Bone Resorbing Breast Cancer Secreted Factors

Breast-cancer secreted factors induce bone resorption by both indirect and direct actions on the osteoclast. Parathyroid hormone-related protein (PTHrP) is the most studied breast cancer-secreted factor. It indirectly activates osteoclastic bone resorption by stimulating osteoblasts and stromal cells to express RANKL, which in turn activates osteoclasts (20). PTHrP was first identified as a causal factor in humoral hypercalcemia of malignancy and was later shown to be a major factor in promoting osteolytic metastases (14). Breast cancer cells that have metastasized to bone express higher PTHrP mRNA levels than in soft tissue sites (21, 22). Inhibiting PTHrP with neutralizing antibodies decreased osteolytic bone metastases formed by MDA-MB-231 breast cancer cells in mice (23). A humanized PTHrP neutralizing antibody is currently in clinical trial for the treatment of breast cancer bone metastasis. Paradoxically, higher PTHrP expression in the primary breast tumor is correlated with a better prognosis and is not associated with the presence of bone metastases (24). Therefore, the role of PTHrP in bone lesion formation is local, and factor expression may be increased subsequent to the arrival of the metastatic tumor cells in bone.

Other secreted factors also act indirectly on osteoclasts via the RANKL pathway, including vascular endothelial growth factor (VEGF), interleukin-11 (IL-11), and interleukin-6 (IL-6) (2). Primary breast tumors express the pro-angiogenic factor VEGF and its receptors (VEGFRs) (25-27). Increased VEGF expression is correlated with increased tumor size and grade (27, 28). Vascular endothelial growth factor (VEGF) is also highly expressed by breast cancer bone metastases, and VEGFRs are expressed by breast cancer bone metastases, osteoclasts, and osteoclast precursors (27, 29, 30). VEGF is also a monocyte chemoattractant (27, 30). VEGF treatment in combination with RANKL, similarly to M-CSF in combination with RANKL, stimulates osteoclast differentiation and bone resorption (27, 29). Therefore, the high VEGF expression found in breast cancer bone metastases may promote osteoclastic bone resorption and promote lytic bone lesions. Anti-VEGF therapies have been developed for anti-angiogenic therapy, including VEGF antibodies, soluble VEGFRs, VEGFR antibodies, and small-molecule receptor kinase inhibitors (31). Anti-VEGFR-2 and anti-VEGFR-3 antibody combination therapy decreased lymph node and lung metastases in an orthotopic spontaneous breast cancer metastasis model (32). Currently, anti-VEGF therapy has only been shown to improve survival in combination with chemotherapy in clinical trials in patients with metastatic colorectal cancer and not in breast cancer (31, 33). However, since VEGF stimulates osteoclastic bone resorption, anti-VEGF therapy may reduce osteolytic breast cancer bone metastases.

Interleukin-11 (IL-11) also indirectly activates osteoclasts via the RANKL pathway (2). IL-11 induced bone resorption in calvarial organ culture assays, and this effect was inhibited by Cox inhibitors (34). IL-11 is expressed by breast cancer cells (17, 35). It is one of five factors that in combination were identified to contribute to the development of bone metastasis (17). IL-11 expression was higher in highly bone metastatic MDA-MB-231 subpopulations compared to parental cells. Combined overexpression of IL-11 and osteopontin, but not overexpression of IL-11 alone, increased bone metastases formed by MDA-MB-231 cells (17).

Interleukin-8 (IL-8) is a breast cancer-secreted factor that induces bone resorption in a PTHrP/RANKL-independent manner by acting directly on the IL-8 receptor (CXCR1) on osteoclasts and osteoclast precursors (36, 37).

The chemokine is expressed by breast cancer cell lines, and higher expression is associated with greater osteolytic potential (37). Patients with breast cancer have elevated IL-8 serum concentrations compared to normal controls, with the highest levels found in patients with advanced disease (38). MDA-MET breast cancer cells are highly metastatic to bone and differ from parental MDA-MB-231 cells by having increased IL-8 expression and no PTHrP expression, suggesting that IL-8 can drive osteolytic metastases to bone (39). An IL-8-specific neutralizing antibody inhibited osteoclast formation induced by MDA-MET conditioned media (37). Combined treatment of mice injected subcutaneously with MDA-MB-231 cells with a human IL-8 antibody and an epidermal growth factor receptor antibody increased overall survival, decreased metastatic spread, and decreased tumor size (40).

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