Tumour-derived TGF-β1 modulates myofibroblast differentiation and promotes HGF/SF-dependent invasion of squamous carcinoma cells

Abstract

The development of an altered stromal microenvironment is a common feature of many tumours including squamous cell carcinoma (SCC), and there is increasing evidence that these changes in the stroma, which include increased expression of proteases and cytokines, may actually promote tumour progression. A common finding is that stromal fibroblasts become 'activated' myofibroblasts, expressing smooth muscle actin and secreting cytokines, proteases and matrix proteins. We show that myofibroblasts are commonly found in the stroma of oral SCC and are often concentrated at the invasive margin of the tumour. Using oral SCC cells and primary oral fibroblasts, we demonstrate that tumour cells directly induce a myofibroblastic phenotype, and that this transdifferentiation is dependent on SCC-derived TGF-b1. In turn, myofibroblasts secrete significantly higher levels of hepatocyte growth factor/scatter factor compared with fibroblast controls, and this cytokine promotes SCC invasion through Matrigel, a mixture of basement membrane proteins. This is the first time that this double paracrine mechanism has been demonstrated between squamous carcinoma cells and fibroblasts, and emphasises that cancer invasion can be promoted indirectly by the release of tumour-induced host factors from stroma.

Evaluation of Myofibroblasts By Expression of Alpha Smooth Muscle Actin: A Marker in Fibrosis, Dysplasia and Carcinoma

“…The coarse fibres of areca nut cause mechanical irritation to the mucosa, and they facilitate diffusion of the contents into the sub-epithelial connective tissue [20]. Cytokines including TGF-β may be involved in the transdifferentiation of fibroblasts to myofibroblasts [21]. It has been accepted that TGF-β has a key role in inducing the differentiation of myofibroblasts in lesions with high levels of inflammatory mediators, which could be the case in OSMF.…”

Characterization of the interaction between fibroblasts and tumor cells on a microfluidic co‐culture device

“…The concept of stromal therapy, namely the protection of stromal cells against the dominating influence of tumor cells in tumor-stroma interaction, has formed the basis for the prevention of transdifferentiation and work as strategies for chemoprevention of tumor invasion [25][26][27]. Here, we further characterized the process of fibroblasts transdifferentiation in co-culture with tumor cells.…”

Comparison of Myofibroblasts Expression in Oral Squamous Cell Carcinoma, Verrucous Carcinoma, High Risk Epithelial Dysplasia, Low Risk Epithelial Dysplasia and Normal Oral Mucosa

“…This happens as a result of induction by a variety of cytokines from cancerous cells [1]. OSCC cells have been shown to secrete high amounts of cytokines and growth factors such as TGFb1, TGF-a, IGF-related factors, and interleukins [36][37][38][39]. TGF-b1, in particular, is responsible for the fibroblast to myofibroblast transdifferentiation in experimental models [40].…”