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Am J Pathol. Jan 1996; 148(1): 225–232.
PMCID: PMC1861613

Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma.

Abstract

Expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR, product of the met proto-oncogene) mRNA were examined by nonisotopic in situ hybridization in a spectrum of benign and malignant human breast tissues. mRNA for both HGFR and HGF was detected in benign ductal epithelium. Epithelial expression of HGF mRNA was particularly intense in regions of ductal epithelial hyperplasia. Positive expression of HGF (but not HGFR) mRNA was also found in adipocytes, endothelial cells, and to varying degrees in stromal fibroblasts. In 12 of 12 cases of ductal carcinoma in situ and infiltrating ductal carcinoma, carcinoma cells showed a heterogeneous pattern of expression for both HGFR and HGF mRNA. In infiltrating ductal carcinomas, intense expression of HGFR mRNA was not restricted to ductular structures but as also seen in non-duct-forming carcinoma cells. The same zones of the tumors (most commonly at the advancing margins) that expressed strongly HGFR mRNA often were also strongly positive for HGF mRNA, suggesting a possible autocrine effect. The expression pattern of HGFR protein in 25 cases including the same series of tissues used for in situ hybridization analysis was similar to that of HGFR mRNA, as determined by an immunoperoxidase technique. The finding that HGFR is expressed by both benign and malignant epithelium, and its not restricted to duct-forming structures, suggests that, although the potential for HGF/HGFR binding is maintained in malignancy, the response to ligand binding at the level of the receptor or the cellular response to receptor activation may change at some point during progression.

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  • Tsarfaty I, Resau JH, Rulong S, Keydar I, Faletto DL, Vande Woude GF. The met proto-oncogene receptor and lumen formation. Science. 1992 Aug 28;257(5074):1258–1261. [PubMed]
  • Gherardi E, Stoker M. Hepatocyte growth factor--scatter factor: mitogen, motogen, and met. Cancer Cells. 1991 Jun;3(6):227–232. [PubMed]
  • Rubin JS, Bottaro DP, Aaronson SA. Hepatocyte growth factor/scatter factor and its receptor, the c-met proto-oncogene product. Biochim Biophys Acta. 1993 Dec 23;1155(3):357–371. [PubMed]
  • Zarnegar R, Michalopoulos G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 1989 Jun 15;49(12):3314–3320. [PubMed]
  • Weidner KM, Arakaki N, Hartmann G, Vandekerckhove J, Weingart S, Rieder H, Fonatsch C, Tsubouchi H, Hishida T, Daikuhara Y, et al. Evidence for the identity of human scatter factor and human hepatocyte growth factor. Proc Natl Acad Sci U S A. 1991 Aug 15;88(16):7001–7005. [PMC free article] [PubMed]
  • Rosen EM, Goldberg ID, Kacinski BM, Buckholz T, Vinter DW. Smooth muscle releases an epithelial cell scatter factor which binds to heparin. In Vitro Cell Dev Biol. 1989 Feb;25(2):163–173. [PubMed]
  • Seki T, Ihara I, Sugimura A, Shimonishi M, Nishizawa T, Asami O, Hagiya M, Nakamura T, Shimizu S. Isolation and expression of cDNA for different forms of hepatocyte growth factor from human leukocyte. Biochem Biophys Res Commun. 1990 Oct 15;172(1):321–327. [PubMed]
  • Noji S, Tashiro K, Koyama E, Nohno T, Ohyama K, Taniguchi S, Nakamura T. Expression of hepatocyte growth factor gene in endothelial and Kupffer cells of damaged rat livers, as revealed by in situ hybridization. Biochem Biophys Res Commun. 1990 Nov 30;173(1):42–47. [PubMed]
  • Rubin JS, Chan AM, Bottaro DP, Burgess WH, Taylor WG, Cech AC, Hirschfield DW, Wong J, Miki T, Finch PW, et al. A broad-spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci U S A. 1991 Jan 15;88(2):415–419. [PMC free article] [PubMed]
  • Birchmeier C, Birchmeier W. Molecular aspects of mesenchymal-epithelial interactions. Annu Rev Cell Biol. 1993;9:511–540. [PubMed]
  • Adams JC, Furlong RA, Watt FM. Production of scatter factor by ndk, a strain of epithelial cells, and inhibition of scatter factor activity by suramin. J Cell Sci. 1991 Mar;98(Pt 3):385–394. [PubMed]
  • Amano O, Matsumoto K, Nakamura T, Iseki S. Expression and localization of hepatocyte growth factor in rat submandibular gland. Growth Factors. 1994;10(2):145–151. [PubMed]
  • Tsao MS, Zhu H, Giaid A, Viallet J, Nakamura T, Park M. Hepatocyte growth factor/scatter factor is an autocrine factor for human normal bronchial epithelial and lung carcinoma cells. Cell Growth Differ. 1993 Jul;4(7):571–579. [PubMed]
  • Wang Y, Selden AC, Morgan N, Stamp GW, Hodgson HJ. Hepatocyte growth factor/scatter factor expression in human mammary epithelium. Am J Pathol. 1994 Apr;144(4):675–682. [PMC free article] [PubMed]
  • Kan M, Zhang GH, Zarnegar R, Michalopoulos G, Myoken Y, McKeehan WL, Stevens JI. Hepatocyte growth factor/hepatopoietin A stimulates the growth of rat kidney proximal tubule epithelial cells (RPTE), rat nonparenchymal liver cells, human melanoma cells, mouse keratinocytes and stimulates anchorage-independent growth of SV-40 transformed RPTE. Biochem Biophys Res Commun. 1991 Jan 15;174(1):331–337. [PubMed]
  • Rahimi N, Saulnier R, Nakamura T, Park M, Elliott B. Role of hepatocyte growth factor in breast cancer: a novel mitogenic factor secreted by adipocytes. DNA Cell Biol. 1994 Dec;13(12):1189–1197. [PubMed]
  • Rosen EM, Meromsky L, Setter E, Vinter DW, Goldberg ID. Smooth muscle-derived factor stimulates mobility of human tumor cells. Invasion Metastasis. 1990;10(1):49–64. [PubMed]
  • Stoker M. Effect of scatter factor on motility of epithelial cells and fibroblasts. J Cell Physiol. 1989 Jun;139(3):565–569. [PubMed]
  • Bhargava M, Joseph A, Knesel J, Halaban R, Li Y, Pang S, Goldberg I, Setter E, Donovan MA, Zarnegar R, et al. Scatter factor and hepatocyte growth factor: activities, properties, and mechanism. Cell Growth Differ. 1992 Jan;3(1):11–20. [PubMed]
  • Rosen EM, Knesel J, Goldberg ID, Jin L, Bhargava M, Joseph A, Zitnik R, Wines J, Kelley M, Rockwell S. Scatter factor modulates the metastatic phenotype of the EMT6 mouse mammary tumor. Int J Cancer. 1994 Jun 1;57(5):706–714. [PubMed]
  • Birchmeier W, Weidner KM, Behrens J. Molecular mechanisms leading to loss of differentiation and gain of invasiveness in epithelial cells. J Cell Sci Suppl. 1993;17:159–164. [PubMed]
  • Watabe M, Matsumoto K, Nakamura T, Takeichi M. Effect of hepatocyte growth factor on cadherin-mediated cell-cell adhesion. Cell Struct Funct. 1993 Apr;18(2):117–124. [PubMed]
  • Montesano R, Matsumoto K, Nakamura T, Orci L. Identification of a fibroblast-derived epithelial morphogen as hepatocyte growth factor. Cell. 1991 Nov 29;67(5):901–908. [PubMed]
  • Tsarfaty I, Rong S, Resau JH, Rulong S, da Silva PP, Vande Woude GF. The Met proto-oncogene mesenchymal to epithelial cell conversion. Science. 1994 Jan 7;263(5143):98–101. [PubMed]
  • Zhu H, Naujokas MA, Park M. Receptor chimeras indicate that the met tyrosine kinase mediates the motility and morphogenic responses of hepatocyte growth/scatter factor. Cell Growth Differ. 1994 Apr;5(4):359–366. [PubMed]
  • Komada M, Kitamura N. The cell dissociation and motility triggered by scatter factor/hepatocyte growth factor are mediated through the cytoplasmic domain of the c-Met receptor. Oncogene. 1993 Sep;8(9):2381–2390. [PubMed]
  • Dean M, Park M, Le Beau MM, Robins TS, Diaz MO, Rowley JD, Blair DG, Vande Woude GF. The human met oncogene is related to the tyrosine kinase oncogenes. Nature. 318(6044):385–388. [PubMed]
  • Bièche I, Champème MH, Matifas F, Hacène K, Callahan R, Lidereau R. Loss of heterozygosity on chromosome 7q and aggressive primary breast cancer. Lancet. 1992 Jan 18;339(8786):139–143. [PubMed]
  • Yamashita J, Ogawa M, Yamashita S, Nomura K, Kuramoto M, Saishoji T, Shin S. Immunoreactive hepatocyte growth factor is a strong and independent predictor of recurrence and survival in human breast cancer. Cancer Res. 1994 Apr 1;54(7):1630–1633. [PubMed]
  • Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A, Tashiro K, Shimizu S. Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989 Nov 23;342(6248):440–443. [PubMed]
  • Park M, Dean M, Kaul K, Braun MJ, Gonda MA, Vande Woude G. Sequence of MET protooncogene cDNA has features characteristic of the tyrosine kinase family of growth-factor receptors. Proc Natl Acad Sci U S A. 1987 Sep;84(18):6379–6383. [PMC free article] [PubMed]
  • Claesson-Welsh L, Eriksson A, Westermark B, Heldin CH. cDNA cloning and expression of the human A-type platelet-derived growth factor (PDGF) receptor establishes structural similarity to the B-type PDGF receptor. Proc Natl Acad Sci U S A. 1989 Jul;86(13):4917–4921. [PMC free article] [PubMed]
  • Yang XM, Park M. Expression of the met/hepatocyte growth factor/scatter factor receptor and its ligand during differentiation of murine P19 embryonal carcinoma cells. Dev Biol. 1993 Jun;157(2):308–320. [PubMed]
  • Rodrigues GA, Naujokas MA, Park M. Alternative splicing generates isoforms of the met receptor tyrosine kinase which undergo differential processing. Mol Cell Biol. 1991 Jun;11(6):2962–2970. [PMC free article] [PubMed]
  • Giaid A, Hamid QA, Springall DR, Yanagisawa M, Shinmi O, Sawamura T, Masaki T, Kimura S, Corrin B, Polak JM. Detection of endothelin immunoreactivity and mRNA in pulmonary tumours. J Pathol. 1990 Sep;162(1):15–22. [PubMed]
  • Prat M, Narsimhan RP, Crepaldi T, Nicotra MR, Natali PG, Comoglio PM. The receptor encoded by the human c-MET oncogene is expressed in hepatocytes, epithelial cells and solid tumors. Int J Cancer. 1991 Sep 30;49(3):323–328. [PubMed]
  • Wolf HK, Zarnegar R, Oliver L, Michalopoulos GK. Hepatocyte growth factor in human placenta and trophoblastic disease. Am J Pathol. 1991 Apr;138(4):1035–1043. [PMC free article] [PubMed]
  • Pontén F, Ren Z, Nistér M, Westermark B, Pontén J. Epithelial-stromal interactions in basal cell cancer: the PDGF system. J Invest Dermatol. 1994 Mar;102(3):304–309. [PubMed]
  • Naldini L, Tamagnone L, Vigna E, Sachs M, Hartmann G, Birchmeier W, Daikuhara Y, Tsubouchi H, Blasi F, Comoglio PM. Extracellular proteolytic cleavage by urokinase is required for activation of hepatocyte growth factor/scatter factor. EMBO J. 1992 Dec;11(13):4825–4833. [PMC free article] [PubMed]
  • Zarnegar R, Michalopoulos G. Purification and biological characterization of human hepatopoietin A, a polypeptide growth factor for hepatocytes. Cancer Res. 1989 Jun 15;49(12):3314–3320. [PubMed]
  • Santos OF, Nigam SK. HGF-induced tubulogenesis and branching of epithelial cells is modulated by extracellular matrix and TGF-beta. Dev Biol. 1993 Dec;160(2):293–302. [PubMed]
  • Behrens J, Weidner KM, Frixen UH, Schipper JH, Sachs M, Arakaki N, Daikuhara Y, Birchmeier W. The role of E-cadherin and scatter factor in tumor invasion and cell motility. EXS. 1991;59:109–126. [PubMed]
  • Birchmeier W, Weidner KM, Behrens J. Molecular mechanisms leading to loss of differentiation and gain of invasiveness in epithelial cells. J Cell Sci Suppl. 1993;17:159–164. [PubMed]
  • Watabe M, Matsumoto K, Nakamura T, Takeichi M. Effect of hepatocyte growth factor on cadherin-mediated cell-cell adhesion. Cell Struct Funct. 1993 Apr;18(2):117–124. [PubMed]
  • Boccaccio C, Gaudino G, Gambarotta G, Galimi F, Comoglio PM. Hepatocyte growth factor (HGF) receptor expression is inducible and is part of the delayed-early response to HGF. J Biol Chem. 1994 Apr 29;269(17):12846–12851. [PubMed]
  • Gorsch SM, Memoli VA, Stukel TA, Gold LI, Arrick BA. Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res. 1992 Dec 15;52(24):6949–6952. [PubMed]
  • Sundberg C, Ljungström M, Lindmark G, Gerdin B, Rubin K. Microvascular pericytes express platelet-derived growth factor-beta receptors in human healing wounds and colorectal adenocarcinoma. Am J Pathol. 1993 Nov;143(5):1377–1388. [PMC free article] [PubMed]
  • Sinha AA, Gleason DF, Deleon OF, Wilson MJ, Sloane BF. Localization of a biotinylated cathepsin B oligonucleotide probe in human prostate including invasive cells and invasive edges by in situ hybridization. Anat Rec. 1993 Feb;235(2):233–240. [PubMed]
  • de Vries TJ, Quax PH, Denijn M, Verrijp KN, Verheijen JH, Verspaget HW, Weidle UH, Ruiter DJ, van Muijen GN. Plasminogen activators, their inhibitors, and urokinase receptor emerge in late stages of melanocytic tumor progression. Am J Pathol. 1994 Jan;144(1):70–81. [PMC free article] [PubMed]

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