Cancer-Associated Fibroblasts: Their Characteristics and Their Roles in Tumor Growth

Abstract

Cancer tissues are composed of cancer cells and the surrounding stromal cells (e.g., fibroblasts, vascular endothelial cells, and immune cells), in addition to the extracellular matrix. Most studies investigating carcinogenesis and the progression, invasion, metastasis, and angiogenesis of cancer have focused on alterations in cancer cells, including genetic and epigenetic changes. Recently, interactions between cancer cells and the stroma have attracted considerable attention, and increasing evidence has accumulated on this. Several researchers have gradually clarified the origins, features, and roles of cancer-associated fibroblasts (CAFs), a major component of the cancer stroma. CAFs function in a similar manner to myofibroblasts during wound healing. We previously reported the relationship between CAFs and angiogenesis. Interleukin-6 (IL-6), a multifunctional cytokine, plays a central role in regulating inflammatory and immune responses, and important roles in the progression, including proliferation, migration, and angiogenesis, of several cancers. We showed that CAFs are an important IL-6 source and that anti-IL-6 receptor antibody suppressed angiogenesis and inhibited tumor-stroma interactions. Furthermore, CAFs contribute to drug-resistance acquisition in cancer cells. The interaction between cancer cells and the stroma could be a potential target for anti-cancer therapy.

The effect of tranilast on fibroblast activation protein α (FAP-α) expression in normal and keloid fibroblasts in vitro

“…Fibroblasty keloidowe mają wiele cech charakterystycznych dla CAF. FAP-α jest jednym ze znanych markerów miofibroblastów, CAF oraz fibroblastów keloidowych występujących podczas gojenia ran [16][17][18]. Uważa się, że jego aktywność enzymatyczna odgrywa ważną rolę w powstawaniu keloidów i ich rozroście poza obszar pierwotnej lokalizacji [14,15].…”

“…Keloid fibroblasts reflect many characteristics of CAFs. The FAP-α is one of the known markers of wound-healing myofibroblasts, CAFs and keloid fibroblasts [16][17][18]. It is believed that its enzymatic activity plays a key role in formation of keloids and in their growth beyond the original location [14,15].…”

CCN family of proteins: critical modulators of the tumor cell microenvironment

“…lung) with lower CCN2 expression) showed opposite effects on the same parameters. Elevated CCN2 expression in stromal cells is associated with the desmoplastic reaction and general stromal effects on tumor cells, likely reflecting the known association with hypoxic microenvironments, cancer associated fibroblasts that modulate angiogenesis, tumor cell migration and metastatic behavior (Rachfal et al 2004;Gilkes et al 2014;Shiga et al 2015;Kim et al 2014). The fact that these can be suppressed in some cancers and stimulated in others suggests a complex scenario of associated interacting factors.…”

Epigenetic Control of the Tumor Microenvironment

“…These cells have been variously referred to as cancer-associated fibroblasts (CAFs), myofibroblasts, stellate cells or mesenchymal cells. There is debate as to the origins of stromal fibroblasts in cancer; they may be derived from several cell types present in normal tissue, as well as recruited from bone marrow-derived mesenchymal cells [8][9][10]. However, given their similar pheno type in tumors, for the purpose of this review we will treat them as a single group and use the terms, fibroblasts or CAFs, to identify them.…”

“…However, given their similar pheno type in tumors, for the purpose of this review we will treat them as a single group and use the terms, fibroblasts or CAFs, to identify them. Fibroblasts are often quiescent in normal tissue but become activated in tumors as a result of tumor cell derived factors (e.g., TGF-β, PDGF and reactive oxygen species) in a process sometimes referred to as transdifferentiation [8,10]. In this process, fibroblasts become increasingly proliferative, secrete increased ECM proteins and various growth factors and alter their actin cytoskeleton to a more contractile configuration with increased stress fibers, often expressing α-smooth muscle actin (SMA) and fibroblast activation protein (FAP) [8,10].…”