Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy

SIMPLE SUMMARY: Cancer-associated fibroblasts (CAFs) are found in the tumor microenvironment and exhibit several protumorigenic functions. Preclinical studies suggest that CAFs can be reduced, eliminated, or reprogrammed; however, clinical translation has not yet occurred. A better understanding of these cells and their functions will undoubtedly improve cancer treatments. In this review, we summarize current research, highlight major challenges, and discuss future opportunities for improving our knowledge of CAF biology and targeting. ABSTRACT: Cancer-associated fibroblasts (CAFs) are a heterogenous group of activated fibroblasts and a major component of the tumor stroma. CAFs may be derived from fibroblasts, epithelial cells, endothelial cells, cancer stem cells, adipocytes, pericytes, or stellate cells. These complex origins may underlie their functional diversity, which includes pro-tumorigenic roles in extracellular matrix remodeling, the suppression of anti-tumor immunity, and resistance to cancer therapy. Several methods for targeting CAFs to inhibit tumor progression and enhance anti-tumor immunity have recently been reported. While preclinical studies have shown promise, to date they have been unsuccessful in human clinical trials against melanoma, breast cancer, pancreas cancer, and colorectal cancers. This review summarizes recent and major advances in CAF-targeting therapies, including DNA-based vaccines, anti-CAF CAR-T cells, and modifying and reprogramming CAF functions. The challenges in developing effective anti-CAF treatment are highlighted, which include CAF heterogeneity and plasticity, the lack of specific target markers for CAFs, the limitations in animal models recapitulating the human cancer microenvironment, and the undesirable off-target and systemic side effects. Overcoming these challenges and expanding our understanding of the basic biology of CAFs is necessary for making progress towards safe and effective therapeutic strategies against cancers in human patients.