Cancer-associated fibroblasts and their role in tumor progression.

M S Ermakov,V A Richter,A A Nushtaeva,O A Koval

doi:10.18699/vjgb-22-03

Abstract

The stromal elements of a malignant tumor can promote cancer progression and metastasis. The structure of the tumor stroma includes connective tissue elements, blood vessels, nerves, and extracellular matrix (ECM). Some of the cellular elements of the tumor stroma are cancer-associated f ibroblasts (CAFs). The origin and function of CAFs have been actively studied over the past thirty years. CAFs produce collagen, the main scaffold protein of the extracellular matrix. Collagen in the tumor stroma stimulates f ibrosis, enhances the rigidity of tumor tissue, and disrupts the transmission of proliferation and differentiation signaling pathways. CAFs control tumor angiogenesis, cell motility, tumor immunogenic properties, and the development of resistance to chemo- and immunotherapy. As a result of metabolic adaptation of rapidly growing tumor tissue to the nutrients and oxygen deprivation, the main type of energy production in cells changes from oxidative phosphorylation to anaerobic glycolysis. These changes lead to sequential molecular alterations, including the induction of specif ied transcriptional factors that result in the CAFs activation. The molecular phenotype of activated CAFs is similar to f ibroblasts activated during inf lammation. In activated CAFs, alpha-smooth muscle actin (α-SMA) is synthetized de novo and various proteases and f ibronectin are produced. Since CAFs are found in all types of carcinomas, these cells are potential targets for the development of new approaches for anticancer therapy. Some CAFs originate from resident f ibroblasts of the organs invaded by the tumor, while others originate from epithelial tumor cells, which are undergoing an epithelial-mesenchymal transition (EMT). To date, many molecular and metabolic inducers of the EMT have been discovered including the transforming growth factor-beta (TGF-β), hypoxia, and inf lammation. This review classif ies modern concepts of molecular markers of CAFs, their functional features, and discusses the stages of epithelial- mesenchymal transition, and the potential of CAFs as a target for antitumor therapy

Highlights

The biology of cancer-associated f ibroblasts Modern concept of tumor morphology postulates that solid tumors are formed by epithelial and stromal cells, such as fibroblasts, endothelial cells, and immune cells (Wang et al, 2017)
Heterogeneity of cancer-associated f ibroblasts (CAFs)’ percussors cells In 1995, a heterogeneous origin of CAFs was hypothesized by Rønnov-Jessen and colleagues, who showed that breast cancer CAFs can originate from resident fibroblasts, vascular smooth muscle cells, and pericytes (Rønnov-Jessen et al, 1995)
For the initiation of the CAFs phenotype in some progenitor cells, additional stimulation with cytokines and growth factors, such as transforming growth factor beta (TGF-β), fibroblast growth factor (FGF), and other signaling molecules is required (Table 1) (Bordignon et al, 2019)

Summary

EMT inductors

Markers of cancer-associated f ibroblasts The involvement of CAFs in carcinogenesis and tumor progression makes them a potential target for the development of novel therapeutic approaches. A potentially clinically significant marker of CAF is the transmembrane mucin-like protein podoplanin (PDPN) (Table 2); to date, PDPN has been described as a marker of lymphoid capillary progenitor cells and CAFs in lung cancers. It has been shown that the expression of the PDGFRβ receptor is increased in the tumor microenvironment cells, where platelet growth factor activates CAFs and, probably, stimulates cancer progression (Anderberg et al, 2009). Serum amyloid A (SAA-1) protein is one of the potential targets of CAFs; its expression and involvement in tumor progression has been shown in CAFs from gastric tumors (Yasukawa et al, 2021).

Lung cancer

Tumor epithelial cells

Findings

Conclusion