Cancer‐associated fibroblasts: Is it a key to an intricate lock of tumorigenesis?

Abstract

The past few decades have witnessed a major leap in knowledge relating to the role of tumor microenvironment (TME) in carcinogenesis and evolving behavior of the tumor. Multiple factors within the TME modulate the cancer cells and the associated therapies. Stephen Paget first asserted that the microenvironment plays an important role in the growth of tumor metastasis. The most important player in the TME is cancer‐associated fibroblast (CAF) which significantly participates in the proliferation, invasion, and metastasis of tumor cells. CAFs show phenotypic and functional heterogeneity. Mostly CAFs originate from quiescent resident fibroblast or mesoderm‐derived precursor cells (mesenchymal stem cells), although several alternate sources of origin have been noted. However, due to lack of specific fibroblast‐restricted markers, it is very difficult to trace lineage and identify the biological origin of distinct subtypes of CAFs. CAFs are predominantly shown by several studies to mainly act as tumor‐promoting agents, however, tumor‐inhibiting actions are also being validated by several studies. A more objectified and comprehensive functional and phenotypic classification of CAF is required, which will help in better way for tumor management. Here, in this review, we have tried to review the current status of CAF origin, along with phenotypic and functional heterogeneity, and recent progress in CAF research.

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“…Noncellular connective tissue component of TME, termed ECM, has a very important role in supporting cells and their functions, and it consists of several proteins, collagen, fibrillin, elastin, laminin, fibronectin, and proteoglycan (Aden et al, 2023). Recruitment, and activation of fibroblast including into myofibroblast, leads to secretion of excessive ECM in fibrosis (Kendall & Feghali-Bostwick, 2014).…”

“…The behavior and progression of tumors depend on conditioning a microenvironment conducive to cancer progression (Aden et al, 2023; Zhao et al, 2021). There is coordinated evolution of tumor and TME with reciprocal signaling among cells of tumor and TME (Aden et al, 2023).…”

“…tumor and TME with reciprocal signaling among cells of tumor and TME(Aden et al, 2023). The tumor microenvironment(TME) comprises the nonepithelial stromal component including fibroblasts, immune cells, endothelial cells, and ECM(Aden et al, 2023).Depending on tumor type, grade, and stage, carcinoma cells might represent a minority of tumor cells, with the bulk composed of components of TME(Baghban et al, 2020). Cancer-associated fibroblasts (CAFs), one of the most important components of TME differ from normal fibroblasts by expression of smooth muscle actin, fibroblast activated protein, fibroblast surface protein, podoplanin, platelet-derived growth factor receptors α and β (PDGF-α and PDGF-β) and NG2 chondroitin sulfate proteoglycan(Aden et al, 2023;Brentnall et al, 2012;Schoppmann et al, 2013).…”

“…The tumor microenvironment(TME) comprises the nonepithelial stromal component including fibroblasts, immune cells, endothelial cells, and ECM(Aden et al, 2023).Depending on tumor type, grade, and stage, carcinoma cells might represent a minority of tumor cells, with the bulk composed of components of TME(Baghban et al, 2020). Cancer-associated fibroblasts (CAFs), one of the most important components of TME differ from normal fibroblasts by expression of smooth muscle actin, fibroblast activated protein, fibroblast surface protein, podoplanin, platelet-derived growth factor receptors α and β (PDGF-α and PDGF-β) and NG2 chondroitin sulfate proteoglycan(Aden et al, 2023;Brentnall et al, 2012;Schoppmann et al, 2013). Signals derived from tumor cells and/or from immune cells in TME are one of the most important factors that are responsible for CAF recruitment and activation(Aden et al, 2023).In general, TGF-β1 secreted by tumor cells and also stromal cells is found to be one of the significant factors leading to mobilization and stimulation of resident fibroblast(Aden et al, 2023).…”

“…Cancer-associated fibroblasts (CAFs), one of the most important components of TME differ from normal fibroblasts by expression of smooth muscle actin, fibroblast activated protein, fibroblast surface protein, podoplanin, platelet-derived growth factor receptors α and β (PDGF-α and PDGF-β) and NG2 chondroitin sulfate proteoglycan(Aden et al, 2023;Brentnall et al, 2012;Schoppmann et al, 2013). Signals derived from tumor cells and/or from immune cells in TME are one of the most important factors that are responsible for CAF recruitment and activation(Aden et al, 2023).In general, TGF-β1 secreted by tumor cells and also stromal cells is found to be one of the significant factors leading to mobilization and stimulation of resident fibroblast(Aden et al, 2023). TGF-β1 stimulates SMAD transcription factor.…”