br Growth supportive characteristics of the
Growth-supportive characteristics of the BM vascular niche Similar to normal tissues, tumours also need functional blood vessels to support their growth via the delivery of oxygen and nutrients. When a DTC starts proliferating into a micrometastasis, it drives angiogenesis to build new blood vessels. If angiogenesis fails and new vasculature is not recruited, micrometastasis remains deprived of oxygen and nutrients. Consequently, cell death balances proliferation thereby preventing the development of clinically detectable metastases . Remarkably, it has been demonstrated that while stable vasculature supports dormancy of DTCs, proliferating cancer order Cisplatin are selectively localized in close proximity to the sprouting vasculature (Fig. 2C). In vitro 3D co-culture experiments with cancer cells and actively growing microvasculature demonstrated that cancer cell proliferation positively correlated with the sprouting microvasculature. These neovascular tips were characterized by high expression of periostin, fibronectin, tenascin, versican, and active transforming growth factor-β1 (TGF-β1) . All these factors have been previously implicated to contribute to the development of the metastatic niche. Further the bone marrow cavity is hypoxic and bone matrix is exceptionally rich in growth factors, cytokines and bone resorbing factors. Endothelial cells secrete several of these growth factors including TGFβs, IGFs, FGFs, PDGFs and BMPs. Blocking of an angiocrine factor – placental growth factor (PlGF), using anti-mouse-PlGF antibodies, resulted in decreased bone metastasis . Additional endothelial factors that can stimulate proliferation and growth of cancer cells in bone include osteopontin, SCF and CXCL12 [5,10,11]. The hypoxic nature of bone, combined with its abundant resource of growth factors and cytokines alter the phenotype of tumour cells to produce aggressive metastatic lesions. Above evidences suggest that, interfering with endothelial cell-cancer cell interactions during early stages of metastatic growth may lead to the development of effective therapeutic strategies to delay or even prevent the metastatic relapse.
Therapeutic targeting of the BM vascular niche The most encouraging perspective of above observations is the potential of disrupting cancer cell-endothelial cell interactions and interfering with the bone marrow vascular niche during the early stage of the disease to sensitize cancer cells to the therapeutic regimes. Lessons from hematological malignancies indeed provide the proof of principle for targeting cancer cell-endothelial cell interactions . This strategy has led to the successful eradication of leukaemic stem cells from patients and substantial improvement in survival rates. Mobilization of cancer cells out of their niche microenvironments render these cells vulnerable to chemotherapy. For instance, treatment with a CXCR4 antagonist AMD3100 sensitizes acute myeloid leukaemic cells to chemotherapy . Another evidence suggests that endothelial Delta-like 4 (DLL4), a Notch signalling ligand induces exit of dormancy in T-ALL cells by interacting with NOTCH3 receptors on these cells. Moreover, vascular endothelial growth factor A (VEGFA) promotes overexpression of DLL4 . Therefore, modulating endothelial cell-DTC interactions by CXCR4 antagonist or VEGF inhibitors offers the possibility to eradicate dormant DTCs. Even though, waking dormant tumour cells offers an exciting opportunity to eradicate them, simultaneous targeting and sensitization of these cells with existing therapies is the key to a successful outcome and the disease free survival.
Introduction Cancer cells disseminate from a primary tumor and enter the circulation, of which less than 0.01% survive and produce metastases . Hematogenous circulation and lymphatic routes appear to be major routes through which disseminating tumor cells (DTCs) navigate. There are many challenges that tumor cells must overcome during the metastatic process including dissociation from neighboring cells of the primary tumor, extravasation, survival, and establishment in distant sites. DTCs have a number of different fates including death, dormancy, or proliferation . The role of the microenvironment in tumor cell fate regulation has been reported as early as Paget\'s “seed and soil hypothesis” . This hypothesis was expanded upon by Fidler , who suggested that tumor cells (i.e. seed) extravagate into circulation, survive, and establish in a distant site (i.e. soil), and their fate (death, dormancy, or growth) is directly influenced by the microenvironment of the distant site. The “seed and soil” hypothesis has been used to describe many different tumor-related diseases, including prostate cancer, which has a particular predilection for metastasis to bone which also houses the hematopoietic stem cell (HSC). Toward this end, 80% of advanced prostate cancer cases exhibit distant site metastasis in bone accompanied by a median survival of approximately 40 months . Here, we discuss insights into the role of the HSC niche in prostate cancer (PCa) bone metastasis.