Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance

Abstract

In the last decades, the role of the microenvironment in tumor progression and therapeutic outcome has gained increasing attention. Cancer-associated fibroblasts (CAFs) have emerged as key players among stromal cells, owing to their abundance in most solid tumors and their diverse tumor-restraining/promoting roles. The interplay between tumor cells and neighboring CAFs takes place by both paracrine signals (cytokines, exosomes and metabolites) or by the multifaceted functions of the surrounding extracellular matrix. Here, we dissect the most recent identified mechanisms underlying CAF-mediated control of tumor progression and therapy resistance, which include induction of the epithelial-to-mesenchymal transition (EMT), activation of survival pathways or stemness-related programs and metabolic reprogramming in tumor cells. Importantly, the recently unveiled heterogeneity in CAFs claims tailored therapeutic efforts aimed at eradicating the specific subset facilitating tumor progression, therapy resistance and relapse. However, despite the large amount of pre-clinical data, much effort is still needed to translate CAF-directed anti-cancer strategies from the bench to the clinic.

Fig. 1

Schematic diagram showing the effects of CAFs on cancer cell metastatic behavior. a) Activated fibroblasts (NAF) originate from normal fibroblasts (NF) upon exposure to inflammatory cytokines. Following contact with cancer cells, they can originate the cancer-associated fibroblasts (CAFs) with enhanced proliferative and paracrine potential. The paracrine activity of CAFs and cancer cells underlying the bidirectional crosstalk between the two cell populations with the specific involved deregulated pathways are depicted. The arrows indicate the stimulatory effect of each cytokine. The induction of EMT in cancer cells relies on the activation of transcription factors, lncRNAs and epigenetic changes. b) CAFs-mediated effect on mesenchymal-independent (cancer cells maintain an epithelial-like phenotype) invasive potential. Different strategies are adopted by CAFs to facilitate cancer cells invasion of ECM, thus favoring their metastatic potential. Among these, we find the co-migration, by which CAFs and cancer cells migrate together thanks to the expression of cell membrane junctions; the ECM digestion that consists in the production of proteases by CAFs that is accompanied by the release of chemokines acting as chemoattractants for cancer cells; the force-mediated ECM remodeling that consists in the augmented contractility of the ECM and the concomitant alignment of Fibronectin (Fn), thus offering to the cancer cells a preferential route in the invasive process

Fig. 2

CAFs promote resistance to anti-cancer therapies through paracrine signals and mutual metabolic reprogramming. Upon exposure to a therapeutic insult, CAFs support an adaptive response in cancer cells that ultimately leads to therapy failure. a) Drug treatment triggers NF-kB and JAK/STAT signaling in CAFs. CAFs-released paracrine signals include exosome-mediated delivery of mRNAs and ncRNAs and a broad range of cytokines (mainly interleukins and growth factors). Activated pathways in cancer cells include pro-survival, anti-apoptotic and stemness programs. Signaling loops are depicted with rectangular-shaped arrows. b) As a mechanism of mutual adaptation to low levels of glutamine and glucose, CAFs provide metabolites that boost mitochondrial metabolism in cancer cells, hence fueling a resistant phenotype. Metabolites can also function as signaling molecules, as for the lactate secreted by cancer cells that induces NF-kB-mediated transcription in CAFs, which results in secretion of HGF that mediates TKIs resistance