Autocrine and paracrine motility factors and their involvement in invasiveness in a human oral carcinoma cell line

Abstract

Summary Invasive potentials of malignant cancer cells are regulated by cell motility factors. To examine the regulation of motility and invasiveness in oral squamous carcinoma, we investigated autocrine-and/or paracrine-acting cell motility factors, using a newly established human cell line (IF cells) from oral squamous cell carcinoma, which has highly invasive and metastatic characteristics. Conditioned medium derived from IF cells stimulated cell scattering and migration of GB-d1 gallbladder carcinoma cells, indicating that IF cells secreted cell motility factors. Using antibodies, IF-derived cell motility factors proved to be transforming growth factor (TGF)-α and TGF-β1. Antibodies against TGF-α and TGF-β1 inhibited autonomous migration of the IF cells. On the other hand, in vitro invasion of IF cells was strongly enhanced by hepatocyte growth factor (HGF) but only slightly by TGF-α and TGF-β1. The conditioned medium from fibroblasts enhanced in vitro invasion of IF cells, an event abrogated by anti-HGF antibody, but not by antibodies against TGF-α and TGF-β1. Importantly, IF cells secreted a factor inducing HGF production in fibroblasts and the factor was identified as interleukin-1, which means that a mutual interaction exists between tumour cells and fibroblasts, as mediated by the HGF/HGF-inducer loop. These results indicate that IF cells utilize TGF-α and TGF-β1 as autocrine-acting motility factors and HGF as a paracrine-acting motility factor, and that invasiveness of IF cells is particularly stimulated by HGF derived from stromal fibroblasts. Utilization of multiple cell motility/invasion factors that act in distinct pathways may confer highly invasive and metastatic potentials in IF oral squamous carcinoma cells.

Hepatocyte growth factor and the Met system as a mediator of tumor–stromal interactions

“…Several reports noted that many types of carcinoma cells secrete a variety of HGF-inducers, through which HGF production in stromal fibroblasts is up-regulated. 19,20,22,32,33 These carcinoma-cell-derived HGF-inducers were identified as interleukin-1b (IL-1b), bFGF, PDGF, transforming growth factor-a (TGF-a) and prostaglandin E2 (PGE2). The expression of HGF in fibroblasts in culture is consistently enhanced by the presence of cocultured carcinoma cells, whereas inhibitors or antibodies against cancer cell-derived HGFinducers suppressed the expression of HGF in fibroblasts, which are associated with the decrease in invasiveness of carcinoma cells (Fig.…”

Induction of endonuclease G-mediated apopotosis in human oral squamous cell carcinoma cells by protein kinase C inhibitor safingol

“…FI was established in this laboratory. 19 Cells were cultured in Dulbecco's modified Eagle's medium supplemented with 10% FBS, 2 mM L-glutamine, 100 µg/ml penicillin and 100 mg/ml streptomycin and grown in an incubator at 37 • C in a humidified atmosphere with 5% CO 2 . FI cells were cultured in the medium with 5% FBS.…”

Role of HGF/c-met system in invasion and metastasis of oral squamous cell carcinoma cellsin vitro and its clinical significance

“…18 It was reported that HGF induced tyrosine phosphorylation of focal adhesion kinase, p125FAK, 19 and promoted the migration and invasion of oral SCC cells. 20 Moreover, in several clinical studies, a relationship between the concentration of HGF in serum or in cancer tissue and the progression of disease has been noted in patients with gastric cancer, 21 breast cancer 22 and lung cancer, 23 but has not been reported in patients with oral cancer.…”