Cancer-Associated Fibroblasts: Mechanisms of Tumor Progression and Novel Therapeutic Targets

Abstract

Cancer-associated fibroblasts (CAFs) are a heterogenous population of stromal cells found in solid malignancies that coexist with the growing tumor mass and other immune/nonimmune cellular elements. In certain neoplasms (e.g., desmoplastic tumors), CAFs are the prominent mesenchymal cell type in the tumor microenvironment, where their presence and abundance signal a poor prognosis in multiple cancers. CAFs play a major role in the progression of various malignancies by remodeling the supporting stromal matrix into a dense, fibrotic structure while secreting factors that lead to the acquisition of cancer stem-like characteristics and promoting tumor cell survival, reduced sensitivity to chemotherapeutics, aggressive growth and metastasis. Tumors with high stromal fibrotic signatures are more likely to be associated with drug resistance and eventual relapse. Clarifying the molecular basis for such multidirectional crosstalk among the various normal and neoplastic cell types present in the tumor microenvironment may yield novel targets and new opportunities for therapeutic intervention. This review highlights the most recent concepts regarding the complexity of CAF biology including CAF heterogeneity, functionality in drug resistance, contribution to a progressively fibrotic tumor stroma, the involved signaling pathways and the participating genes.

Comprehensive analysis of transcriptome characteristics and identification of TLK2 as a potential biomarker in dermatofibrosarcoma protuberans

“…Meanwhile, it is worth noting that cancer-associated fibroblasts were significantly upregulated in DFSP. Cancer-associated fibroblasts are a heterogeneous population of stromal cells that play a vital role in tumor progression and drug resistance ( Czekay et al, 2022 ). They also show intrastromal crosstalk with other types of immune cells, including T cells, dendritic cells, and macrophages ( Saw et al, 2022 ).…”

Metastasis and MAPK Pathways

“…Cancer progression has been linked to TAMs and CAFs, which have been implicated in the RAS and MAPK signaling cascades. Moreover, CAFs promote primary tumor development via the secretion of cytokines such as interleukin 1 (IL-1) [ 6 , 69 ].…”

Immunomodulatory Properties of Immune Checkpoint Inhibitors—More than Boosting T-Cell Responses?

“…Further, cancer-associated fibroblasts (CAF) as activated by factors produced by tumor and stromal cells (e.g., TGF-β, EGF, platelet-derived growth factor and fibroblast growth factor 2) [ 32 ], support tumor growth by secreting EGF, hepatocyte growth factor, insulin growth factor-like family member (IGFL)1 and IGFL2 [ 33 ], and promote angiogenesis via VEGF release [ 34 ]. It has been shown that the crosstalk between CAF and TAM sustains tumor progression [ 35 ] and that the generation of IL-1α and IL-1β by melanoma cells may promote this malignant interaction [ 36 ].…”