Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

Cell-matrix interactions have major effects upon phenotypic features such as gene regulation, cytoskeletal structure, differentiation, and aspects of cell growth control. Programmed cell death (apoptosis) is crucial for maintaining appropriate cell number and tissue organization. It was therefore of interest to determine whether cell-matrix interactions affect apoptosis. The present report demonstrates that apoptosis was induced by disruption of the interactions between normal epithelial cells and extracellular matrix. We have termed this phenomenon "anoikis." Overexpression of bcl-2 protected cells against anoikis. Cellular sensitivity to anoikis was apparently regulated: (a) anoikis did not occur in normal fibroblasts; (b) it was abrogated in epithelial cells by transformation with v-Ha-ras, v-src, or treatment with phorbol ester; (c) sensitivity to anoikis was conferred upon HT1080 cells or v-Ha-ras-transformed MDCK cells by reverse-transformation with adenovirus E1a; (d) anoikis in MDCK cells was alleviated by the motility factor, scatter factor. The results suggest that the circumvention of anoikis accompanies the acquisition of anchorage independence or cell motility.

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Disruption of epithelial cell-matrix interactions induces apoptosis

Hepatocyte growth factor/scatter factor and its receptor, the tyrosine kinase Met, arose late in evolution and are unique to vertebrates In spite of this, Met uses molecules such as Gab1 — homologues of which are present in Caenorhabditis elegans and Drosophila melanogaster — for downstream signalling Pivotal roles for Met in development and cancer have been established: Met controls cell migration and growth in embryogenesis; it also controls growth, invasion and metastasis in cancer cells; and activating Met mutations predispose to human cancer

Met, metastasis, motility and more

Hepatocyte growth factor (HGF) is a plasminogen-like protein thought to be a humoral mediator of liver regeneration A 145-kilodalton tyrosyl phosphoprotein observed in rapid response to HGF treatment of intact target cells was identified by immunoblot analysis as the beta subunit of the c-met proto-oncogene product, a membrane-spanning tyrosine kinase Covalent cross-linking of 125I-labeled ligand to cellular proteins of appropriate size that were recognized by antibodies to c-met directly established the c-met product as the cell-surface receptor for HGF

https://science.sciencemag.org/content/sci/251/4995/802.full.pdf

Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product

This is a free sample of content from Signaling by Receptor Tyrosine Kinases Click here for more information or to buy the book. This is a free sample of content from Signaling by Receptor Tyrosine Kinases Click here for more information or to buy the book. Front cover artwork: Stylized representations of the 20 different receptor tyrosine kinase (RTK) families found in humans—accounting for a total of 58 different receptors. The common intra-cellular tyrosine kinase domain (lower part of each receptor) is shown as a red rectangle. Domains in the extracellular region (upper part of each receptor) are much more variable across families and include immunoglobulin domains (blue), fibronectin type III domains (orange), and many others. The chapters in this volume describe mechanisms by which ligand binding to the extracellular region controls activity of the intracellular kinase domain, which vary substantially across the family and drive a variety of intracellular signaling pathways. All World Wide Web addresses are accurate to the best of our knowledge at the time of printing. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by Cold Spring Harbor Laboratory Press, provided that the appropriate fee is paid directly to the Copyright Clearance Center (CCC). Write or call CCC at 222 Rosewood Drive, Danvers, MA 01923 (978-750-8400) for information about fees and regulations. Prior to photocopying items for educational classroom use, contact CCC at the above address. Additional information on CCC can be obtained at CCC Online at www.copyright.com.

Signaling by Receptor Tyrosine Kinases

Hepatocyte growth factor is a synergistic factor for the growth of hematopoietic progenitor cells.

A 6.7-kilobase met complementary DNA (cDNA) was isolated from a pcD cDNA library prepared from C3H mouse fibroblast cell line polyadenylated RNA. Sequence analysis of 6.7-kilobase met cDNA insert revealed that it contained the entire open reading frame and shared an overall homology of 88.1% with the human met gene. Using the mouse met cDNA as probe, high levels of met expression were observed in the kidney, brain, lung, skin, and embryonic tissue as well as in several factor responsive mouse myeloid cell lines. Under SV40 promoter control, the mouse met protooncogene cDNA in the pCD vector was able to transform NIH 3T3 cells. These transformed cells possess multiple copies of mouse met cDNA and exhibit properties of malignant cells, including growth in soft agar and induction of tumors in nude mice. Tumor explant cell lines analyzed by Western blot also reveal the presence of high levels of Mr 170,000 and 140,000 met protein product(s).

http://cgd.aacrjournals.org/cgi/reprint/1/2/87.pdf

Structure, tissue-specific expression, and transforming activity of the mouse met protooncogene.

The present invention relates to a complex comprising hepatocyte growth factor (HGF) and met proto-oncogene protein. The present invention also relates to methods for detecting the presence of HGF ligand, met proto-oncogene receptor and methods for isolating either the ligand or receptor or complex comprising both. The present invention further relates to methods of diagnostic proliferative disorders and diseases such as hepatitis or hepatocarcinogenesis by detecting these ligand-receptor pairs.

Thomas E. Kmiecik

Papers

Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product

Hepatocyte growth factor is a synergistic factor for the growth of hematopoietic progenitor cells.

Structure, tissue-specific expression, and transforming activity of the mouse met protooncogene.

Methods for stimulating hematopoietic progenitors using hepatocyte growth factor and lymphokines

Hepatic growth factor receptor