Targeting the tumor stroma as a novel therapeutic approach for prostate cancer

Abstract

Interactions between epithelium and the surrounding stroma are required to maintain organ function. These interactions provide proliferative and migratory restraints that define anatomical and positional information, mediated by growth factors and extracellular matrix components. When cancer develops, transformed cells lose these constraints while stroma adapts and coevolves to support the "function" of the tumor. The prostate is a good example of an organ that relies on its surrounding stroma during normal development and cancer progression. Carcinoma-associated fibroblasts (CAFs) constitute a substantial volume of the tumor stroma and play a pivotal role in tumor maintenance, dissemination, and even drug resistance. The origins of CAF and the exact mechanisms by which they promote tumor progression are still debated. CAF acquire an activated phenotype quite similar to the one seen during wound repair in sites of injury. Here, we describe the CAF ontogeny, the similarities with activated fibroblasts during physiological wound repair, and potential pathways that can be targeted to prevent their appearance in tumors and their protumorigenic functions in cancer progression. A strategy to identify aspects of stromal cell biology for therapeutic targeting is becoming increasingly plausible, driven by the increased understanding of the complex interplays between the cells and tissues of which tumors are comprised. Several preclinical and clinical studies show that targeting the stroma may be a promising and attractive therapeutic option for the treatment of cancer and has the potential to play an increasingly prominent role in future treatment strategies.