Autophagy is deregulated in cancer-associated fibroblasts from oral cancer and is stimulated during the induction of fibroblast senescence by TGF-β1

Abstract

Many of the characteristics ascribed to cancer-associated fibroblasts (CAFs) are shared by activated, autophagic and senescent fibroblasts. Whilst most oral squamous cell carcinomas (OSCCs) are genetically unstable (GU-OSCC), genetically stable variants (GS-OSCC) have been described and, notably, CAF activation (myofibroblast differentiation) and senescence are characteristics particularly associated with GU-OSCCs. However, it is not known whether autophagy is disrupted in these cells or whether autophagy regulates the development of the myofibroblast and senescent phenotypes. In this study, we show that senescent CAFs from GU-OSCCs contained more autophagosomes than normal human oral fibroblasts (NHOFs) and CAFs from GS-OSCCs possibly due to autophagic impairment. Further, we show that deregulation of autophagy in normal fibroblasts, either by inhibition with autophagy inhibitor, SAR405, or activation with TGF-β1, induced fibroblast activation and senescence: In response to TGF-β1, autophagy was induced prior to the development of the activated and senescent phenotypes. Lastly, we show that both SAR405- and TGF-β1-treated NHOFs enhance OSCC cell migration but only TGF-β1-treated cells increase OSCC invasion through Matrigel, indicating that TGF-β1 has additional effects that are independent of fibroblast activation/senescence. These results suggest a functional role for autophagy in the development of myofibroblast and CAF phenotypes.

Construction an autophagy-clinical prognostic index in oral cancer

“…Autophagy can affect the phenotype of myo broblasts and cancer-associated broblasts. Increased numbers of senescence markers and autophagosomes in cancer-associated broblasts in OSCC [11].In the occurrence of oral cancer, the PIK3CA gene is mutated, which activates PI3K and promotes autophagy [12]. In the early stage of tumorigenesis, autophagy is inhibited, but as the tumor volume increases, the cells in the outer layer of the tumor near the blood vessels can continue to proliferate.The cancer cells in the center lack nutrients, but autophagy can help them survive [13].…”

The role of cancer stromal fibroblasts in mediating the effects of tobacco-induced cancer cell growth

“…Autophagy, the process by which cells degrade specific auto-cytoplasmic protein or organelles, is one of the characteristics of myofibroblastic differentiation [ 33 ]. Some scholars point out that autophagy is a significant mechanism in the interactions between fibroblasts and tumor cells.…”

Emerging Role of Autophagy in the Development and Progression of Oral Squamous Cell Carcinoma

“…Autophagy is known to play an important role in the mechanisms via which CAFs are known to promote tumor progression in a variety of cancers, such as pancreatic cancer [ 161 , 162 ]. Notably, Tan et al [ 163 ] showed autophagy induction via TGF-β1 in normal oral fibroblast results in fibroblast activation and senescence, which are known to be associated with more aggressive tumors [ 164 ] and enhanced OSCC migration [ 163 ]. However, the exact role of autophagy in CAF mediated OSCC progression is currently elusive and is an important area for future research.…”

“…This discrepancy may be due to the specificity of each inhibitor and may suggest that targeting autophagy at different stages may result in different cellular response [ 268 ]. Notably, autophagy inhibition via SAR405 induced normal oral fibroblast activation into myofibroblast [ 163 ].…”