Cancer-Associated Fibroblasts: Tumorigenicity and Targeting for Cancer Therapy

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.

Therapeutic Targeting of Cancer-Associated Fibroblasts in the Non-Small Cell Lung Cancer Tumor Microenvironment

“…New research technologies, including scRNA-seq, which allows access to changes among stromal, immune, and cancer cells involved in tumor progression, as multiplex spatial analysis methods, have recently been developed [145]. These technologies can provide valuable insight into the effects of cellular crosstalk dynamics and heterogeneity on cancer patient prognosis and response to various treatments [146].…”

Dual Role of Fibroblasts Educated by Tumour in Cancer Behavior and Therapeutic Perspectives

“…Since the stromal and epithelial components of a tissue, malignant or healthy, act in an integrated and reciprocal manner, combination therapy might be an effective treatment choice. In conclusion, general CAFs depletion is probably not the best strategy for anti-CAFs therapies, while the reversal of the CAFs phenotype to a “non-CAFs” phenotype or inhibition of CAFs protumourigenic signals might instead offer better therapeutic options [ 275 , 276 ] ( Figure 6 ).…”

“…CAFs reprogramming, as well as short-term inhibition of CAFs-predominant signalling pathways, have been recognized as better strategies than complete ablation or chronic inhibition. Indeed, several studies have found that strategies aimed at CAF ablation are ineffective [ 275 , 302 ].…”

Radiotherapy plus CAR-T cell therapy to date: A note for cautions optimism?

“…Indeed, the production of extracellular matrix (ECM) from tumor cells and cancer-associated fibroblasts (CAFs) would restrict the entry of T cells into the tumor, especially as high collagen density tumors display infiltrating T cells at lower levels. In this regard, CAR-T cells designed to express matrix-degrading enzymes, target CAFs, or disrupt tumor vasculature have demonstrated promising tumor infiltration of CAR-T cells ( 62 , 63 ).…”