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

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)-alpha and TGF-beta1. Antibodies against TGF-alpha and TGF-beta1 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-alpha and TGF-beta1. 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-alpha and TGF-beta1. 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-alpha and TGF-beta1 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.