Osteoid cell-derived chemokines drive bone-metastatic prostate cancer

Abstract

One of the greatest challenges in improving prostate cancer (PCa) survival is in designing new therapies to effectively target bone metastases. PCa regulation of the bone environment has been well characterized; however, bone-targeted therapies have little impact on patient survival, demonstrating a need for understanding the complexities of the tumor-bone environment. Many factors contribute to creating a favorable microenvironment for prostate tumors in bone, including cell signaling proteins produced by osteoid cells. Specifically, there has been extensive evidence from both past and recent studies that emphasize the importance of chemokine signaling in promoting PCa progression in the bone environment. Chemokine-focused strategies present promising therapeutic options for treating bone metastasis. These signaling pathways are complex, with many being produced by (and exerting effects on) a plethora of different cell types, including stromal and tumor cells of the prostate tumor-bone microenvironment. ​This review highlights an underappreciated molecular family that should be interrogated for treatment of bone metastatic prostate cancer (BM-PCa).

Keywords: bone; cancer; chemokine; metastasis; prostate; therapy.

Figure 1

Osteoid cell-derived chemokines and their roles in bone-metastatic prostate cancer.​ Many chemokines produced by osteoid cells in the bone promote bone-metastatic prostate cancer progression. Specifically, mesenchymal stem cells produce CXCL8, CXCL12, CCL5, and CX3CL1; osteoblasts produce CXCL12, CXCL13, CCL2, and CX3CL1, and osteocytes produce CXCL16 and CCL5. Among these, CXCL8 and CXCL16 have been found to promote chemoresistance. CXCL8, CXCL12, CXCL13, CCL2, CCL5 and CX3CL1 enhance tumor cell proliferation. CXCL8, CXCL16, and CCL2 contribute tumor-induced angiogenesis. CXCL8, CXCL12, CXCL13, CXCL16, CCL2, CCL5, and CX3CL1 induce tumor cell migration and invasion. CXCL8 drives a pro-tumoral immune response, often involving myeloid cell suppression of anti-tumor effector cells. CXCL8, CXCL12, and CCL2 induce osteoclastogenesis and tumor-induced osteolysis. CCL5 increases the population of cancer stem cells. Created by Biorender.com.