The many pathways involved provide multiple targets for therapeutic strategies against bone metastases also. factor, microRNA, autotaxin, receptor activator of nuclear factor kappa-B ligand, parathyroid hormone-related protein, osteoprotegerin, calcium-sensing receptor, tumor necrosis factor, granulocyte-macrophage colony-stimulating factor, endothelin-1, Dickkopf-1 Malignancy cell escape and dissemination The ability of tumor cells to escape their GSK461364 local microenvironment and degrade ECM proteins is an integral part of the malignancy of cancers. To intravasate into the bloodstream and colonize the metastatic site, tumor cells must pass through the basement membrane and the ECM. MMPs are a superfamily of multiple zinc-dependent proteinases that degrade ECM proteins.218 High MMP levels have been observed in various malignancies, including prostate, bladder, lung, and breast cancers, as well as head and neck squamous cell carcinomas,219C222 and are correlated with poor clinical outcome.223,224 The MMP family is closely correlated with angiogenesis. Both in vitro and in vivo investigations have reported the antiangiogenic effect of MMP inhibitors.225C227 The angiogenic response was shown to be significantly reduced in MMP-deficient mice.228,229 Of all the MMP members, MMP-2 is the best-studied protein due to its function in angiogenesis. The addition of exogenous pro-MMP-2 to endothelial cell culture could lead to morphologic changes that show angiogenesis.230 Furthermore, MMP-2 acts synergistically with adhesion molecules (e.g., E-cadherin).231 High expression of both MMP-2 and MMP-9 (an MMP family member closely related to MMP-2) was linked to a poor prognosis in breast cancer.224 In support of this hypothesis, MMP-2 positivity indicated an increase in the risk of death in the first 10-year follow-up.232 Furthermore, MMP-2 was substantially elevated in patients with HER2/neu gene-amplified tumors, known as an aggressive tumor phenotype. A previous investigation evaluating the association between MMP-2 and clinicopathological parameters found that MMP-2 was an indication of more invasive phenotypes and was related to lymph node metastasis.233 MMP-2 also induces angiogenesis through the regulation of VEGF and the cleavage of ECM molecules (e.g., type IV collagen)234,235 and therefore facilitates angiogenesis in the tumor microenvironment.236 However, previous studies have found that MMP-2 promotes the release of bioactive fragments of ECM, such as endostatin,237 restin,238 and arrestin,239 which inhibits angiogenesis. This inhibitory effect is related to the dormancy of breast malignancy, where MMP-2 induces disseminated breast tumor cells to enter dormancy by promoting the expression of the dormancy promoter TGF-2 in the BM.240 A recent report found that thrombospondin-2 could promote the migration of prostate malignancy cells by enhancing MMP-2 expression.241 Osteolytic bone metastasis was significantly reduced in an MMP-7-deficient prostate malignancy model, which experienced low levels of osteolysis due to defects in RANKL processing and osteoclast activation.242 MMP-7, producing a soluble form of RANKL from membrane-bound RANKL, promotes osteolytic bone metastases in prostate cancer.242 In prostate cancers, tumor growth in the bone microenvironment can GSK461364 be stimulated by osteoclast-derived MMP-9, which enhances angiogenesis without altering the osteolytic or osteogenic properties of tumors.243 However, GSK461364 BMP-6, a member of the TGF- superfamily, suppresses the paracrine secretion of MMP-9 in breast cancer cells via MAPK/p38/AP-1 signaling.244 MMP-13 overexpression was first detected in breast carcinomas and was potentially induced by IL-1 and IL-1.245,246 In squamous cell carcinomas, MMP-13 is predominantly expressed on cancer cells and the stromal fibroblasts surrounding the cancer cells. In addition, MMP-13 is usually strongly indicative Mouse monoclonal antibody to Tubulin beta. Microtubules are cylindrical tubes of 20-25 nm in diameter. They are composed of protofilamentswhich are in turn composed of alpha- and beta-tubulin polymers. Each microtubule is polarized,at one end alpha-subunits are exposed (-) and at the other beta-subunits are exposed (+).Microtubules act as a scaffold to determine cell shape, and provide a backbone for cellorganelles and vesicles to move on, a process that requires motor proteins. The majormicrotubule motor proteins are kinesin, which generally moves towards the (+) end of themicrotubule, and dynein, which generally moves towards the (-) end. Microtubules also form thespindle fibers for separating chromosomes during mitosis of the invasive and metastatic capacity of tumors.247,248 The specific role of MMP-13 has not yet been elucidated in breast cancer. A recent investigation revealed that this upregulation of MMP-13 in the tumor-stromal conversation, especially at the GSK461364 tumor-bone interface, is crucial to tumor-induced osteolysis, suggesting the potential value of MMP-13 in the treatment of breast cancers with bone.