Hepatocyte growth factor/scatter factor induces a variety of tissue- specific morphogenic programs in epithelial cells

Hepatocyte growth factor/scatter factor (HGF/SF) is the mesenchymal ligand of the epithelial tyrosine kinase receptor c-Met. In vitro, HGF/SF has morphogenic properties, e.g., induces kidney epithelial cells to form branching ducts in collagen gels. Mutation of the HGF/SF gene in mice results in embryonic lethality due to severe liver and placenta defects. Here, we have evaluated the morphogenic activity of HGF/SF with a large variety of epithelial cells grown in three- dimensional collagen matrices. We found that HGF/SF induces SW 1222 colon carcinoma cells to form crypt-like structures. In these organoids, cells exhibit apical/basolateral polarity and build a well- developed brush border towards the lumen. Capan 2 pancreas carcinoma cells, upon addition of HGF/SF, develop large hollow spheroids lined with a tight layer of polarized cells. Collagen inside the cysts is digested and the cells show features of pancreatic ducts. HGF/SF induces EpH4 mammary epithelial cells to form long branches with end- buds that resemble developing mammary ducts. pRNS-1-1 prostate epithelial cells in the presence of HGF/SF develop long ducts with distal branching as found in the prostate. Finally, HGF/SF simulates alveolar differentiation in LX-1 lung carcinoma cells. Expression of transfected HGF/SF cDNA in LX-1 lung carcinoma and EpH4 mammary epithelial cells induce morphogenesis in an autocrine manner. In the cell lines tested, HGF/SF activated the Met receptor by phosphorylation of tyrosine residues. These data show that HGF/SF induces intrinsic, tissue-specific morphogenic activities in a wide variety of epithelial cells. Apparently, HGF/SF triggers respective endogenous programs and is thus an inductive, not an instructive, mesenchymal effector for epithelial morphogenesis.

[1]  J. Gordon,et al.  Spatial differentiation of the intestinal epithelium: analysis of enteroendocrine cells containing immunoreactive serotonin, secretin, and substance P in normal and transgenic mice. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[2]  M J Bissell,et al.  Lumen formation by epithelial cell lines in response to collagen overlay: a morphogenetic model in culture. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[3]  P. Herrlich,et al.  A human homologue of the rat metastasis-associated variant of CD44 is expressed in colorectal carcinomas and adenomatous polyps , 1993, The Journal of cell biology.

[4]  C. Birchmeier,et al.  Transient and locally restricted expression of the ros1 protooncogene during mouse development. , 1991, The EMBO journal.

[5]  Michael Stoker,et al.  Scatter factor is a fibroblast-derived modulator of epithelial cell mobility , 1987, Nature.

[6]  W. Birchmeier,et al.  A functional domain in the heavy chain of scatter factor/hepatocyte growth factor binds the c-Met receptor and induces cell dissociation but not mitogenesis. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[7]  M. Bernfield,et al.  Remodelling of the basement membrane: morphogenesis and maturation. , 1984, Ciba Foundation symposium.

[8]  L. Orci,et al.  Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor , 1991, Cell.

[9]  M. Takeichi,et al.  Epimorphin: A mesenchymal protein essential for epithelial morphogenesis , 1992, Cell.

[10]  L. Orci,et al.  Hepatocyte growth factor stimulates extensive development of branching duct-like structures by cloned mammary gland epithelial cells. , 1995, Journal of cell science.

[11]  S. Hamamoto,et al.  Sustained growth and three-dimensional organization of primary mammary tumor epithelial cells embedded in collagen gels. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[12]  G. Michalopoulos,et al.  Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. , 1989, Cancer research.

[13]  E. Lack.  Primary tumors of the exocrine pancreas. Classification, overview, and recent contributions by immunohistochemistry and electron microscopy. , 1989, The American journal of surgical pathology.

[14]  C. Harris,et al.  Transformation of human neonatal prostate epithelial cells by strontium phosphate transfection with a plasmid containing SV40 early region genes. , 1989, Cancer research.

[15]  W. Bodmer,et al.  Control of differentiation in human colorectal carcinoma cell lines: Epithelial—mesenchymal interactions , 1988, The Journal of pathology.

[16]  B. Foster,et al.  The role of growth factors in the development and growth of the prostate and seminal vesicle , 1994 .

[17]  H. Bern,et al.  Development of mammary tumors from hyperplastic alveolar nodules transplanted into gland-free mammary fat pads of female C3H mice. , 1959, Cancer research.

[18]  C. Cordon-Cardo,et al.  Expression of the HER-2/neu proto-oncogene in normal human adult and fetal tissues. , 1990, Oncogene.

[19]  C. Birchmeier,et al.  Scatter factor/hepatocyte growth factor and its receptor, the c-met tyrosine kinase, can mediate a signal exchange between mesenchyme and epithelia during mouse development , 1993, The Journal of cell biology.

[20]  H. Kleinman,et al.  Scatter factor (hepatocyte growth factor) is a potent angiogenesis factor in vivo. , 1993, Symposia of the Society for Experimental Biology.

[21]  Y. Yarden,et al.  Regulated coupling of the Neu receptor to phosphatidylinositol 3'-kinase and its release by oncogenic activation. , 1992, The Journal of biological chemistry.

[22]  A. Bardelli,et al.  Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor. , 1991, The EMBO journal.

[23]  J. Taylor‐Papadimitriou,et al.  Branching morphogenesis of human mammary epithelial cells in collagen gels. , 1994, Journal of cell science.

[24]  M Dym,et al.  Extracellular matrix regulates Sertoli cell differentiation, testicular cord formation, and germ cell development in vitro , 1985, The Journal of cell biology.

[25]  C. Grobstein,et al.  Morphogenetic Interaction between Embryonic Mouse Tissues separated by a Membrane Filter , 1953, Nature.

[26]  Frank Costantini,et al.  Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret , 1994, Nature.

[27]  C H Streuli,et al.  Laminin mediates tissue-specific gene expression in mammary epithelia , 1995, The Journal of cell biology.

[28]  G. Cunha.  Role of mesenchymal‐epithelial interactions in normal and abnormal development of the mammary gland and prostate , 1994, Cancer.

[29]  C. D. VAN CLEAVE.  Embryonic induction. , 1946, Modern hospital.

[30]  D. Bennett.  Morphogenesis of branching tubules in cultures of cloned mammary epithelial cells , 1980, Nature.

[31]  K. Tashiro,et al.  Molecular cloning and expression of human hepatocyte growth factor , 1989, Nature.

[32]  U. K. Laemmli,et al.  Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4 , 1970, Nature.

[33]  J. Spring,et al.  Epimorphin is related to a new class of neuronal and yeast vesicle targeting proteins. , 1993, Trends in biochemical sciences.

[34]  W. Birchmeier,et al.  E-cadherin-mediated cell-cell adhesion prevents invasiveness of human carcinoma cells , 1991, The Journal of cell biology.

[35]  M. Mathan,et al.  Morphogenesis of fetal rat duodenal villi. , 1976, The American journal of anatomy.

[36]  T. Sakakura.  New aspects of stroma-parenchyma relations in mammary gland differentiation. , 1991, International review of cytology.

[37]  L. Naldini,et al.  Hepatocyte growth factor is a potent angiogenic factor which stimulates endothelial cell motility and growth , 1992, The Journal of cell biology.

[38]  S. Werner,et al.  Targeted expression of a dominant negative FGF receptor blocks branching morphogenesis and epithelial differentiation of the mouse lung. , 1994, The EMBO journal.

[39]  J. Rubin,et al.  Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. , 1991, Science.

[40]  久岡 正典.  Pancreatic morphogenesis and extracellular matrix organization during rat development , 1994 .

[41]  J Vandekerckhove,et al.  Scatter factor: molecular characteristics and effect on the invasiveness of epithelial cells , 1990, The Journal of cell biology.

[42]  P. Weijerman,et al.  Characterization of adult human prostatic epithelial-cells immortalized by polybrene-induced DNA transfection with a plasmid containing an origin-defective sv40-genome. , 1994, International journal of oncology.

[43]  K.,et al.  The motility signal of scatter factor/hepatocyte growth factor mediated through the receptor tyrosine kinase met requires intracellular action of Ras. , 1994, The Journal of biological chemistry.

[44]  M J Bissell,et al.  Functional differentiation and alveolar morphogenesis of primary mammary cultures on reconstituted basement membrane. , 1989, Development.

[45]  W. Bodmer,et al.  Integrin‐receptor‐mediated differentiation and growth inhibition are enhanced by transforming growth factor‐β in colorectal tumour cells grown in collagen gel , 1989, International journal of cancer.

[46]  Carmen Birchmeier,et al.  Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud , 1995, Nature.

[47]  L. Orci,et al.  Hepatocyte growth factor increases urokinase-type plasminogen activator (u-PA) and u-PA receptor expression in Madin-Darby canine kidney epithelial cells. , 1992, The Journal of biological chemistry.

[48]  M. Rao,et al.  Formation of ductular structures in vitro by rat pancreatic epithelial oval cells. , 1993, Experimental cell research.

[49]  S. Nigam,et al.  HGF-induced tubulogenesis and branching of epithelial cells is modulated by extracellular matrix and TGF-beta. , 1993, Developmental biology.

[50]  L. Orci,et al.  Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors , 1991, Cell.

[51]  Tetsuo Noda,et al.  Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor , 1995, Nature.

[52]  G. Cunha,et al.  Stromal-epithelial interactions and heterogeneity of proliferative activity within the prostate. , 1986, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[53]  C. Little,et al.  Cellular events associated with lung branching morphogenesis including the deposition of collagen type IV. , 1987, Developmental biology.

[54]  B. Timms,et al.  Ductal budding and branching patterns in the developing prostate. , 1994, The Journal of urology.

[55]  W. Bodmer,et al.  The role of the arginine-glycine-aspartic acid-directed cellular binding to type I collagen and rat mesenchymal cells in colorectal tumour differentiation. , 1991, Differentiation; research in biological diversity.

[56]  M. Okigaki,et al.  Molecular cloning and sequence analysis of cDNA for human hepatocyte growth factor. , 1989, Biochemical and biophysical research communications.

[57]  W. Birchmeier,et al.  Evidence for the identity of human scatter factor and human hepatocyte growth factor. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[58]  M. Sharpe,et al.  Scatter factor/hepatocyte growth factor is essential for liver development , 1995, Nature.

[59]  J. Rubin,et al.  Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. , 1991, Science.

[60]  W. Birchmeier,et al.  The Met receptor tyrosine kinase transduces motility, proliferation, and morphogenic signals of scatter factor/hepatocyte growth factor in epithelial cells , 1993, The Journal of cell biology.

[61]  H. Pelham.  Is epimorphin involved in vesicular transport? , 1993, Cell.

[62]  C. Daniel,et al.  Similar growth pattern of mouse mammary epithelium cultivated in collagen matrix in vivo and in vitro. , 1984, Developmental biology.

[63]  Toshikazu Nakamura,et al.  Purification and subunit structure of hepatocyte growth factor from rat platelets , 1987, FEBS letters.

[64]  J. Rubin,et al.  Keratinocyte growth factor functions in epithelial induction during seminal vesicle development. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[65]  L. Orci,et al.  Collagen matrix promotes reorganization of pancreatic endocrine cell monolayers into islet-like organoids , 1983, The Journal of cell biology.

[66]  B. Groner,et al.  New mammary epithelial and fibroblastic cell clones in coculture form structures competent to differentiate functionally , 1989, The Journal of cell biology.

[67]  C. F. Anderson.  The Kidney: Physiology and Pathophysiology , 1985 .

[68]  N. K. Wessells.  Tissue interactions and development , 1973 .

[69]  T. Nakamura,et al.  Expression of hepatocyte growth factor gene in endothelial and Kupffer cells of damaged rat livers, as revealed by in situ hybridization. , 1990, Biochemical and biophysical research communications.