Multiple roles of chemokine (C-C motif) ligand 2 in promoting prostate cancer growth

Abstract

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.

Figure 1

Roles of chemokine (C-C motif) ligand 2 (CCL2) in prostate cancer cells and the bone microenvironment. The CCL2/CCR2 axis has been identified as an important contributor to prostate tumorigenesis. CCL2, by binding to its receptor CCR2, directly stimulates prostate cancer cell proliferation, survival, and migration. In addition, CCL2 contributes to the development of metastases in the bone microenvironment by stimulating macrophage recruitment and education, angiogenesis, and activation of osteoclastogenesis. Prostate cancer cells produce parathyroid hormone related peptide (PTHrP), which stimulates CCL2 expression from osteoblasts. CCL2 appears to mediate the interactions between tumor-derived factors, such as PTHrP, and host-derived chemokines and cytokines, which act together to promote metastatic tumor growth in bone. IGF = insulin-like growth factor; IL-8 = interleukin 8; PCa = prostate cancer; RANKL = receptor activator of nuclear factor kappaB ligand; TGF-β = transforming growth factor β; VEGF = vascular endothelial growth factor.