The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis

Abstract

Prostate cancer (PCa) is the second leading cause of cancer death in men worldwide. Most PCa deaths are due to osteoblastic bone metastases. What triggers PCa metastasis to the bone and what causes osteoblastic lesions remain unanswered. A major contributor to PCa metastasis is the host microenvironment. Here, we address how the primary tumor microenvironment influences PCa metastasis via integrins, extracellular proteases, and transient epithelia-mesenchymal transition (EMT) to promote PCa progression, invasion, and metastasis. We discuss how the bone-microenvironment influences metastasis; where chemotactic cytokines favor bone homing, adhesion molecules promote colonization, and bone-derived signals induce osteoblastic lesions. Animal models that fully recapitulate human PCa progression from primary tumor to bone metastasis are needed to understand the PCa pathophysiology that leads to bone metastasis. Better delineation of the specific processes involved in PCa bone metastasize is needed to prevent or treat metastatic PCa. Therapeutic regimens that focus on the tumor microenvironment could add to the PCa pharmacopeia.

Keywords: EMT; bone metastasis; cancer; prostate; tumor microenvironment.

Figures

Figure 1

Interactions of PCa cells with an extracellular matrix that is remodeled by cancer-associated fibroblasts, and soluble factors and proteases released within the tumor microenvironment induce EMT and subsequent invasion and dissemination of cancer cells. In the primary tumor microenvironment, the epithelial cancer cells are surrounded by the cancer-associated fibroblasts (CAF), pericytes, and various extracellular matrix (ECM) proteins. This tumor microenvironment produces various factors like TNFα, TGFβ, Wnt, and HIF-1α which promote EMT via up-regulation of specific transcription factors. EMT programing leads to a mesenchymal phenotype of the cancer cells and with the help of various proteases (MMPs, Matriptase, Hepsin), the cancer cells cleave the ECM, break away from the tumor microenvironment and intravasate into the blood vesicles to travel to distal organs.

Figure 2

PCa cells home to bone by chemo-attractants and colonize through direct association with osteoblasts, where the PCa cells secrete factors that promote osteoblastic responses and the osteoblasts reinforce tumor cell survival and growth. Expression of various chemo-attractants (Osteonectin, TGFβ, CXCL12, VEGF) guide PCa cells to extravasate and home toward the bone. Once in the bone-microenvironment the cancer cells interact with bone-forming osteoblasts via Cadherin-11. Factors like BMP, ET-1, Wnt, or PDGF, secreted from the cancer cells promote the proliferation and differentiation of osteoblasts. In turn the bone-microenvironment secretes soluble factors like FGF, IGF, and TGFβ to promote tumor cell survival and proliferation.