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The Hematopoietic Stem Cell Niche and Bone Metastasis

, , , and .

Author Information

,1 ,1 ,°,2 and °,*,1.

1 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, Michigan, USA;
2 Departments of Urology and Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan, USA
° These authors contributed equally to the work
* Corresponding Author: Russell S. Taichman—Email: ude.hcimu@hciatr

Metastatic Cancer: Clinical and Biological Perspectives edited by Rahul Jandial.
©2013 Landes Bioscience.
Read this chapter in the Madame Curie Bioscience Database here.

Bone is the preferred target of neoplasms such as prostate, breast, lung and melanoma cancers. Disseminated tumor cells (DTCs) from these cancers take advantage of the protective bone marrow niche normally occupied by hematopoietic stem cells (HSCs) and home to this space in a multistep process involving a variety of chemokines, adhesion molecules and physical factors. Once in the marrow, DTCs compete with and evict HSCs from the niche in order to take advantage of the dormancy-inducing properties found in the niche. DTCs undergo G0 growth arrest and acquire cell adhesion-mediated drug resistance against chemotherapeutics targeting rapidly-dividing cells. Understanding the interactions that facilitate homing and allow cancer to survive in patients who show no clinical signs of disease will allow for the targeted design of new therapeutic drugs.

Introduction

Despite improvements in local treatments including surgery, chemotherapy and radiation, bone metastases claim the lives of 350,000 people in the United States each year. This number likely doubles or triples if the European Union and Japan are also included.1 Bone metastasis occurs in 70% of breast, melanoma, lung and prostate cancer and 15-30% of colon, stomach, bladder, uterus, rectum, thyroid and kidney carcinomas.2 Early detection and treatment strategies have greatly increased cancer survival rates. However, once tumors have metastasized to the bone they are generally incurable.3 In addition, patients with bone metastases experience reduced quality of life due to severe bone pain believed to be associated with the osteolytic process, pathological bone fractures and deformities, spinal cord and nerve-compression syndromes.4,5 Osteoblast and osteoclast recruitment is associated with tumor invasion into the bone and results in the release of growth factors from the bone matrix that can propagate more bone metastases.1,4-7

The bone marrow can serve as a protective holding-space for dormant tumor cells to resist chemotherapy treatment, an observation known as minimal residual disease (MRD).8 These disseminated tumor cells (DTCs) which home to the bone marrow in a multi-step process, can emerge at a later time once the patient has ceased treatment and is believed to be disease-free. It is at this point that new metastases in bone and other organs can develop.9-12 Since MRD can cause a patient to relapse, homing of DTCs to the marrow is a sign of an unfavorable prognosis.

Certain cancer cells migrate to the bone marrow using mechanisms similar to those used by hematopoietic stem cells (HSC).13-18 When prostate cancer (PCa) cells home to the bone marrow niche they compete with HSC to occupy the resident HSC niche.19 As a result of this competition, DTCs can actually evict HSCs into the peripheral blood or drive them into progenitor pools.19 Bone resorption is also a contributing factor in HSC mobilization and homing. The role of various chemokines, adhesion molecules and physical factors involved in the homing and mobilization processes will be discussed, and the concept of a "niche" will be further illustrated. This chapter will conclude with a discussion of how understanding the role of the bone marrow HSC niche in metastasis formation can lead to improved drug design targeting metastatic cancer to potentially increase patient survival.

Metastatic Tumor Cells in the Bone Marrow Environment/ Disseminated Tumor Cells

Mr. W. is a 66 year-old man. At a routine physical 6 year ago he was diagnosed with clinical stage T1cNxMx, localized prostate cancer (PCa) and found to have elevated prostate cancer antigen (PCA) in his blood. A diagnostic ultrasound of the prostate and biopsy classified the lesion as a Gleason 7 cancer and Mr. W chose to have his prostate removed by radical retropubic prostatectomy. All of his lymph nodes were negative for cancer and he was considered cured of his disease. A year ago Mr. W's PSA became detectable and 3 lesions can be seen on a bone scan. His doctors have now diagnosed him with incurable metastatic prostate cancer.

Some patients like Mr. W develop bone metastases several years after the resection of a primary tumor. This phenomenon has been attributed to the presence of disseminated tumor cells (DTCs) which leave the initial lesion and home to the bone marrow. Once in the marrow, DTCs enter a dormant phase to avoid recognition as an invader in the foreign microenvironment and resulting apoptosis by the immune system.12 The ability to engage in a state of G0 growth arrest is a characteristic of stem cells known as quiescence. Quiescence is critical for protecting stem cells so they can retain their long-term self-renewal capacity. Most HSCs are in a quiescent G0 state within marrow, cycling approximately every 57 days.20 Similarly, disseminated tumor cells that invade the bone marrow may exhibit G0 growth arrest, termed "cellular dormancy"21. As a result, metastatic tumor cells may acquire cell adhesion-mediated drug resistance, or de novo drug resistance. Since the majority of standard chemotheraputics target rapidly dividing cells, cells that are in a state of growth arrest are immune.22,23Additionally, most DTC that arrive at a distant site undergo apoptosis, but cellular dormancy appears to be a way for tumor cells to evade apoptosis and survive until they can adequately survive in their new environment.24

The state in which small numbers of neoplastic cells remain in the patient during treatment or after the patient no longer shows overt signs or symptoms of disease following treatment is called minimal residual disease (MRD). The presence of DTCs in patients' bone marrow has been shown to be an independent predictor of recurrence in 70% of 569 men undergoing radical prostatectomy8 and been correlated with poorer prognosis in a 10 year follow up study of women with primary breast cancer lacking signs of bone metastases as compared with women without DTCs.25 Furthermore, DTCs were present in 30% of these women at the time of diagnosis, suggesting that, in addition to its predictive value in poorer prognosis, homing takes place early in the disease process. Circulating tumor cells (CTCs) can be detected in the peripheral blood where they travel through the circulation and are known to seed to various tissues in the body. Presence of these presumably shorter-lived CTC also has been shown to predict tumor relapse.26,27 How these cells traffic to the bone, become dormant, and ultimately begin to proliferate is the subject of intense study. As more is learned about behavior of both DTCs and CTCs, drug development may be possible to prevent homing to the bone.

The Concept of a Niche

In 1889, Stephen Paget proposed his "seed and soil" hypothesis stating that metastasis depends on cross-talk between selected cancer cells (the seeds) and specific organ microenvironments (the soil). In this case the "microenvironment" referred to is a specific set of physical, chemical and biological conditions in the locality that can be sensed by or have an effect on the cells. Paget developed his hypothesis after analyzing autopsy samples from 735 women who had died of breast cancer and finding that the cancer had preferentially metastasized to bone in many of these patients.28 It was not until 1978 that Richard Schofield published his concept of a stem cell "niche" in which a stem cell is kept in an undifferentiated and immature state as a result of its interactions with parenchymal cells which determine its behavior and assure its continued proliferation as a stem cell.29 The stem cell niche is regulated by several elements: the structural elements of the architectural space, the physical attachment of the stem cell membrane to neighboring cells and surfaces, paracrine and endocrine signals, neural input and metabolic products of tissue activity.30 It is in the bone marrow niche that HSCs are maintained as unipotent while supporting the expansion of blood cell populations. Since the niche regulates the stem-ness of HSCs, we have hypothesized that it can be parasitized by opportunistic neoplasms or solid tumors seeking to tap into the resources and protection from chemotherapeutics, provided by the niche.31 The stem cell niche and the effect of the microenvironment on tumor cell behavior continue to be active areas of research today.15,32,33

Pre-Metastatic Niche

Recent work has highlighted the concept of a pre-metastatic niche. A pre-metastatic niche may be formed by conditioning the bone to facilitate invasion and implantation of tumor cells via endocrine-like actions. Primary tumors produce circulating factors that target cells in the bone marrow microenvironment to allow colonization of this area. Examples of such factors that cause bone resorption include heparanase in breast cancer34 and parathyroid hormone-related hormone (PTHRP).6,35 Osteopontin (OPN) can promote bone marrow cell recruitment and tumor formation,36 while matrix metalloproteinase (MMP) production by osteoclasts promotes skeletal metastasis.37 Throughout this chapter, the "microenvironment" can be defined as a specific set of physical, chemical and biological conditions in the vicinity of the cells which can be sensed and have an effect on the cells. It has recently been shown that bone marrow-derived hematopoietic progenitor cells (HPCs) expressing vascular endothelial growth factor receptor 1 (VEGFr1) serve as the basis for establishing a pre-metastatic niche in peripheral tissues including the lung and liver for the development of metastases.37 As the complicated mechanisms of tumor dissemination are studied further, more light will be shed on the concept of a pre-metastatic niche.

Homing

EMT and Spread of the Primary Tumor

Homing of cancer cells to the bone marrow involves many steps. Tumors of epithelial origin typically have strong attachments to the basement membrane, which must be broken in order for metastasis to take place. Through an epithelial to mesenchymal transition (EMT) process also used by embryonic cells undergoing mesoderm and neutral tube formation,38-40 cancer cells adopt a mesenchymal phenotype induced largely by factors in the tumor stroma including transforming growth factor-β (TGF-β), platelet derived growth factor (PDGF), epidermal growth factor (EGF) and hepatocyte growth factor (HGF). This transformation allows cancer cells to be migratory, invasive, and increasingly resistant to apoptosis and gain the ability to degrade the extra cellular matrix (ECM). In addition to the aforementioned factors released by fibroblasts, immune cells, the basement membrane and capillaries of the tumor stroma, regions of hypoxia and acidity in the microenvironment surrounding solid tumors stabilize hypoxia-inducible factor-1 (HIF1-α) which promotes EMT and subsequent mobilization by upregulating specific genes.41,42

Cancer cells also release various ECM-degrading enzymes that allow them to leave the primary tumor site. These include the large family of zinc containing matrix metalloproteinases (MMPs),43 lysosomal derived cathepsins,44 urokinase type plasminogen activator (uPA),45,46 and CD26/ dipeptidylpeptidase IV (DPPIV).47

Chemotaxis toward Bone: Role of Cytokines

Chemokines are a subset of signaling molecules that act by binding to G-protein coupled receptors. They play an important role in organ-specific metastasis including directing cancer cells toward bone and lymph nodes. Chemokines are also involved in the directing of various hematopoietic cells to the bone and the homing processes. One of the most studied chemokines secreted by bone marrow stromal cells and many epithelial cells is stromal cell-derived factor-1 (SDF-1) (also known as CXCL12).48 Osteoblasts in the endosteal regions of the bone marrow produce SDF-1, which signals by binding to CXCR4, a 7-transmembrane G protein coupled receptor found on a variety of hematopoietic, endothelial, stromal and neuronal cells.49,50 The SDF-1/CXCR4 signaling pathway directs migration of both bone marrow cells and various cancer cell types including prostate cancer (PCa) cell lines PC3, DU145, C42B, LNCAP, and acute myeloid leukemia (AML) to the bone.51,52 Additionally, SDF-1 plays a role in allowing PCa cells to invade through the basement membrane. In fact, highly metastatic cancer lesions produce elevated levels of CXCR4 which interacts with the higher levels of SDF-1 in tissues harboring the lesions.53,54 The overexpression of CXCR4 along with other bone metastasis signature genes such as IL11, connective tissue growth factor (CTGF) and MMP1 in breast cancer cell lines increased their capacity to metastasize to bone.51,55 Substantial research has also demonstrated a direct role for CXCR4-SDF-1 in breast and prostate cancer cell proliferation,54-59 suggesting that this pathway might actually be required for tumor colonization in bone.

SDF-1 has another chemokine receptor described as CXCR7 which regulates the invasiveness of tumor cells and its expression increases as cells become more aggressive. CXCR7 helps PCa cells adhere to and invade tissues and promotes angiogenesis.59 CXCL16 chemokine and its receptor CXCR6 have a similar role in promoting prostate cancer cell migration and invasion but whose function has yet to be proven in animals.60

Chemotaxis toward Bone: Role of Cell to Cell Adhesion Molecules

Adhesive molecules play a significant role in the attraction of cancer cells and HSCs to the bone marrow and their retention once they arrive. A few of the major players will be discussed here. Annexin2 (Anxa2) is a protein expressed on the peripheral membrane of bone marrow endothelial cells and osteoblasts61 and acts as an adhesion ligand for HSC homing to the bone marrow.62 Again sharing similarities with HSCs, certain invasive cancers express Anxa2 receptor (Anxa2-R) to localize to and proliferate in the marrow. Anxa2 supports prostate cancer survival in the marrow space through the mitogen-activated protein kinase (MAPK) pathway.63

Growth arrest-specific 6 (GAS-6) is a ligand secreted by osteoblasts in the bone marrow that interacts with the receptor Mer on acute lymphoblastic leukemia (ALL) cells. GAS-6/Mer allows ALL cells to associate closely with osteoblasts and enter a dormant state which prevents their apoptosis during chemotherapy targeting rapidly dividing cells.63 Axl is another tyrosine kinase receptor for GAS-6 which helps prostate cancer cells invade bone, proliferate and survive in the niche.64

Other cell-surface proteins involved in adhesion are integrins, cadherins, and receptor activator of nuclear factor kappa-B ligand (RANKL), the latter which will be discussed in more detail later. Vascular Cell Adhesion Molecule 1 (VCAM-1), an endothelial ligand for tumor cell surface integrin VLA-4 (Very Late Antigen-4 or α4β1) interacts with the ECM proteins in the bone microenvironment and has been associated with metastasis, osteolysis and bone colonization in breast and prostate cancers.65 Bone morphogenic proteins (BMPs), Notch transmembrane protein, nestin intermediate filament protein, and the extracellular matrix protein osteopontin (OPN) (also known as bone sialoprotein 1 (BSP-1) also play significant roles.66-74

Chemotaxis toward Bone: Role of Physical Factors

Physical factors of the bone such as its normally hypoxic state, low pH and high concentration of calcium play a role in the homing of cancer cells to the bone marrow. In addition to promoting EMT, the reduced oxygen concentration within bone supports tumorigenesis and increases the production of HIF1-α, promoting skeletal metastases.7,75 Acidosis results in the destruction of normal tissues while allowing tumor cells to proliferate and spread. A low pH promotes osteoclastic activity which breaks down bone and causes the release of proteolytic enzymes to degrade ECM, while inhibiting osteoblast activity.76 Hypoxia increases lactic acid production through HIF1-α, which also induces the expression of glycolytic enzymes. Tumor cells have developed resistance mechanisms to thrive in this harsh acidic environment, while normal cells are at risk for apoptosis.

Increased osteoclast activity results in elevated levels of calcium, the major inorganic component in bone.77 This increase is sensed by a G-protein coupled receptor, the extracellular calcium receptor (CaSR), which may promote metastasis to bone by regulating the secretion of parathyroid hormone-related protein (PTHrP).78 PTHrP functions to regulate the development of endochondral bones by maintaining the growth plate at a constant width in health. But it is also secreted by certain types of cancers including breast, PCa and lung where it can cause hypercalcemia by inducing bone resorption through the production of local factors such as CCL2.6,79 As further evidence of its role in predicting metastasis, CaSR have been found to be elevated in breast and PCa while its knockdown was associated with decreased PCa proliferation in vitro and an absence of bone metastases in mice.80-82

The Process of Bone Colonization

Certain cancers such as breast, prostate, lung and thyroid carcinomas have an especially high tendency of migrating to the bone and consequently prefer to adhere to bone marrow endothelial cells rather than to endothelial cells that are derived from other organs.83 Such adherent cancer cells may extravasate through the bone marrow endothelium to take up residence within the cortical bone. In order to expand in the bone and establish micrometastases, bone-residing tumors such as myeloma must neovascularize and recruit endothelial cells to aid in this process.73

The types of cancer that are commonly associated with profound osteolysis include breast, lung and renal cancer, as well as multiple myeloma and adult T cell leukemia. Clinical and experimental evidence indicates that bone resorption is also increased in osteoblastic metastases. Indeed, concentration of the bone resorption marker, N-telopeptide (NTX), is high in patients with PCa with osteoblastic disease and is a strong predictor of morbidity and mortality. Tumor-derived PTHrP was one of the first characterized mediators of local bone destruction to be associated with bone metastases.7

Disseminated Tumor Cells (DTCs) Compete with Hematopoietic Stem Cells (HSCs) for the Bone Marrow Niche

Many similarities exist between DTCs and HSCs, which home to the bone marrow using the same physiological mechanisms. DTCs from metastatic PCa and possibly other types of cancers compete directly for occupancy of the HSC niche in the bone marrow. After entering the niche, DTCs are likely to evict HSCs into the peripheral blood or drive them into progenitor pools.19 A mechanism PCa cells may use in the competition for the HSC niche is to directly and indirectly drive HSC maturity so they vacate the niche. Research investigating this possibility has shown that HSCs isolated from animals with DTCs in the marrow expressed lower levels of the adhesion molecules Notch-185 and Tie-286 involved in maintenance of the HSC foothold in the niche. These HSCs also expressed lower levels of transcription factors Bmi-1 and INK4a, responsible for regulating HSC self-renewal and proliferation.87,88 Fewer HSCs are found in mice with tumors in the bone as DTCs alter HSC ability to self-renew and speed up their cell cycle rate so they emerge from dormancy and exit the niche. Although DTCs have a direct effect on the cell cycle of HSCs, they do not promote their apoptosis. As a result of the competition with DTCs, more hematopoietic progenitor cells (HPCs) are found circulating in the peripheral blood of patients with metastatic PCa than either patients with localized PCa (no evidence of bone invasion) or healthy age-matched controls.19 Under normal physiologic conditions, HSCs are believed to reside mainly within the bone marrow HSC niche, while some HSCs are known to leave the marrow, differentiate into HPCs, and circulate throughout the body.19 However, the question as to whether HPCs mobilized by DTCs are functionally the same as normal HPCs remains unanswered.

Bone Resorption Contributes to HSC Mobilization and Homing

Bone remodeling is a tightly regulated process necessary for bone maintenance and health. This process is dependent largely upon HSC-derived osteoclasts responding to RANKL from osteoblasts to proliferate, differentiate and regulate bone-resorbing activity. This communication takes place on the bone surface and endosteum, in close proximity to the HSC and progenitor cell niche. In fact, osteoblasts lining the endosteum physically HSC and provide signals that maintain their undifferentiated state and continued self-renewal.89,90

Due to their nearby location to the stem cell niche, osteoclasts are involved in the stress-induced mobilization of progenitor cells. Stress signals cause the release of signaling molecules in the endosteum region, causing osteoclast precursors to differentiate into active cells. Osteoclasts proliferate and increase in number to take the place of osteoblasts on the endosteal lining, where they secrete various enzymes that result in the cleavage of SDF-1, osteopontin (OPN) and SCF on the osteoblast cell surface, weakening the extracellular matrix and stem cell anchorage. Inflammation, injury, chemotherapy, or other stress situations such as treatment with granulocyte colony-stimulating factor (G-CSF) swing the equilibrium in favor of stem cell mobilization into the blood. In addition to osteoblasts, several immune cells present in inflammation, including B- and T-lymphocytes can prompt pre-osteoclasts to differentiate into active, bone-resorbing osteoclast using RANKL. Although both RANKL and G-CSF promote progenitor mobilization, RANKL is a much more selective and effective mobilizer, while treatment of G-CSF in mice also results in massive proliferation, differentiation and mobilization of maturing bone marrow neutrophils out of the bone marrow. RANKL reduces the expression of major components of the endosteal stem cell niche involved in anchorage, survival and quiescence. Conversely, inhibiting osteoclasts reduces the number of circulating progenitor cells.91

Therapeutic Strategies

Research on in vivo models has shed light on potential strategies for eradicating cancers that metastasize to bone. Cancer cells target the bone marrow microenvironment for HSCs, or the HSC niche, during metastasis.19 Recent studies have focused on illustrating the interaction between tumor cells and their microenvironment in hopes of eliminating tumor cells by manipulating their interactions with non-tumor host cells. New approaches to treat PCa target mobilizing cells from the bone marrow. Some of these promising treatments are as follows. There is a positive correlation between tissues containing metastatic cancer lesions and the levels of SDF-1 expressed. Blocking the CXCR4 axis with targeting antibodies in mice reduced the skeletal metastases of PCa.51 Likewise, blocking CXCR4 and CXCR7 reduced breast cancer metastases in vivo.92 Since SDF-1/CXCR4 is required for cell chemotaxis to bone marrow stromal cells, treatment of mice with small peptide antagonists has been shown to effectively block migration.93 G-CSF and AMD3100 are two small molecule inhibitors of CXCR4 and successfully mobilized HSCs in animal models. AMD3100 was also successful in regulating the cell cycle to mobilize myeloma95 and acute promyelocytic leukemia (APL)96 into the circulation. Once mobilized, tumor cells have shown sensitivity to chemotherapeutic drugs.98

Currently there are only a few drugs that prevent the establishment of cancer in the bone in humans. The standard of care for patients with skeletal metastases involves treatment with bisphosphonates or receptor activator of NF-κB ligand (RANKL; also known as TNFSF11) antibodies that target osteoclastogenesis.90,97-99 Bisphosphonates are synthetic analogs of pyrophosphate which can reduce osteolytic bone resorption. There is emerging data that these anti-resorptive agents can also have direct antitumor effects and reduce bone pain.99 Denosumab, a monoclonal antibody that binds RANKL to inhibit osteoclasts was successful in preventing bone resorption in prostate and breast cancers in phase II clinical trials.99 Although 30-50% of patients on current therapies still develop new bone metastases and skeletal complications,4 the good news is that several new and promising drugs are being tested in preclinical models and clinical trials. As of now, early detection with routine physical exams continues to be the best way to beat cancer (Fig. 1).

Figure 1.. A conceptual scheme of a niche target therapy for bone metastatic disease.

Figure 1.

A conceptual scheme of a niche target therapy for bone metastatic disease.

DTCs target the osteoblastic hematopoietic stem cell (HSC) niche and are believed to compete for residency in the niche with HSCs. Both DTCs and HSCs are believed to use the CXCL12/CXCR4 axis to gain access to osteoblasts. Once bound to the niche, HSCs and DTCs undergo growth arrest, also known as quiescence or dormancy, which allows them to evade chemotherapy drugs targeting rapidly-dividing cells. If DTCs are brought out of quiescence and mobilized out of the niche using HSC mobilizing agents (e.g., G-CSF, AMD 3100), the current existing chemotherapies can be used to treat metastatic disease (Table 1 and Fig. 1).

Table 1.. Mobilization of disseminated tumor cells.

Table 1.

Mobilization of disseminated tumor cells.

Conclusion

HSCs and DTCs both use the bone marrow niche for quiescence, self-renewal and protection. DTCs mimic the behavior of HSCs to home to the marrow in a complicated multi-step process involving a series of cytokines, adhesion molecules and physical factors. Additionally, communication with host cells allows DTCs to gain access to the niche and proliferate. Pre-clinical models have shed light on the interactions of DTCs with host cells and animal models show promising results in preventing cancers invasion of the niche. As a result, drugs that aim to block DTC invasion of the bone marrow niche are currently being tested in clinical trials. Continuing to understanding the homing process will lead to the development of improved therapeutic strategies that allow for earlier detection of cancer and better prevention of metastatic cancer.

Acknowledgments

This work is directly supported by the National Cancer Institute (CA093900, CA163124, Y.S. K.J.P., and R.S.T.), NIDDK, (DK08248, R.T.) The Fund for Cancer Research (R.T.), Department of Defense (K.J.P., Y.S., and R.S.T.), and the Prostate Cancer Foundation (Y.S., K.J.P., R.S.T.).

K.J.P. receives support as an American Cancer Society Clinical Research Professor, NIH SPORE in prostate cancer grant P50 CA69568, and the Cancer Center support grant P30 CA46592.

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