Cancer-associated fibroblasts as accomplices to confer therapeutic resistance in cancer

Abstract

The "seed and soil" concept has reformed paradigms for cancer treatment in the past decade. Accumulating evidence indicates that the intimate crosstalk between cancer cells and stromal cells plays a tremendous role in tumor progression. Cancer-associated fibroblasts (CAFs), the largest population of stroma cells, influence therapeutic effects through diverse mechanisms. Herein, we summarize the recent advances in the versatile functions of CAFs regarding their heterogeneity, and we mainly discuss the pro-tumorigenic functions of CAFs which promote tumorigenesis and confer therapeutic resistance to tumors. Targeting CAFs is emerging as one of the most appealing strategies in anticancer therapies. The endeavors to target or reprogram the specific subtypes of CAFs provide great cancer treatment opportunities, which may provide a better clinical benefit to cancer patients.

Keywords: CAFs targeting; Cancer-associated fibroblasts (CAFs); heterogeneity; therapeutic resistance.

Figure 1

Roles of cancer-associated fibroblasts (CAFs) in cancer drug resistance. CAFs affect almost all cancer treatments, including traditional chemotherapy, targeted therapy, and immunotherapy. There are various mechanisms, such as secretion of growth factors, production of extracellular vesicles, and metabolites, through which CAFs promote drug resistance. Chemoresistance is enhanced by secreted factors from CAFs. Among them, TGF-β2 and IL-6/IL-8 from CD10⁺GPR77⁺ CAFs induce GLI2 upregulation and NF-κB activation, respectively, to maintain the stemness of cancers. IL-6 and/or IL-8 from CAFs were also found to induce EMT or chromatin remodeling in cancer cells. Upon stimulation with cytokines, such as IL-6, IL-8, NRG1, and HGF, the response to targeted therapies can be undermined by BRD4 modification, HER3 signaling activation, and MAPK and PI3K/AKT activation. Furthermore, CAFs mitigate tumor immunity by polarizing macrophages into the M2 phenotype, suppressing the function of NK and T cells and oncolytic viruses through Chi3L1, TGF-β, NetG1, CXCL12, IL-1α/β, and IFN-β1. Although appealing, targeting CAFs remains a big challenge today. The efforts to define CAF subtypes and further decipher their functions in the microenvironment may shed light on discovering new targeting strategies and provide more benefits to cancer patients. EMT: Epithelial-to-mesenchymal transition; CAF: cancer-associated fibroblast.

Figure 2

Targeting cancer-associated fibroblasts (CAFs) in cancer. Four main strategies targeting cancer-associated fibroblasts (CAFs) as cancer treatment are discussed. CAFs can be depleted by several treatments targeting CAF-specific markers, such as FAP and α-SMA. The normalization of CAFs from a pro-tumorigenic status to a quiescent or tumor-suppressive state can also be used for cancer treatment with small molecules such as ATRA or VDR ligands. The crucial signalings for CAF tumor-promoting function, such as cytokines and growth factors signalings, can be targeted to inactivate CAFs. Finally, CAF-derived extracellular matrix (ECM) proteins or related signalings can be targeted to induce ECM remodeling. MDSC: Myeloid-derived suppressor cell; FAP: fibroblast activation protein; CAR: chimeric antigen receptor; ATRA: all-trans retinoic acid; VDR: vitamin D receptor; FGFR: fibroblast growth factor receptor; SMO: smoothened; MMP: matrix metalloproteinase.