The role of cancer-associated fibroblasts and exosomal miRNAs-mediated intercellular communication in the tumor microenvironment and the biology of carcinogenesis: a systematic review

Abstract

CAFs (cancer-associated fibroblasts) are highly flexible cells of the cancer microenvironment. They produce the extracellular matrix (ECM) constituents that form the structure of the tumor stroma but are also a source of metabolites, growth factors, chemokines, and exosomes that impact every aspect of the tumor, including its response to treatment. It is believed that exosomal miRNAs facilitate intercellular signaling, which is essential for the development of cancer. The role of miRNAs and CAFs in the tumor microenvironment (TME) and carcinogenesis is reviewed in this paper. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guidelines were used to perform a systematic review. Several databases, including Web of Science, Medline, Embase, Cochrane Library, and Scopus, were searched using the following keywords: CAFs, CAF, cancer-associated fibroblasts, stromal fibroblasts, miRNA, exosomal miRNAs, exosome and similar terms. We identified studies investigating exosomal miRNAs and CAFs in the TME and their role in carcinogenesis. A total of 12,572 papers were identified. After removing duplicates (n = 3803), 8774 articles were screened by title and abstract. Of these, 421 were excluded from further analysis. It has been reported that if exosomal miRNAs in CAFs are not functioning correctly, this may influence the secretory phenotype of tip cells and contribute to increased tumor invasiveness, tumor spread, decreased treatment efficacy, and a poorer prognosis. Under their influence, normal fibroblasts (NFs) are transformed into CAFs. Furthermore, they participate in metabolic reprogramming, which allows for fast proliferation of the cancer cell population, adaptation to growing energy demands, and the capacity to avoid immune system identification.

Fig. 1. CAFs are mainly derived from local precursor cells that include: mesothelial, bone marrow-derived fibrocytes, epithelial cells, NFs, pericytes, quiescent pancreatic stellate cells (qPSCs), endothelial cells, adipocytes, and mesenchymal stem cells (MSCs).

The processes of cell conversion to CAFs consist of the following processes: EMT epithelial-to-mesenchymal transition, EndMT endothelial-to-mesenchymal transition, mesothelial-to-mesenchymal transition MMT. Also, CAF-derived exosomes play a role in the following processes, which include: tumor cell proliferation; conversion of drug-sensitive cancer cells into drug-resistant cancer cells; enhancement of the metastatic capacity of cancer cells; an antitumor immune response by regulating the activity of immune cells. CAF-derived exosomes initiate several molecular processes in tumorigenesis, including TGF-β, to promote EMT, the Wnt signaling cascade contributing to the metastasis of breast cancer, the MMP-2 signaling enhancing the migration and invasiveness of gastric cancer cells. The sonic hedgehog (SHH) signaling pathway thus increases the proliferation and metastasis of ESCC cells.

Fig. 2. PRISMA flowchart of study selection.

*Consider, if feasible to do so, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.