Fas signaling promotes motility and metastasis through epithelial–mesenchymal transition in gastrointestinal cancer

Abstract

Fas signaling was reported to participate in cell apoptosis. However, this pathway has also been shown to promote tumor cell motility, leading to the hypothesis that Fas signaling may induce epithelial-mesenchymal transition (EMT) to promote metastasis. The effects of Fas-ligand (FasL) treatment and inhibition of Fas signaling on colorectal and gastric cancer cells were tested using motility assay, immunofluorescence, RT-PCR and immunoblot analyses. Fas signaling downregulated epithelial markers, upregulated mesenchymal markers and promoted motility in gastrointestinal (GI) cancer cells. FasL treatment also increased the expression of EMT transcriptional factors in the nucleus and induced a spindle shape cell morphology in these cells. Knockdown of Snail or Twist expression significantly decreased FasL-induced motility. The ERK1/2 pathway was activated by Fas signaling and is required for FasL-induced EMT and motility. Moreover, oxaliplatin, a chemotherapeutic agent, induced EMT partly through Fas signaling. Evaluation of human GI clinical specimens showed that FasL expression increased whereas E-cadherin expression decreased during GI cancer progression. Both markers were significantly inversely correlated. Tissue samples with a non-EMT phenotype were mainly distributed in patients with early cancer stages, whereas samples with an EMT phenotype were mostly distributed in patients with advanced cancer stages. A non-EMT phenotype significantly correlated with better prognosis. Altogether, these data indicate that Fas signaling may induce EMT to promote tumor motility and metastasis in GI cancer in vivo and in vitro.

Dice

“…18 The expression of CD95 on cancer cells suggests that cancer cells maintain CD95 expression for activities other than apoptosis induction. Consistent with this assumption are data demonstrating roles for CD95 in promoting cancer cell migration, growth, epithelial-to-mesenchymal transition (EMT), and development, as shown in lung cancer, 19,20 colon cancer, [21][22][23][24] gastrointestinal cancers, 25,26 pancreatic cancer, 27,28 glioblastoma multiforme (GBM), 29 and in 22 cell lines representing various cancers. 30 Our most recent finding is that cancer fails to develop in mouse models of low-grade or endometrioid ovarian cancer or liver cancer unless CD95 is expressed, 14,31 suggesting that the reason cancer cells usually express CD95 goes beyond a function of CD95 as a tumor promoter.…”

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

“…Although the mechanisms of migration are still poorly understood, EMT and mesenchymal-epithelial transition is a good model to explain how solid tumors metastasize from the site of origin to a new site. [29][30][31] Herein, we showed that GPR120 signaling promoted migration and induced EMT of CRC cells in vitro and in xenograph mouse model. Furthermore, we found that expression of GPR120 and E-cadherin was inversely correlated in CRC specimens, suggesting that GPR120 might induce EMT in vivo.…”

A Phase II, Randomized, Study of Weekly APG101+Reirradiation versus Reirradiation in Progressive Glioblastoma

“…Expression of CD95L ( Supplementary Fig. S3) seems to be associated with impaired prognosis in other malignancies as well (30). The main reason for a poor outcome in glioblastoma is therapy resistance, the highly invasive behavior as well as the local immunosuppression.…”