Fibroblasts are classic spindle-shaped cells and have multiple distinct functions. Principally, they build up and degrade the ECM by releasing collagens, MMPs, and other fibrous molecules. The interaction among fibroblasts is driven by integrin signaling and it affects the distribution of collagens (ref). Similarly, collagen fibers affect the allocation of fibroblasts in ECM. They have also an impact on homeostasis and tissue maintenance through the expression of enzymes from cytochrome P450 (CYP) family that degrades potentially harmful molecules. Moreover, fibroblasts have an important role in inflammation by secreting cytokines and chemokines.
Under normal conditions, fibroblasts are at quiescent state, but they are able to migrate and secrete cytokines, ECM molecules, etc. Fibroblasts can be activated in different ways such as through regulation of growth factors (e.g. transforming growth factor-beta (TGFβ), PDGF, interleukin-6 (IL-6)) or upon certain pathological conditions, for instance, wound healing. After activation, the ECM molecule production, remodeling properties, secretion phenotype of fibroblasts have changed. In acute wound healing, the response would become fast and temporary. Therefore, this process involves the recruitment of immune cells, activation of fibroblast, induction of angiogenesis and recovery of the ECM. A great part of the ECM and basement membrane such as collagens, fibronectin and laminins are created by activated fibroblasts or myofibroblasts. When the wound is healed, some of fibroblasts are eliminated by apoptosis, and a majority of the resting state “quiescent” is restored.
If the threatening factors become continious, for example, chronic diseases or extensive exposure of toxic materials, the wound losts its ability to heal. The tissue repair process becomes chronic and it is called as tissue fibrosis. Hence, tissue fibrosis can be defined as continuous wound healing activity by displaying endless repair functions. Epigenetic mechanisms are included in tissue fibrosis to control apoptosis, thus, fibrosisassociated fibroblasts (FAFs) may be included depending on the tissue.
Cancer is also an activator for fibroblasts and it is widely referred to as “wound that does not heal”. The role of myofibroblasts or CAFs in wound healing is well established, however, their functions in tumor progression are still under investigation due to their complexity and context-dependent behavior. They have both tumorpromoting and tumor-restraining effects. In acute or chronic damage, fibroblasts are recruited through secretion of TGFβ, PDGF and FGF2 from cancer cells. In many types of cancer, enlisting of activated fibroblasts is dependent on TGFβ. Also, TGFβ induces the proliferation of neighboring CAFs. Of note, several studies were stated that fibroblast activation is a defense mechanism of host against tumor development. Everything considered, it is still unknown the detailed mechanisms of tumor stroma accumulation affecting the tumorigenesis and awaits to be discovered.
Detailed association between wounding and cancer in mammals is not clarified yet, but some studies have indicated that presence of previous tissue fibrosis increases the risk of carcinoma outgrowth particularly in liver, pancreas and lung. The occurrence of hepatocellular carcinoma (HCC) was indirectly associated with previous existence of chronic damage including ROS accumulation, genomic instability, and liver fibrosis.
Activated fibroblasts are considered to orchestrate the stromal activities and signaling pathways of cancer cells predominantly. Transdifferentiation of quiescent fibroblasts to CAFs is controlled by complex mechanisms and various signaling molecules including TGFβ. On the other hand, accumulating data demonstrates that this transition may be governed by epigenetic mechanisms. In tumorigenesis, unlike wound healing CAFs are not eliminated by apoptosis, thus once activated follows irreversible cycle of activation through several factors. Therefore, CAFs are persistent players of malignant stroma.