Treating advanced prostate cancer by disrupting host cell interactions in the tumor microenvironment

AACR Centennial Conference: Translational Cancer Medicine-- July 20-23, 2008; Monterey, CA PL07-03 We have identified monocyte chemoattractant protein - 1 (MCP-1, CCL2) as a novel and potent regulator of prostate cancer tumorigenesis. The mechanisms by which elevated levels of chemokines and upregulation of chemokine receptors influence cancer development and metastasis is an area of active investigation. Increasing evidence suggests that chemokines secreted from stromal elements directly stimulate tumor cells that express (or overexpress) chemokine receptors and regulate tumor cell proliferation and migration. Alternatively, tumor cells themselves secrete elevated levels of chemokines to induce a paracrine/autocrine response on tumor growth. Furthermore, dysregulation of chemokines and chemokine receptors has been demonstrated to alter tumor development and progression via enhanced proliferation, increased invasiveness, increased angiogenesis, and recruitment of immune cells that promote tumor growth, including Tumor Associated Macrophages (TAMs). CCL2 is a member of the CC chemokine family and was originally described for its sentinel role in regulating monocyte / macrophage migration to sites of inflammation and wound repair. CCL2 has been shown to be an active mediator of tumorigenesis and metastasis of several cancers, including a role in regulating the migration and proliferation of breast, cervical, pancreatic, multiple myeloma, and prostate cancer cells. We have demonstrated: 1. Utilizing tissue procured through the Prostate SPORE Rapid Autopsy Program at the University of Michigan, we determined that CCL2 was significantly overexpressed in bone metastases as compared to normal tissues as well as metastases from other sites. 2. Analysis of CCL2 secretion by several constituents of the bone-tumor microenvironment by ELISA revealed that the bone marrow endothelial cells secrete significantly higher basal levels of CCL2 compared to PCa cells, osteoblasts, and adipocytes. 3. Analysis of human tumors from metastases as well as from in vivo preclinical models reveals a high percentage of infiltrating macrophages. 4. CCL2 in vitro induced PCa cell proliferation through stimulation of the Akt pathway via a G-coupled protein receptor. 5. CCL2 in vitro induced PCa cell survival by up-regulating survivin 6. CCL2 in vitro induced PCa cell migration in a dose dependent fashion, which was accompanied by cytoskeletal rearrangement and filopodia extension. 7. CCL2 attracts monocytes to tumor sites and educates them to a TAM (M2) phenotype in vivo . These TAMs are associated with increased angiogenesis and stimulate prostate tumor growth. Stimulation of prostate cancer growth: CCL2 directly stimulates the proliferation of prostate cancer PC-3 cells. 8. CCL2 stimulates the maturation of osteoclasts in the bone tumor microenvironment. 9. Inhibition of CCL2 in vivo leads to significant inhibition of tumor growth in multiple preclinical models of prostate cancer. CCL2, therefore, mediates tumor growth through effects on cancer cell proliferation and migration, macrophage recruitment and education, and osteoclast maturation. Taken together, it is clear that CCL2 is an important molecule in the progression of metastatic prostate cancer. Strategies that inhibit CCL2 are in active clinical development.