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

Sourik S Ganguly,Cindy K Miranti,Xiaohong Li

doi:10.3389/fonc.2014.00364

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.

Highlights

It is widely accepted that the tumor microenvironment, or stromal compartment, is biologically heterogeneous, consisting of various cell types, such as fibroblasts, endothelial cells, and immune cells, along with growth factors and cytokines, and numerous extracellular matrix (ECM) components
BMPs and sonic hedgehog (Shh) cooperatively provided cues for the growth of Prostate cancer (PCa) cells and the differentiation of bone stromal cells. All these results indicate that BMPs and Shh from the PCa cells play an important role in inducing osteoblast differentiation from bone stromal cells, and likely contribute to osteoblastic bone phenotypes
Understanding how cancer cells metastasize toward the bone is needed to design drugs that prevent or interfere with PCa metastasis

Summary

INTRODUCTION

It is widely accepted that the tumor microenvironment, or stromal compartment, is biologically heterogeneous, consisting of various cell types, such as fibroblasts, endothelial cells, and immune cells, along with growth factors and cytokines, and numerous extracellular matrix (ECM) components. Targeting specific integrins and their matrix interactions may provide a way to prevent metastatic bone PCa. PROTEASES IN PCa TUMOR INVASION AND METASTASIS Breakdown of the basement membrane surrounding the prostatic ducts and invasion of prostate cells into the stromal compartment defines the pathology of prostate adenocarcinoma. Laminin-5 expression is lost in PCa, coinciding with the 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. While EMT is well-established in several other epithelial cancer types, its specific role in PCa remains controversial This is complicated by the histological data demonstrating that PCa remains very epithelial-like in both primary tumors and in metastatic tissues; expressing E-cadherin and other classical prostate epithelial markers [94, 102]. Understanding the specific genetic and epigenetic alterations that promote EMT-like phenotypes in PCa will be important to understanding the switch between indolent and lethal PCa, improving staging and prognosis of PCa patients and preventing over treatment

TUMOR MICROENVIRONMENT IN PROSTATE CANCER BONE HOMING AND COLONIZATION

Findings

CONCLUSION AND PERSPECTIVES