Abstract
Neoplastic epithelial cells coexist in carcinomas with various non-neoplastic stromal cells, together creating the tumor microenvironment. There is a growing interest in the cross-talk between tumor cells and stromal fibroblasts referred to as carcinoma-associated fibroblasts (CAFs), which are frequently present in human carcinomas. CAF populations extracted from different human carcinomas have been shown to possess the ability to influence the hallmarks of cancer. Indeed, several mechanisms underlying CAF-promoted tumorigenesis are elucidated. Activated fibroblasts in CAFs are characterized as alpha-smooth muscle actin-positive myofibroblasts and actin-negative fibroblasts, both of which are competent to support tumor growth and progression. There are, however, heterogeneous CAF populations presumably due to the diverse sources of their progenitors in the tumor-associated stroma. Thus, molecular markers allowing identification of bona fide CAF populations with tumor-promoting traits remain under investigation. CAFs and myofibroblasts in wound healing and fibrosis share biological properties and support epithelial cell growth, not only by remodeling the extracellular matrix, but also by producing numerous growth factors and inflammatory cytokines. Notably, accumulating evidence strongly suggests that anti-fibrosis agents suppress tumor development and progression. In this review, we highlight important tumor-promoting roles of CAFs based on their analogies with wound-derived myofibroblasts and discuss the potential therapeutic strategy targeting CAFs.
Highlights
Injured epithelial tissues are repaired by the formation of granulation tissues rich in α-smooth muscle actin (α-SMA)-positive myofibroblasts, platelets, newly formed blood vessels, macrophages, and other inflammatory cells and extracellular matrix (ECM)
The transforming growth factor-β (TGF-β) signal pathway is involved in the emergence of myofibroblasts, which contribute to the production of matrix metalloproteinase (MMP) and ECM proteins, such as collagen I, fibronectin and hyaluronic acid [1,2,3,4]
As plasminogen activator inhibitor-1 (PAI-1) prevents lung fibroblasts from undergoing apoptosis induced by plasminogen, ectopic secreted protein acidic and rich in cysteine (SPARC) expression in Idiopathic pulmonary fibrosis (IPF) apparently mediates the progression of interstitial fibrosis by inhibiting apoptosis in lung myofibroblasts via β-catenin activation and PAI-1 expression in collaboration with the TGF-β signal pathway
Summary
Injured epithelial tissues are repaired by the formation of granulation tissues rich in α-smooth muscle actin (α-SMA)-positive myofibroblasts (a hallmark of activated fibroblasts), platelets, newly formed blood vessels, macrophages, and other inflammatory cells and extracellular matrix (ECM). It was previously shown that normal colonic fibroblasts differentiate into α-SMA-positive CAFs and secrete larger amounts of MMP2 and urokinase-type plasminogen activator (uPA) associated with various cancer cells [44,45] These proteolytic enzymes have been suggested to cleave various ECM components such as decorin, which covalently and potently binds to TGF-β and prevents the potential ligand from binding to the TGF-β receptor in adjacent cancer cells [46]. ECM components act as a reservoir for various cytokines; since decorin is able to bind TGF-β1, proteolytic degradation of decorin results in the release of this sequestered TGF-β ligand [47] These lines of evidence all strongly suggest that paracrine signaling from CAFs and myofibroblasts in a wound regulates epithelial-mesenchymal plasticity in nearby epithelial cells to further promote tumor progression and fibrosis, respectively
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