The bundles of microfilaments in myofibroblasts interact with the ECM proteins through fibronexus adhesion complexes, thereby allowing myofibroblasts to sense the tension in their surrounding microenvironment and maintain the cellular contractile force through the network of cytoskeletal proteins. Myofibroblasts are different from normal fibroblasts in many aspects, including (1) ruffled membranes and a highly active endoplasmic reticulum ( Baum and Duffy, 2011) (2) expression of alpha smooth muscle actin (α-SMA or ACTA2) and increased levels of vimentin (VIM) ( Ronnov-Jessen and Petersen, 1993) and (3) formation of complex and organized stress fibers and fibronexus adhesion complexes ( Rao et al., 2016). As the wound closes and heals, myofibroblasts become apoptotic and finally disappear as the scar is formed ( Desmouliere et al., 1995). The major roles of myofibroblasts in wound healing are to contract the wounds and produce and organize the ECM ( Darby et al., 2014). Myofibroblasts were first identified in the tissue wound repair process, during which fibroblasts or smooth muscle cells differentiate and gain a contractile phenotype ( McAnulty, 2007). Under normal physiological conditions, non-contractile fibroblasts are generally flat, spindle-shaped and recognized as quiescent and inert cells in the ECM ( Valkenburg et al., 2018). In the stroma of normal human skin, fibrous proteins fill in the interstitial space between stromal fibroblasts while epithelial keratinocytes rest on the sheet-like basement membrane. Activated stroma is molecularly, biochemically and pathologically different from the normal stroma. Tumors are often referred to as “wounds that never heal” ( Dvorak, 1986) because the stroma of a wound and a tumor share many similarities, such as fibroblast activation, increased extracellular matrix (ECM) protein production and intensive remodeling processes ( Foster et al., 2018). Stromal Fibroblasts, Myofibroblasts, and CAFs However, in this review, we will mainly explore the tumor-promoting interactions between cancer cells and fibroblasts and how CAFs may be persuaded using novel therapeutic approaches to renounce their fealty to the tumor cells and even produce a tumor-suppressive “soil.” It is clear that the TME and CAFs are not always pro-tumorigenic due to the complexities of their interactions with tumor cells. As cancer-associated fibroblasts (CAFs) appear to be a major TME component in many tumors and are critical for shaping the “soil” within which the tumor cells thrive ( LeBleu and Kalluri, 2018), they have become the prime target for the efforts to modify non-tumor cell behavior to suppress tumor growth. The TME influences the penetration, distribution, and metabolism of therapeutic agents, and produces molecular factors and signals, which positively or negatively regulate how tumor cells grow, migrate and respond to therapeutic agents. An Achilles’ heel of many current therapeutic approaches is that these therapies primarily target the fast-growing tumor “seeds” but largely ignore the fertilizing tumor “soil” – the tumor microenvironment (TME) ( de Groot et al., 2017). One major reason for this lack of substantial improvement is the development of drug resistance in tumor cells, which usually reveals itself within a few months after patients are treated with anti-cancer drugs. In the last decades, despite considerable advances in the development of novel immunotherapies and targeted therapies, no significant improvements have been made in overall survival rates for patients with malignant solid tumors. While there is growing enthusiasm for the development of CAF-targeting therapies, a better understanding of the complexities of CAF-ECM and CAF-cancer cell interactions is necessary before novel therapeutic strategies targeting the malignant tumor “soil” can be successfully implemented in the clinic. Although there is no denial that the TME and CAFs may have anti-tumor effects as well, a great deal of findings reported in recent years have convincingly revealed the tumor-promoting effects of CAFs and CAF-derived ECM proteins, enzymes, chemical factors and other downstream effectors. Cancer-associated fibroblasts (CAFs), as an abundant and active stromal cell population in the TME, function as the signaling center and remodeling machine to aid the creation of a desmoplastic tumor niche. Tumor cells reside in a highly complex and heterogeneous tumor microenvironment (TME), which is composed of a myriad of genetically stable non-cancer cells, including fibroblasts, immune cells, endothelial cells, and epithelial cells, and a tumor-specific extracellular matrix (ECM).
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