  • Is the ability of tumour cells to proliferate in secondary sites the major rate-limiting determinant in metastasis?
  • What is the relevance of circulating tumour cells (or tumour cells in the draining lymph nodes or bone marrow) with regard to establishment of distant metastases?
  • Can microarrays or proteomics of tumours (or normal tissues) be used in the clinic to predict probability and/or sites of metastasis?
  • How can early detection of metastases be improved?
  • Is metastasis a tractable therapeutic option?
  • What are the most promising molecular targets for preventing/treating metastases?
  • How can we monitor minimal residual disease during therapy with a high degree of sensitivity and specificity?
  • What are the molecular mechanisms responsible for tumour dormancy?


Conflicts of interest statement

We declare that we have no conflict of interest.


1. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57–70. [PubMed]
2. Eccles SA, Paon L. Breast cancer metastasis: when, where, how? Lancet. 2005;365:1006–07. [PubMed]
3. Cifone MA, Fidler IJ. Increasing metastatic potential is associated with increasing genetic instability of clones isolated from murine neoplasms. Proc Natl Acad Sci USA. 1981;78:6949–52. [PMC free article] [PubMed]
4. Heppner GH, Miller FR. The cellular basis of tumor progression. Int Rev Cytol. 1998;177:1–56. [PubMed]
5. Strauss BS. Hypermutability and silent mutations in human carcinogenesis. Semin Cancer Biol. 1998;8:431–38. [PubMed]
6. Welch DR, Tomasovic SP. Implications of tumor progression on clinical oncology. Clin Exp Metastasis. 1985;3:151–88. [PubMed]
7. Hart IR, Fidler IJ. The implications of tumor heterogeneity for studies on the biology of cancer metastasis. Biochim Biophys Acta. 1981;651:37–50. [PubMed]
8. Nicolson GL. Cancer metastasis. Organ colonization and the cell-surface properties of malignant cells. Biochim Biophys Acta. 1982;695:113–76. [PubMed]
9. Poste G. Experimental systems for analysis of the malignant phenotype. Cancer Metastasis Rev. 1982;1:141–99. [PubMed]
10. Neri A, Welch D, Kawaguchi T, Nicolson GL. Development and biologic properties of malignant cell sublines and clones of a spontaneously metastasizing rat mammary adenocarcinoma. J Natl Cancer Inst. 1982;68:507–17. [PubMed]
11. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820–27. [PMC free article] [PubMed]
12. Kaplan RN, Psaila B, Lyden D. Bone marrow cells in the ‘pre-metastatic niche’: within bone and beyond. Cancer Metastasis Rev. 2006;25:521–29. [PubMed]
13. Kitamura T, Kometani K, Hashida H, et al. SMAD4-deficient intestinal tumors recruit CCR1+ myeloid cells that promote invasion. Nat Genet. 2007;39:467–75. [PubMed]
14. Thompson EW, Newgreen DF, Tarin D. Carcinoma invasion and metastasis: a role for epithelial-mesenchymal transition? Cancer Res. 2005;65:5991–95. [PubMed]
15. Xu J, Wang R, Xie ZH, et al. Prostate cancer metastasis: role of the host microenvironment in promoting epithelial to mesenchymal transition and increased bone and adrenal gland metastasis. Prostate. 2006;66:1664–73. [PubMed]
16. Larue L, Bellacosa A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene. 2005;24:7443–54. [PubMed]
17. Lee JM, Dedhar S, Kalluri R, Thompson EW. The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 2006;172:973–81. [PMC free article] [PubMed]
18. Thiery JP, Sleeman JP. Complex networks orchestrate epithelialxmesenchymal transitions. Nat Rev Mol Cell Biol. 2006;7:131–42. [PubMed]
19. Huber MA, Kraut N, Beug H. Molecular requirements for epithelial-mesenchymal transition during tumor progression. Curr Opin Cell Biol. 2005;17:548–58. [PubMed]
20. Robson EJ, Khaled WT, Abell K, Watson CJ. Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines. Differentiation. 2006;74:254–64. [PubMed]
21. Wicki A, Lehembre F, Wick N, Hantusch B, Kerjaschki D, Christofori G. Tumor invasion in the absence of epithelial-mesenchymal transition: podoplanin-mediated remodeling of the actin cytoskeleton. Cancer Cell. 2006;9:261–72. [PubMed]
22. Heisenberg CP, Tada M, Rauch GJ, et al. Silberblick/Wnt11 mediates convergent extension movements during zebrafish gastrulation. Nature. 2000;405:76–81. [PubMed]
23. Tarin D, Thompson EW, Newgreen DF. The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Res. 2005;65:5996–6000. [PubMed]
24. Frisch SM, Ruoslahti E. Integrins and anoikis. Curr Opin Cell Biol. 1997;9:701–06. [PubMed]
25. Frisch SM, Screaton RA. Anoikis mechanisms. Curr Opin Cell Biol. 2001;13:555–62. [PubMed]
26. Liotta LA, Kohn E. Anoikis: cancer and the homeless cell. Nature. 2004;430:973–74. [PubMed]
27. Mehlen P, Puisieux A. Metastasis: a question of life or death. Nat Rev Cancer. 2006;6:449–58. [PubMed]
28. Townson JL, Naumov GN, Chambers AF. The role of apoptosis in tumor progression and metastasis. Curr Mol Med. 2003;3:631–42. [PubMed]
29. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 2004;430:1034–39. [PubMed]
30. Geiger TR, Peeper DS. The neurotrophic receptor TrkB in anoikis resistance and metastasis: a perspective. Cancer Res. 2005;65:7033–36. [PubMed]
31. Bardelli A, Parsons DW, Silliman N, et al. Mutational analysis of the tyrosine kinome in colorectal cancers. Science. 2003;300:949. [PubMed]
32. Nakamura K, Martin KC, Jackson JK, Beppu K, Woo CW, Thiele CJ. Brain-derived neurotrophic factor activation of TrkB induces vascular endothelial growth factor expression via hypoxia-inducible factor-1alpha in neuroblastoma cells. Cancer Res. 2006;66:4249–55. [PubMed]
33. Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401–10. [PubMed]
34. Folkman J. Angiogenesis. Annu Rev Med. 2006;57:1–18. [PubMed]
35. Leenders WP, Kusters B, de Waal RM. Vessel co-option: how tumors obtain blood supply in the absence of sprouting angiogenesis. Endothelium. 2002;9:83–87. [PubMed]
36. Hendrix MJ, Seftor EA, Kirschmann DA, Quaranta V, Seftor RE. Remodeling of the microenvironment by aggressive melanoma tumor cells. Ann N Y Acad Sci. 2003;995:151–61. [PubMed]
37. Klos KS, Wyszomierski SL, Sun M, et al. ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Res. 2006;66:2028–37. [PubMed]
38. Mizukami Y, Fujiki K, Duerr EM, et al. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem. 2006;281:13957–63. [PubMed]
39. Erler JT, Bennewith KL, Nicolau M, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006;440:1222–26. [PubMed]
40. Schioppa T, Uranchimeg B, Saccani A, et al. Regulation of the chemokine receptor CXCR4 by hypoxia. J Exp Med. 2003;198:1391–402. [PMC free article] [PubMed]
41. Maroni P, Bendinelli P, Matteucci E, Desiderio MA. HGF differs from hypoxia in activating Ets1 for CXCR4 expression and invasiveness of MCF-7 breast cancer cells. Carcinogenesis. 2006;28:267–79. [PubMed]
42. Phillips RJ, Mestas J, Gharaee-Kermani M, et al. Epidermal growth factor and hypoxia-induced expression of CXC chemokine receptor 4 on non-small cell lung cancer cells is regulated by the phosphatidylinositol 3-kinase/PTEN/AKT/mammalian target of rapamycin signaling pathway and activation of hypoxia inducible factor-1alpha. J Biol Chem. 2005;280:22473–81. [PubMed]
43. Dachs GU, Tozer GM. Hypoxia modulated gene expression: angiogenesis, metastasis and therapeutic exploitation. Eur J Cancer. 2000;36:1649–60. [PubMed]
44. Liu L, Simon MC. Regulation of transcription and translation by hypoxia. Cancer Biol Ther. 2004;3:492–97. [PubMed]
45. Murdoch C, Giannoudis A, Lewis CE. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues. Blood. 2004;104:2224–34. [PubMed]
46. Bindra RS, Glazer PM. Genetic instability and the tumor microenvironment: towards the concept of microenvironment-induced mutagenesis. Mutat Res. 2005;569:75–85. [PubMed]
47. Huang LE, Bindra RS, Glazer PM, Harris AL. Hypoxia-induced genetic instability—a calculated mechanism underlying tumor progression. J Mol Med. 2007;85:139–48. [PubMed]
48. Peng XH, Karna P, Cao Z, Jiang BH, Zhou M, Yang L. Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem. 2006;281:25903–14. [PMC free article] [PubMed]
49. Saharinen P, Tammela T, Karkkainen MJ, Alitalo K. Lymphatic vasculature: development, molecular regulation and role in tumor metastasis and inflammation. Trends Immunol. 2004;25:387–95. [PubMed]
50. Witte MH, Jones K, Wilting J, et al. Structure function relationships in the lymphatic system and implications for cancer biology. Cancer Metastasis Rev. 2006;25:159–84. [PubMed]
51. Achen MG, Stacker SA. Tumor lymphangiogenesis and metastatic spread—new players begin to emerge. Int J Cancer. 2006;119:1755–60. [PubMed]
52. Van Trappen PO, Pepper MS. Lymphangiogenesis and lymph node microdissemination. Gynecol Oncol. 2001;82:1–3. [PubMed]
53. Beasley NJ, Prevo R, Banerji S, et al. Intratumoral lymphangiogenesis and lymph node metastasis in head and neck cancer. Cancer Res. 2002;62:1315–20. [PubMed]
54. Dadras SS, Lange-Asschenfeldt B, Velasco P, et al. Tumor lymphangiogenesis predicts melanoma metastasis to sentinel lymph nodes. Mod Pathol. 2005;18:1232–42. [PubMed]
55. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7:192–98. [PubMed]
56. Cao R, Bjorndahl MA, Religa P, et al. PDGF-BB induces intratumoral lymphangiogenesis and promotes lymphatic metastasis. Cancer Cell. 2004;6:333–45. [PubMed]
57. He Y, Rajantie I, Pajusola K, et al. Vascular endothelial cell growth factor receptor 3-mediated activation of lymphatic endothelium is crucial for tumor cell entry and spread via lymphatic vessels. Cancer Res. 2005;65:4739–46. [PubMed]
58. O-charoenrat P, Rhys-Evans P, Eccles SA. Expression of vascular endothelial growth factor family members in head and neck squamous cell carcinoma correlates with lymph node metastasis. Cancer. 2001;92:556–68. [PubMed]
59. Hirakawa S, Kodama S, Kunstfeld R, Kajiya K, Brown LF, Detmar M. VEGF-A induces tumor and sentinel lymph node lymphangiogenesis and promotes lymphatic metastasis. J Exp Med. 2005;201:1089–99. [PMC free article] [PubMed]
60. Tammela T, Petrova TV, Alitalo K. Molecular lymphangiogenesis: new players. Trends Cell Biol. 2005;15:434–41. [PubMed]
61. Zhang L, Giraudo E, Hoffman JA, Hanahan D, Ruoslahti E. Lymphatic zip codes in premalignant lesions and tumors. Cancer Res. 2006;66:5696–706. [PubMed]
62. Cao Y. Opinion: emerging mechanisms of tumour lymphangiogenesis and lymphatic metastasis. Nat Rev Cancer. 2005;5:735–43. [PubMed]
63. Sleeman JP. The lymph node as a bridgehead in the metastatic dissemination of tumors. Recent Results Cancer Res. 2000;157:55–81. [PubMed]
64. Achen MG, Mann GB, Stacker SA. Targeting lymphangiogenesis to prevent tumour metastasis. Br J Cancer. 2006;94:1355–60. [PMC free article] [PubMed]
65. Pantel K, Brakenhoff RH. Dissecting the metastatic cascade. Nat Rev Cancer. 2004;4:448–56. [PubMed]
66. Pantel K, Woelfle U. Detection and molecular characterisation of disseminated tumour cells: implications for anti-cancer therapy. Biochim Biophys Acta. 2005;1756:53–64. [PubMed]
67. Wong SY, Hynes RO. Lymphatic or hematogenous dissemination: how does a metastatic tumor cell decide? Cell Cycle. 2006;5:812–17. [PMC free article] [PubMed]
68. Butler TP, Gullino PM. Quantitation of cell shedding into efferent blood of mammary adenocarcinoma. Cancer Res. 1975;35:512–16. [PubMed]
69. Fidler IJ. Metastasis: guantitative analysis of distribution and fate of tumor embolilabeled with 125 I-5-iodo-2'-deoxyuridine. J Natl Cancer Inst. 1970;45:773–82. [PubMed]
70. Wong CW, Lee A, Shientag L, et al. Apoptosis: an early event in metastatic inefficiency. Cancer Res. 2001;61:333–38. [PubMed]
71. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–72. [PubMed]
72. Kang Y, Siegel PM, Shu W, et al. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell. 2003;3:537–49. [PubMed]
73. Welch DR. Microarrays bring new insights into understanding of breast cancer metastasis to bone. Breast Cancer Res. 2004;6:61–64. [PMC free article] [PubMed]
74. Condeelis J, Singer RH, Segall JE. The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu Rev Cell Dev Biol. 2005;21:695–718. [PubMed]
75. Wang W, Goswami S, Sahai E, Wyckoff JB, Segall JE, Condeelis JS. Tumor cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol. 2005;15:138–45. [PubMed]
76. Tanaka T, Bai Z, Srinoulprasert Y, Yang BG, Hayasaka H, Miyasaka M. Chemokines in tumor progression and metastasis. Cancer Sci. 2005;96:317–22. [PubMed]
77. Dano K, Behrendt N, Hoyer-Hansen G, et al. Plasminogen activation and cancer. Thromb Haemost. 2005;93:676–81. [PubMed]
78. Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006;25:9–34. [PubMed]
79. Duffy MJ. The urokinase plasminogen activator system: role in malignancy. Curr Pharm Des. 2004;10:39–49. [PubMed]
80. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2:161–74. [PubMed]
81. Eccles SA. Parallels in invasion and angiogenesis provide pivotal points for therapeutic intervention. Int J Dev Biol. 2004;48:583–98. [PubMed]
82. Strieter RM, Burdick MD, Mestas J, Gomperts B, Keane MP, Belperio JA. Cancer CXC chemokine networks and tumour angiogenesis. Eur J Cancer. 2006;42:768–78. [PubMed]
83. Friedl P, Wolf K. Tumour-cell invasion and migration: diversity and escape mechanisms. Nat Rev Cancer. 2003;3:362–74. [PubMed]
84. Coussens LM, Fingleton B, Matrisian LM. Matrix metalloproteinase inhibitors and cancer: trials and tribulations. Science. 2002;295:2387–92. [PubMed]
85. Jodele S, Blavier L, Yoon JM, DeClerck YA. Modifying the soil to affect the seed: role of stromal-derived matrix metalloproteinases in cancer progression. Cancer Metastasis Rev. 2006;25:35–43. [PubMed]
86. Christofori G. Changing neighbours, changing behaviour: cell adhesion molecule-mediated signalling during tumour progression. EMBO J. 2003;22:2318–23. [PMC free article] [PubMed]
87. van 't Veer LJ, Dai H, van de Vijver MJ, et al. Gene expression profiling predicts clinical outcome of breast cancer. Nature. 2002;415:530–36. [PubMed]
88. Glinsky GV. Genomic models of metastatic cancer: functional analysis of death-from-cancer signature genes reveals aneuploid, anoikis-resistant, metastasis-enabling phenotype with altered cell cycle control and activated polycomb group (PcG) protein chromatin silencing pathway. Cell Cycle. 2006;5:1208–16. [PubMed]
89. Glinsky GV, Berezovska O, Glinskii AB. Microarray analysis identifies a death-from-cancer signature predicting therapy failure in patients with multiple types of cancer. J Clin Invest. 2005;115:1503–21. [PMC free article] [PubMed]
90. Ramaswamy S, Ross KN, Lander ES, Golub TR. A molecular signature of metastasis in primary solid tumors. Nat Genet. 2003;33:49–54. [PubMed]
91. Sorlie T. Molecular portraits of breast cancer: tumour subtypes as distinct disease entities. Eur J Cancer. 2004;40:2667–75. [PubMed]
92. Weigelt B, Glas AM, Wessels LF, Witteveen AT, Peterse JL, van't Veer LJ. Gene expression profiles of primary breast tumors maintained in distant metastases. Proc Natl Acad Sci USA. 2003;100:15901–05. [PMC free article] [PubMed]
93. Weigelt B, Peterse JL, van 't Veer LJ. Breast cancer metastasis: markers and models. Nat Rev Cancer. 2005;5:591–602. [PubMed]
94. Wang Y, Klijn JG, Zhang Y, et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet. 2005;365:671–79. [PubMed]
95. Perou CM, Sorlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747–52. [PubMed]
96. Smid M, Wang Y, Klijn JG, et al. Genes associated with breast cancer metastatic to bone. J Clin Oncol. 2006;24:2261–67. [PubMed]
97. Woelfle U, Cloos J, Sauter G, et al. Molecular signature associated with bone marrow micrometastasis in human breast cancer. Cancer Res. 2003;63:5679–84. [PubMed]
98. Hoang CD, Guillaume TJ, Engel SC, Tawfic SH, Kratzke RA, Maddaus MA. Analysis of paired primary lung and lymph node tumor cells: a model of metastatic potential by multiple genetic programs. Cancer Detect Prev. 2005;29:509–17. [PubMed]
99. Xi L, Lyons-Weiler J, Coello MC, et al. Prediction of lymph node metastasis by analysis of gene expression profiles in primary lung adenocarcinomas. Clin Cancer Res. 2005;11:4128–35. [PMC free article] [PubMed]
100. Jones J, Otu H, Spentzos D, et al. Gene signatures of progression and metastasis in renal cell cancer. Clin Cancer Res. 2005;11:5730–39. [PubMed]
101. O'Donnell RK, Kupferman M, Wei SJ, et al. Gene expression signature predicts lymphatic metastasis in squamous cell carcinoma of the oral cavity. Oncogene. 2005;24:1244–51. [PubMed]
102. Minn AJ, Kang Y, Serganova I, et al. Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors. J Clin Invest. 2005;115:44–55. [PMC free article] [PubMed]
103. Minn AJ, Gupta GP, Siegel PM, et al. Genes that mediate breast cancer metastasis to lung. Nature. 2005;436:518–24. [PMC free article] [PubMed]
104. Chu JH, Sun ZY, Meng XL, et al. Differential metastasis-associated gene analysis of prostate carcinoma cells derived from primary tumor and spontaneous lymphatic metastasis in nude mice with orthotopic implantation of PC-3M cells. Cancer Lett. 2006;233:79–88. [PubMed]
105. Bandyopadhyay A, Elkahloun A, Baysa SJ, Wang L, Sun LZ. Development and gene expression profiling of a metastatic variant of the human breast cancer MDA-MB-435 cells. Cancer Biol Ther. 2005;4:168–74. [PubMed]
106. Lee H, Lin EC, Liu L, Smith JW. Gene expression profiling of tumor xenografts: In vivo analysis of organ-specific metastasis. Int J Cancer. 2003;107:528–34. [PubMed]
107. Nagaraja GM, Othman M, Fox BP, et al. Gene expression signatures and biomarkers of noninvasive and invasive breast cancer cells: comprehensive profiles by representational difference analysis, microarrays and proteomics. Oncogene. 2006;25:2328–38. [PubMed]
108. Norton L, Massague J. Is cancer a disease of self-seeding? Nat Med. 2006;12:875–78. [PubMed]
109. Schmidt-Kittler O, Ragg T, Daskalakis A, et al. From latent disseminated cells to overt metastasis: genetic analysis of systemic breast cancer progression. Proc Natl Acad Sci USA. 2003;100:7737–42. [PMC free article] [PubMed]
110. Allinen M, Beroukhim R, Cai L, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6:17–32. [PubMed]
111. Kurose K, Hoshaw-Woodard S, Adeyinka A, Lemeshow S, Watson PH, Eng C. Genetic model of multi-step breast carcinogenesis involving the epithelium and stroma: clues to tumour-microenvironment interactions. Hum Mol Genet. 2001;10:1907–13. [PubMed]
112. Kopfstein L, Christofori G. Metastasis: cell-autonomous mechanisms versus contributions by the tumor microenvironment. Cell Mol Life Sci. 2006;63:449–68. [PubMed]
113. Ein-Dor L, Kela I, Getz G, Givol D, Domany E. Outcome signature genes in breast cancer: is there a unique set? Bioinformatics. 2005;21:171–78. [PubMed]
114. Massague J. Sorting out breast cancer gene signatures. N Engl J Med. 2007;356:294–96. [PubMed]
115. Chang HY, Nuyten DS, Sneddon JB, et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc Natl Acad Sci USA. 2005;102:3738–43. [PMC free article] [PubMed]
116. Adler AS, Lin M, Horlings H, Nuyten DS, van de Vijver MJ, Chang HY. Genetic regulators of large-scale transcriptional signatures in cancer. Nat Genet. 2006;38:421–30. [PMC free article] [PubMed]
117. Glinsky GV. Death-from-cancer signatures and stem cell contribution to metastatic cancer. Cell Cycle. 2005;4:1171–75. [PubMed]
118. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–73. [PubMed]
119. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–58. [PubMed]
120. Nicolson GL. Paracrine and autocrine growth mechanisms in tumor metastasis to specific sites with particular emphasis on brain and lung metastasis. Cancer Metastasis Rev. 1993;12:325–43. [PubMed]
121. Dai CY, Haqq CM, Puzas JE. Molecular correlates of site-specific metastasis. Semin Radiat Oncol. 2006;16:102–10. [PubMed]
122. Eccles SA. Targeting key steps in metastatic tumour progression. Curr Opin Genet Dev. 2005;15:77–86. [PubMed]
123. Souglakos J, Vamvakas L, Apostolaki S, et al. Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumor cells and with the HER2/neu status. Breast Cancer Res. 2006;8:R36. [PMC free article] [PubMed]
124. Weil RJ, Palmieri DC, Bronder JL, Stark AM, Steeg PS. Breast cancer metastasis to the central nervous system. Am J Pathol. 2005;167:913–20. [PMC free article] [PubMed]
125. Parker C, Roseman BJ, Bucana CD, Tsan R, Radinsky R. Preferential activation of the epidermal growth factor receptor in human colon carcinoma liver metastases in nude mice. J Histochem Cytochem. 1998;46:595–602. [PubMed]
126. Herynk MH, Stoeltzing O, Reinmuth N, et al. Down-regulation of c-Met inhibits growth in the liver of human colorectal carcinoma cells. Cancer Res. 2003;63:2990–96. [PubMed]
127. Guise TA, Kozlow WM, Heras-Herzig A, Padalecki SS, Yin JJ, Chirgwin JM. Molecular mechanisms of breast cancer metastases to bone. Clin Breast Cancer. 2005;5(suppl 2):S46–53. [PubMed]
128. Knerr K, Ackermann K, Neidhart T, Pyerin W. Bone metastasis: osteoblasts affect growth and adhesion regulons in prostate tumor cells and provoke osteomimicry. Int J Cancer. 2004;111:152–59. [PubMed]
129. Raubenheimer EJ, Noffke CE. Pathogenesis of bone metastasis: a review. J Oral Pathol Med. 2006;35:129–35. [PubMed]
130. Bidus MA, Risinger JI, Chandramouli GV, et al. Prediction of lymph node metastasis in patients with endometrioid endometrial cancer using expression microarray. Clin Cancer Res. 2006;12:83–88. [PubMed]
131. Xi L, Coello MC, Litle VR, et al. A combination of molecular markers accurately detects lymph node metastasis in non-small cell lung cancer patients. Clin Cancer Res. 2006;12:2484–91. [PMC free article] [PubMed]
132. Weigelt B, Wessels LF, Bosma AJ, et al. No common denominator for breast cancer lymph node metastasis. Br J Cancer. 2005;93:924–32. [PMC free article] [PubMed]
133. Rinker-Schaeffer CW, O'Keefe JP, Welch DR, Theodorescu D. Metastasis suppressor proteins: discovery, molecular mechanisms, and clinical application. Clin Cancer Res. 2006;12:3882–89. [PMC free article] [PubMed]
134. Berger JC, Vander Griend DJ, Robinson VL, Hickson JA, Rinker-Schaeffer CW. Metastasis suppressor genes: from gene identification to protein function and regulation. Cancer Biol Ther. 2005;4:805–12. [PubMed]
135. Nash KT, Welch DR. The KISS1 metastasis suppressor: mechanistic insights and clinical utility. Front Biosci. 2006;11:647–59. [PMC free article] [PubMed]
136. Shevde LA, Welch DR. Metastasis suppressor pathways—an evolving paradigm. Cancer Lett. 2003;198:1–20. [PubMed]
137. Steeg PS, Ouatas T, Halverson D, Palmieri D, Salerno M. Metastasis suppressor genes: basic biology and potential clinical use. Clin Breast Cancer. 2003;4:51–62. [PubMed]
138. Kauffman EC, Robinson VL, Stadler WM, Sokoloff MH, Rinker-Schaeffer CW. Metastasis suppression: the evolving role of metastasis suppressor genes for regulating cancer cell growth at the secondary site. J Urol. 2003;169:1122–33. [PubMed]
139. Steeg PS. Metastasis suppressors alter the signal transduction of cancer cells. Nat Rev Cancer. 2003;3:55–63. [PubMed]
140. Bandyopadhyay S, Zhan R, Chaudhuri A, et al. Interaction of KAI1 on tumor cells with DARC on vascular endothelium leads to metastasis suppression. Nat Med. 2006;12:933–38. [PubMed]
141. Nash K, Phadke P, Navenot J-M, et al. Requirement of KISS1 secretion for multiple organ metastasis suppression and maintenance of tumor dormancy. J Natl Cancer Inst. 2007;99:309–21. [PMC free article] [PubMed]
142. Bandyopadhyay S, Pai SK, Hirota S, et al. Role of the putative tumor metastasis suppressor gene Drg-1 in breast cancer progression. Oncogene. 2004;23:5675–81. [PubMed]
143. Comoglio PM, Trusolino L. Cancer: the matrix is now in control. Nat Med. 2005;11:1156–59. [PubMed]
144. Mueller MM, Fusenig NE. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004;4:839–49. [PubMed]
145. Bissell MJ, Kenny PA, Radisky DC. Microenvironmental regulators of tissue structure and function also regulate tumor induction and progression: the role of extracellular matrix and its degrading enzymes. Cold Spring Harb Symp Quant Biol. 2005;70:343–56. [PMC free article] [PubMed]
146. Eckhardt BL, Parker BS, van Laar RK, et al. Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix. Mol Cancer Res. 2005;3:1–13. [PubMed]
147. Tenta R, Sotiriou E, Pitulis N, Thyphronitis G, Koutsilieris M. Prostate cancer cell survival pathways activated by bone metastasis microenvironment. J Musculoskelet Neuronal Interact. 2005;5:135–44. [PubMed]
148. Hill R, Song Y, Cardiff RD, Van Dyke T. Selective evolution of stromal mesenchyme with p53 loss in response to epithelial tumorigenesis. Cell. 2005;123:1001–11. [PubMed]
149. Topczewska JM, Postovit LM, Margaryan NV, et al. Embryonic and tumorigenic pathways converge via Nodal signaling: role in melanoma aggressiveness. Nat Med. 2006;12:925–32. [PubMed]
150. Hunter K. Host genetics influence tumour metastasis. Nat Rev Cancer. 2006;6:141–46. [PubMed]
151. Park YG, Zhao X, Lesueur F, et al. Sipa1 is a candidate for underlying the metastasis efficiency modifier locus Mtes1. Nat Genet. 2005;37:1055–62. [PMC free article] [PubMed]
152. Yang H, Yu LR, Yi M, et al. Parallel analysis of transcript and translation profiles: identification of metastasis-related signal pathways differentially regulated by drug and genetic modifications. J Proteome Res. 2006;5:1555–67. [PMC free article] [PubMed]
153. Michaelson JS, Cheongsiatmoy JA, Dewey F, et al. Spread of human cancer cells occurs with probabilities indicative of a nongenetic mechanism. Br J Cancer. 2005;93:1244–49. [PMC free article] [PubMed]
154. Shinozaki M, Hoon DS, Giuliano AE, et al. Distinct hypermethylation profile of primary breast cancer is associated with sentinel lymph node metastasis. Clin Cancer Res. 2005;11:2156–62. [PubMed]
155. Chen Y, Rittling SR. Novel murine mammary epithelial cell lines that form osteolytic bone metastases: effect of strain background on tumor homing. Clin Exp Metastasis. 2003;20:111–20. [PubMed]
156. Fehm T, Braun S, Muller V, et al. A concept for the standardized detection of disseminated tumor cells in bone marrow from patients with primary breast cancer and its clinical implementation. Cancer. 2006;107:885–92. [PubMed]
157. Gospodarowicz MK, Miller D, Groome PA, Greene FL, Logan PA, Sobin LH. The process for continuous improvement of the TNM classification. Cancer. 2004;100:1–5. [PubMed]
158. Sobin LH. TNM, sixth edition: new developments in general concepts and rules. Semin Surg Oncol. 2003;21:19–22. [PubMed]
159. Ewing J. Neoplastic disease. WB Saunders; Philadelphia: 1919.
160. Naumov GN, Bender E, Zurakowski D, et al. A model of human tumor dormancy: an angiogenic switch from the nonangiogenic phenotype. J Natl Cancer Inst. 2006;98:316–25. [PubMed]
161. Hedley BD, Allan AL, Chambers AF. Tumor dormancy and the role of metastasis suppressor genes in regulating ectopic growth. Future Oncol. 2006;2:627–41. [PubMed]
162. Quesnel B. Cancer vaccines and tumor dormancy: a long-term struggle between host antitumor immunity and persistent cancer cells? Expert Rev Vaccines. 2006;5:773–81. [PubMed]
163. Aguirre-Ghiso JA. The problem of cancer dormancy: understanding the basic mechanisms and identifying therapeutic opportunities. Cell Cycle. 2006;5:1740–43. [PMC free article] [PubMed]
164. Sledge GW., Jr Circulating tumor cells in breast cancer: blood will tell. Clin Cancer Res. 2006;12:6321–22. [PubMed]
165. Wulfing P, Borchard J, Buerger H, et al. HER2-positive circulating tumor cells indicate poor clinical outcome in stage I to III breast cancer patients. Clin Cancer Res. 2006;12:1715–20. [PubMed]
166. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353:1673–84. [PubMed]
167. Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369:29–36. [PubMed]
168. Palmieri D, Halverson DO, Ouatas T, et al. Medroxyprogesterone acetate elevation of Nm23-H1 metastasis suppressor expression in hormone receptor-negative breast cancer. J Natl Cancer Inst. 2005;97:632–42. [PubMed]
169. Bild AH, Potti A, Nevins JR. Linking oncogenic pathways with therapeutic opportunities. Nat Rev Cancer. 2006;6:735–41. [PubMed]
170. Klein S, McCormick F, Levitzki A. Killing time for cancer cells. Nat Rev Cancer. 2005;5:573–80. [PubMed]
171. Sawyers CL. Making progress through molecular attacks on cancer. Cold Spring Harb Symp Quant Biol. 2005;70:479–82. [PubMed]
172. Workman P. New cancer drugs on the horizon. Future Oncol. 2005;1:315–18. [PubMed]
173. Panares RL, Garcia AA. Bevacizumab in the management of solid tumors. Expert Rev Anticancer Ther. 2007;7:433–45. [PubMed]
174. Kramer I, Lipp HP. Bevacizumab, a humanized anti-angiogenic monoclonal antibody for the treatment of colorectal cancer. J Clin Pharm Ther. 2007;32:1–14. [PubMed]
175. Wu M, Sun Q, Yang C, et al. Synthesis and activity of combretastatin A-4 analogues: 1,2,3-thiadiazoles as potent antitumor agents. Bioorg Med Chem Lett. 2007;17:869–73. [PubMed]
176. Salmon BA, Siemann DW. Characterizing the tumor response to treatment with combretastatin a4 phosphate. Int J Radiat Oncol Biol Phys. 2007;68:211–17. [PMC free article] [PubMed]
177. Moreira IS, Fernandes PA, Ramos MJ. Vascular endothelial growth factor (VEGF) inhibition—a critical review. Anticancer Agents Med Chem. 2007;7:223–45. [PubMed]
178. Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS. Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res. 2007;67:3560–64. [PubMed]
179. Liu T, Kuljaca S, Tee A, Marshall GM. Histone deacetylase inhibitors: multifunctional anticancer agents. Cancer Treat Rev. 2006;32:157–65. [PubMed]
180. Yoo CB, Jones PA. Epigenetic therapy of cancer: past, present and future. Nat Rev Drug Discov. 2006;5:37–50. [PubMed]
181. Hess-Stumpp H, Bracker TU, Henderson D, Politz O. MS-275, a potent orally available inhibitor of histone deacetylases—the development of an anticancer agent. Int J Biochem Cell Biol. published online [Au: date?] doi:10.1016/j.biocel.2007.02.009. [PubMed]
182. Marchion D, Munster P. Development of histone deacetylase inhibitors for cancer treatment. Expert Rev Anticancer Ther. 2007;7:583–98. [PubMed]
183. Spannhoff A, Heinke R, Bauer I, et al. Target-based approach to inhibitors of histone arginine methyltransferases. J Med Chem. 2007 published online [Au: date?] doi:10.1021/jm061250e. [PubMed]
184. Carducci MA, Jimeno A. Targeting bone metastasis in prostate cancer with endothelin receptor antagonists. Clin Cancer Res. 2006;12:6296s–300s. [PubMed]
185. Abrahamsen B, Teng AY. Technology evaluation: denosumab, Amgen. Curr Opin Mol Ther. 2005;7:604–10. [PubMed]
186. Thiele W, Sleeman JP. Tumor-induced lymphangiogenesis: a target for cancer therapy? J Biotechnol. 2006;124:224–41. [PubMed]
187. Elvin P, Garner AP. Tumour invasion and metastasis: challenges facing drug discovery. Curr Opin Pharmacol. 2005;5:374–81. [PubMed]
188. Millar AW, Lynch KP. Rethinking clinical trials for cytostatic drugs. Nat Rev Cancer. 2003;3:540–45. [PubMed]
189. Rothenberg ML, Carbone DP, Johnson DH. Improving the evaluation of new cancer treatments: challenges and opportunities. Nat Rev Cancer. 2003;3:303–09. [PubMed]
190. Overall CM, Kleifeld O. Towards third generation matrix metalloproteinase inhibitors for cancer therapy. Br J Cancer. 2006;94:941–46. [PMC free article] [PubMed]
191. Cohnheim J. Congenitales, quergestreiftes Muskelsarkon der Nireren. Virchows Arch. 1875;65:64.
192. Pierce GB. Teratocarcinoma: model for a developmental concept of cancer. Curr Top Dev Biol. 1967;2:223–46. [PubMed]
193. Buick RN, Pollak MN. Perspectives on clonogenic tumor cells, stem cells, and oncogenes. Cancer Res. 1984;44:4909–18. [PubMed]
194. Behbod F, Rosen JM. Will cancer stem cells provide new therapeutic targets? Carcinogenesis. 2005;26:703–11. [PubMed]
195. Blagosklonny MV. Target for cancer therapy: proliferating cells or stem cells. Leukemia. 2006;20:385–91. [PubMed]
196. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res. 2006;66:1883–90. [PubMed]
197. Shackleton M, Vaillant F, Simpson KJ, et al. Generation of a functional mammary gland from a single stem cell. Nature. 2006;439:84–88. [PubMed]
198. Stingl J, Eirew P, Ricketson I, et al. Purification and unique properties of mammary epithelial stem cells. Nature. 2006;439:993–97. [PubMed]
199. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–88. [PMC free article] [PubMed]
200. Hirschmann-Jax C, Foster AE, Wulf GG, et al. A distinct “side population” of cells with high drug efflux capacity in human tumor cells. Proc Natl Acad Sci USA. 2004;101:14228–33. [PMC free article] [PubMed]
201. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer. 2005;5:275–84. [PubMed]
202. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat Rev Cancer. 2005;5:744–49. [PubMed]
203. Athale C, Mansury Y, Deisboeck TS. Simulating the impact of a molecular ‘decision-process’ on cellular phenotype and multicellular patterns in brain tumors. J Theor Biol. 2005;233:469–81. [PubMed]
204. Polyak K, Hahn WC. Roots and stems: stem cells in cancer. Nat Med. 2006;12:296–300. [PubMed]
205. Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature. 2006;442:823–26. [PubMed]
206. Leong KG, Karsan A. Recent insights into the role of Notch signaling in tumorigenesis. Blood. 2006;107:2223–33. [PubMed]
207. Rehman AO, Wang CY. Notch signaling in the regulation of tumor angiogenesis. Trends Cell Biol. 2006;16:293–300. [PubMed]
208. Zayzafoon M, Abdulkadir SA, McDonald JM. Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. J Biol Chem. 2004;279:3662–70. [PubMed]
209. Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res. 2006;66:6063–71. [PubMed]
210. Puisieux A, Valsesia-Wittmann S, Ansieau S. A twist for survival and cancer progression. Br J Cancer. 2006;94:13–17. [PMC free article] [PubMed]
211. Zhou BP, Hung MC. Wnt, hedgehog and snail: sister pathways that control by GSK-3beta and beta-Trcp in the regulation of metastasis. Cell Cycle. 2005;4:772–76. [PubMed]
212. Krivtsov AV, Twomey D, Feng Z, et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature. 2006;442:818–22. [PubMed]
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