IntroductionProstate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer death among men in the US. The most common site of prostate cancer metastasis is the bone, with up to 84% of patients demonstrating skeletal metastases (1). While initially thought to be primarily osteoblastic, it is now recognized that prostate cancer skeletal metastases have an extensive bone resorptive component (2, 3) that is caused primarily by osteoclasts (4). This accounts, in part, for the ability of bisphosphonates, which are antiosteoclastogenic agents, to diminish osteolysis, decrease pain, and improve mobility in patients with prostate cancer skeletal metastasis (5). However, the mechanisms through which prostate cancer skeletal metastases induce osteolytic lesions are not defined.The presence of an osteolytic component in prostate cancer skeletal metastases suggests that osteoclastogenesis may play a role in the establishment of these lesions. Recently, the discovery and characterization of a novel cytokine system -the TNF family member, receptor activator of NF-κB ligand (RANKL, also called OPGL, TRANCE, and ODF); its receptor, receptor activator of NF-κB (RANK, also called ODAR); and its decoy receptor, osteoprotegerin (OPG, also called OCIF and TR1) -has established a common mechanism through which osteoclastogenesis is regulated in normal bone (reviewed in ref. 6). RANKL, a transmembrane molecule located on bone marrow stromal cells and osteoblasts, binds to RANK, which is located on the surface of osteoclast precursors. This ligand-receptor interaction activates NF-κB, which stimulates differentiation of osteoclast precursors to osteoclasts. OPG, also produced by osteoblasts/stromal cells, binds to RANKL, sequestering it from binding to RANK, which results in inhibition of osteoclastogenesis. The requirement for RANKL to induce osteoclastogenesis suggests that it may mediate the osteolytic component of prostate cancer skeletal lesions. However, it is currently unknown if prostate cancer uses the Prostate cancer (CaP) forms osteoblastic skeletal metastases with an underlying osteoclastic component. However, the importance of osteoclastogenesis in the development of CaP skeletal lesions is unknown. In the present study, we demonstrate that CaP cells directly induce osteoclastogenesis from osteoclast precursors in the absence of underlying stroma in vitro. CaP cells produced a soluble form of receptor activator of NF-κB ligand (RANKL), which accounted for the CaP-mediated osteoclastogenesis. To evaluate for the importance of osteoclastogenesis on CaP tumor development in vivo, CaP cells were injected both intratibially and subcutaneously in the same mice, followed by administration of the decoy receptor for RANKL, osteoprotegerin (OPG). OPG completely prevented the establishment of mixed osteolytic/osteoblastic tibial tumors, as were observed in vehicle-treated animals, but it had no effect on subcutaneous tumor growth. Consistent with the role of osteoclasts in tumor development, oste...

MCP-1 acts as a paracrine and autocrine factor for CaP growth and invasion.

Prostate cancer continues to be the most common nonskin cancer diagnosed and the second leading cause of cancer death in men in the United States. Prostate cancer that has metastasized to bone remains incurable. The interactions between prostate cancer cells and the various cells of the host microenvironment result in enhanced growth of tumor cells and activation of host cells that together culminate in osteoblastic bone metastases. These dynamic tumor-host interactions are mediated by cancer and host-produced cytokines and chemokines. Among them, chemokine (C-C motif) ligand 2 (CCL2) has been identified as a prominent modulator of metastatic growth in the bone microenvironment. CCL2 is produced by bone marrow osteoblasts, endothelial cells, stromal cells, and prostate cancer cells. It has been demonstrated to modulate tumor-associated macrophage migration and promote osteoclast maturation. In addition, CCL2 functions through binding to its receptor CCR2 to induce prostate cell proliferation, migration, and invasion in both autocrine and paracrine manners. CCL2 protects prostate cancer cells from autophagic death by activating survivin through a PI3K/AKT (phosphatidylinositol 3-kinase/protein kinase B)-dependent mechanism. Inhibition of CCL2 substantially decreases macrophage infiltration, decreases osteoclast function, and inhibits prostate cancer growth in bone in preclinical animal models. The multiple roles of CCL2 in the tumor microenvironment make it an attractive therapeutic target in metastatic prostate cancer as well as in other cancers.