Hepatocyte growth factor promotes in vitro scattering and morphogenesis of human cervical carcinoma cells

Objective: Hepatocyte growth factor (HGF) enhances cell dissociation and morphogenesis in many forms of carcinomas including some, but not all, cervical carcinomas. In this study, we examined the effects of HGF on two cervical cancer cell lines, derived from the same tumor, with different growth patterns in vivo and in vitro.

Methods: Two cell lines, derived from the same cervical carcinoma, express spinous (C-4I) and basal (C4-II) squamous cell differentiation, respectively. A cell scattering assay was used to determine whether HGF would stimulate cell dissociation and motility. The morphogenetic capacity of HGF was assessed in collagen gel cultures, expression of the HGF receptor c-Met by Western blot analysis, and cadherin expression by immunofluorescence microscopy.

Results: HGF-induced cell scattering was intense in C-4II, but limited in C-4I cultures. In collagen gels, C-4I cells formed large, spherical compact colonies with necrotic centers while C-4II cells formed small, irregular colonies with no necrosis. HGF induced proliferation and branching morphogenesis in both lines, but more prominently in C-4II cultures. There was no difference in c-Met or E- and P-cadherin expression between C-4I and C-4II cultures, but the lines differed in their signal transduction responses to HGF. The scatter response was mediated primarily by phosphatidylinositol 3-kinase in line C-4I, but by mitogen-activated protein kinase in line C-4II. HGF induced collagen gel contraction by C-4 cells, demonstrating for the first time that HGF has the capacity to induce this function.

Conclusions: The HGF-induced cell dispersion, morphogenesis, and collagen gel contraction in two cervical carcinoma cell lines were greatly influenced by differences between the lines in differentiation-associated properties. These properties, which include variations in extracellular matrix, junctional proteins, and signal transduction, may also modulate HGF action in vivo and thus determine patterns of invasiveness and growth of cervical carcinomas.