K M Weidner

Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor.

Scatter Factor (SF) is a fibroblast‐secreted protein which promotes motility and matrix invasion of epithelial cells. Hepatocyte Growth Factor (HGF) is a powerful mitogen for hepatocytes and other epithelial tissues. SF and HGF, purified according to their respective biological activities, were interchangeable and equally effective in assays for cell growth, motility and invasion. Both bound with identical affinities to the same sites in target cells. The receptor for SF and HGF was identified as the product of the MET oncogene by: (i) ligand binding and coprecipitation in immunocomplexes; (ii) chemical crosslinking to the Met beta subunit; (iii) transfer of binding activity in insect cells by a baculovirus carrying the MET cDNA; (iv) ligand‐induced tyrosine phosphorylation of the Met beta subunit. SF and HGF cDNA clones from human fibroblasts, placenta and liver had virtually identical sequences. We conclude that the same molecule (SF/HGF) acts as a growth or motility factor through a single receptor in different target cells.

Molecular mechanisms leading to loss of differentiation and gain of invasiveness in epithelial cells

SUMMARY It has been realized for some time that the loss of epithelial differentiation in carcinomas, which is accompanied by higher mobility and invasiveness of the tumor cells, is a consequence of reduced intercellular adhesion. A variety of recent reports have indicated that the primary cause for the ‘scattering’ of the cells in invasive carcinomas is a loss of the integrity of intercellular junctions. Thus, defects in expression or structure of several components of the epithelial adherens junctions (e.g. E-cadherin, α-catenin) can occur, and our increased knowledge about the molecules of the junctions allows an explanation of these defects in molecular terms in some of the cases. Furthermore, tyrosine phosphorylation of junctional components (e.g. β-catenin) appears to play a role in the assembly and disassembly of cell-cell contacts. Some of the effectors of epithelial junction formation are tyrosine protein kinases, e.g. the scatter factor/hepatocyte growth factor receptor c-Met, the FGF receptors and the pp60src kinase. The importance of tyrosine phosphorylation in junctions during tumor development is becoming increasingly evident.

Epithelial Differentiation and the Control of Metastasis in Carcinomas

Tumors of epithelial origin (carcinomas) are of major medical importance (DeVita et al. 1993). Multiple genetic changes in dominant and recessive oncogenes that contribute to carcinoma formation and progression have been identified. The most frequent mutations found in carcinomas include activating mutations in the ras family of genes, mutations that interfere with the function of p53, and amplification or overexpression of genes encoding tyrosine kinase receptors (Barbacid 1987; Aronson 1991; Hollstein et al. 1991; Vogelstein and Kinzler 1993; Hinds and Weinberg 1994). These mutations affect both the growth and the genetic stability of affected cells. A further critical step in the development of malignant carcinomas is their ability to invade the underlying tissue and to metastasize to distant sites. Early genetic approaches for the analysis of oncogenes have focused mainly on the induction of transformation, i.e., unregulated growth in fibroblasts, which has led in the past decade to a wealth of data on the pathways controlling normal and aberrant growth. In comparison, there has been a lag in understanding the molecular causes leading to the acquisition of the metastatic potential of carcinoma cells.