Dynamic role of myofibroblasts in oral lesions

Abstract

Fibroblasts are the most abundant cellular components of connective tissue. They possess phenotypical heterogenicity and may be present in the form of smooth muscle cells or myofibroblasts (MFs). MFs are spindle-shaped cells with stress fibres and well-developed fibronexus, and they display α-smooth muscle actin immunohistochemically and smooth-muscle myofilaments ultrastructurally. MFs play a crucial role in physiological and pathological processes. Derived from various sources, they play pivotal roles not only by synthesizing and producing extracellular matrix components, such as other connective tissue cells, but also are involved in force production. In the tissue remodelling phase of wound closure, integrin-mediated interactions between MFs and type I collagen result in scar tissue formation. The tumour stroma in oral cancer actively recruits various cell types into the tumour mass, where they act as different sources of MFs. This article reviews the importance of MFs and its role in pathological processes such as wound healing, odontogenic cysts and tumours, salivary gland tumours, oral preneoplasia, and oral squamous cell carcinoma. Research oriented on blocking the transdifferentiation of fibroblasts into MFs can facilitate the development of noninvasive therapeutic strategies for the treatment of fibrosis and/or cancer.

Keywords: Carcinoma-associated fibroblasts; Fibroblasts; Myofibroblasts; Neoplasm; Precancerous conditions; Precancerous lesions.

Figure 1

Origin of myofibroblasts-multicellular origin. Multicellular origin of myofibroblasts: Fibroblast, pericytes, endothelial cells, circulating hematopoietic precursor cells and fibrocytes can transform into myofibroblasts. E-MT: Epithelial-mesenchymal transition.

Figure 2

Differentiation of promyofibroblast to myofibroblast. By getting stimulus from various cytokines profibroblasts (promyofibroblasts) transforms into myofibroblasts by expressingα-smooth muscle actin. TGF-β1: Transforming growth factor-β1; ECM: Extracellular matrix; IL-1: Interleukin-1; KGF-1: Keratinocyte growth factor-1.

Figure 3

Transdifferentiation of fibroblasts into myofibroblasts. Major alkaloid of areca nuts, up-regulates keratinocyte αvß6 expression which induced transdifferentiation of oral fibroblasts into MF. OSMF: Oral submucous fibrosis.

Figure 4

Transdifferentiation of fibroblast into carcinoma associated fibroblast in oral squamous cell carcinoma. Mutual paracrine effect between oral cancer cells and normal fibroblasts is responsible for transdifferentiation of the latter into malignant fibroblasts. CAF: Carcinoma associated fibroblast; TGF-β: Transforming growth factor-β; B.V: Blood Vessels; E-M: Epithelial-mesenchymal.

Figure 5

Functional similarities and differences between wound healing and tumerogenesis. Wound healing and tumour progression phenomenon in relation with MF. TGF-β: Transforming growth factor-β; ECM: Extracellular matrix; CAF: Carcinoma-associated fibroblasts; OSMF: Oral submucous fibrosis; MMP: Matrix metalloproteinase; MF: Myofibroblast.