Abstract
The tyrosine kinase receptor encoded by the MET oncogene has the unusual property of mediating the invasive growth of epithelial cells upon binding with the hepatocyte growth factor (HGF). The MET/HGF receptor is known to be overexpressed in thyroid carcinomas originated from follicular cells, but has not been reported in C cell tumors. To investigate the role of HGF and of its receptor (encoded by MET oncogene) in medullary carcinoma of the thyroid (MCT), we studied the expression of HGF and MET in 20 cases by means of different techniques. By RT-PCR, HGF mRNA was found in 10/20 cases, while MET mRNA presence was demonstrated in 8/20, of which 7 also expressed HGF. Northern blot analysis and in situ hybridization were performed in selected cases and confirmed RT-PCR data in some cases, although the lower sensitivity of these procedures did not allow the identification of all RT-PCR positive cases. By immunohistochemistry (using specific monoclonal antibodies) HGF was demonstrated in 8/9 RT-PCR positive cases ald a monoclonal to MET immunostained 5/6 RT-PCR positive cases. All receptor positive cases also expressed the ligand in the same tumor cell population. These findings demonstrate MET and HGF co-expression in a subset of MCT, in which autocrine/paracrine circuits may be active. No correlation was found between HGF/MET expression and clinico-pathological parameters, except for the more common multifocality of HGF/MET positive MCT. Whether the potential activation of MET in MCT is responsible for local invasion and malignant evolution is to be further investigated, especially in multifocal and aggressive tumors.
Similar content being viewed by others
References
Suarez HG, duVillard JA, Severino M, Caillou B, Schlumberger M, Tubiana M, et al. Presence of mutations of all three ras genes in human thyroid tumors. Oncogene 5:565–570, 1990.
Pilotti S, Collini P, Rilke F, Cattoretti G, Delbo R, Pierotti M. bcl-2 protein expression in carcinomas originating from the follicular epithelium of the thyroid gland. J Pathol 172:337–342, 1994.
Pilotti S, Collini P, Delbo R, Cattoretti G, Pierotti MA, Rilke F. A novel panel of antibodies that segregates immunocyto hemically poorly differentiaced carcinoma from undifferentiated carcinoma of the thyroid gland. Am J Surg Pathol 18:1054–1064, 1994.
Matias-Guiu X, Villanueva A, Cuatrecasas M, Capella G, DeLeiva A, Prat J. p53 in a thyroid follicular carcinoma with foci of poorly differentiated and anaplastic carcinoma. Path Res Pract 192:1242–1249, 1996.
Fusco A, Grieco M, Santoro M, Berlingeri MT, Pilotti S, Pierotti MA, Della Porta G, Vecchio GC. A new oncogene in human thyroid papillary carcinomas and their lymphnodal metastases. Nature 328:170–172, 1987.
Grieco M, Santoro M, Berlingeri MT, Melillo RM, Donghi R, Bongarzone I, Pierotti MA, DellaPorta G, Fusco A, Vecchio GC. PTC is a novel rearranged form of the ret protooncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60:557–563, 1990.
Komminoth P, Kunz EK, Matias-Guiu X, Hiort O, Christiansen G, Colomer A, Roth J, Heitz PhU. Analysis of RET protooncogene point mutations distinguishes heritable from nonheritable medullary carcinomas. Cancer 76:479–89, 1995.
Naldini L, Vigna E, Narsimhan R, Gaudino G, Zarnegar R, Michalopoulos GK, Comoglio PM. Hepatocyte growth factor (HGF) stimulates the tyrosine kinase activity of the receptor encoded by the proto-oncogene c-met. Oncogene 6:501–504, 1991.
Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM, VandeWoude G. Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311:29–33, 1984.
Di Renzo MF, Narsimhan RP, Olivero M, Bretti S, Giordano S, Medico E, et al. Expression of the met/HGF receptor in normal and neoplastic human tissues. Oncogene 6:1997–2003, 1991.
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 49:323–328, 1991.
Scotlandi K, Baldini N, Olivero M, DiRenzo MF, Martano M, Serra M, et al. Expression of MET/Hepatocyte growth factor receptor gene and malignant behavior of musculoskeletal tumors. Am J Pathol 149:1209–1219, 1996.
Nabeshima K, Shimao Y, Sato S, Kataoka H, Horiyama T, Kawano H, et al. Expression of c-Met correlates with grade of malignancy in human astrocytic tumors: an immunohistochemical study. Histopathol 31:436–443, 1997.
Naka T, Iwamoto Y, Shinohara N, Ushijima M, Chuman H, Tsuneyoshi M. Expression of c-met proto-oncogene product (c-MET) in benign and malignant bone tumors. Mod Pthol 10:832–838, 1997.
Schmidt L, Duh FM, Chen F, Kishida T, Glenn G, Choyke P, et al. Germline and somatic mutations in the tyrosine kinase domain of the MET protooncogene in papillary renal carcinomas. Nat Genet 16:68–73, 1997.
Olivero M, Valente G, Bardelli A, Longati P, Ferrero N, Cracco C, et al. A novel mutation in the ATP binding site of the MET oncogene tyrosine kinase in a HPRCC family. Int. J. Cancer:82, 640–643, 1999
Belfiore A, Gangemi P, Costantino A, Russo G, Santonocito GM, Ippolito O, et al. Negative/low expression of the Met/hepatocyte growth factor receptor identifies papillary thyroid carcinomas with high risk of distant metastases. J Clin Endocrinol Metab 82:2322–2328, 1997.
Oyama T, Ichimura E, Sano T, Kashiwabara K, Fukuda T, Nakajiama T. c-Met expression of thyroid tissue with special reference to papillary carcinoma. Pathol Int 48:763–768, 1998.
Di Renzo MF, Olivero M, Ferro S, Prat M, Bongarzone I, Pilotti S, et al. Overexpression of the c-MET/HGF receptor gene in human thyroid carcinomas. Oncogene 7:2549–2553, 1992.
Ruco LP, Ranalli T, Marzullo A, Bianco P, Prat M, Comoglio PM, Baroni C. Expression of Met protein in thyroid tumors. J Pathol 180:266–270, 1996.
Trovato M, Villari D, Bartolone L, Spinella S, Simone A, Violi MA, et al. Expression of the hepatocyte growth factor and c-met in normal thyroid, non-neoplastic, and neoplastic nodules. Thyroid 8:125–131, 1998.
Papotti M, Sambataro D, Pecchioni C, Bussolati G. The pathology of medullary carcinoma of the thyroid. Endocrine Pathol 7:1–20, 1996.
Albores-Saavedra J, Monforte H, Nadji M, Morales AR. C-cell hyperplasia in thyroid tissue adjacent to follicular cell tumors. Hum Pathol 19:795–799, 1988.
Chirgwin JM, Przybyla AE, McDonald RJ, Rutter WJ. Isolation of biologically active RNA from sourses enriched in ribonuclease. Biochemistry 18:5294–5297, 1979.
Ferraccini R, Di Renzo MF, Scotlandi K, Baldini N, Olivero M, Lollini P, et al. The Met/HGF receptor is over-expressed in human osteosarcomas and is activated by either a paracrine or an autocrine circuit. Oncogene 1:739–749, 1995.
Papotti M, Pacchioni D, Negro F, Bonino F, Bussolati G. Albumin gene expression in liver tumors: diagnostic interest in fine needle aspiration biopsies. Modern Pathol 7:271–275, 1994.
Park M, Dean M, Kaul K, Braun MJ, Gonda MA, Vande Woude G. Sequence of MET protooncogene cDNA has features characteristic of the thyrosine kinase family of growth factor receptors. Proc Natl Acad Sci USA 84:6379–6383, 1987.
Sitzmann JH, LeMotte PK. Rapid and efficient generation of PCR-derived riboprobe templates for in situ hybridisation histochemistry. J Histochem Cytochem 41:773–776, 1993.
DiRenzo MF, Poulson R, Olivero M, Comoglio PM, Lemoine NR. Expression of the Met/Hepatocyte growth factor receptor in human pancreatic cancer. Cancer Res 55:1129–1138, 1995.
Zanetti A, Stoppacciaro A, Marzullo A, Ciabatta M, Fazioli F, Prat M, et al. Expression of MET protein and urokinase-type plasminogen activator receptor (uPA-R) in papillary carcinoma of the thyroid. J Pathol 186:287–291, 1998.
Bergstrom JD, Hermansson A, Diaz de Stahl T, Heldin NE. Non-autocrine, constitutive activation of Met in human anaplastic thyroid carcinoma cells in culture. Br J Cancer 80:650–656, 1999.
Zarnegar R, Muga S, Enghild J, Michalopulos G. Tissue distribution of hepatopoietin A∶a heparin binding polypeptide growth factor for hepatocytes. Proc Natl Acad Sci USA 87: 1252–1256, 1990.
Zarnegar R. Regulation of HGF and HGFR gene expression. EXS 74:33–49, 1995.
Boccaccio C, Gaudino G, Gambarotta G, Galimi F, Comoglio PM. Hepatocyte growth factor (HGF) receptor expression in inducible and is part of the delayed-early response to HGF. J Biol Chem 269:12846–12851, 1994.
Humphrey PA, Zhu X, Zarnegar R, Swanson PE, Ratliff TL, Vollmer RT, Day ML. Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147:386–396, 1995.
Olivero M, Rizzo M, Madeddu R, Casadio C, Pennechietti S, Nicotra MR, et al. Overexpression and activation of hepatocyte growth factor/scatter factor in human nonsmall-cell lung carcinomas. Br J Cancer 74:1862–1868, 1996.
Ljubimova JY, Petrovic LM, Wilson SE, Geller SA, Demetriou AA. Expression of HGF, its receptor c-met, c-myc, and albumin in cirrhotic and neoplastic human liver tissue. J Histochem Cytochem 45:79–87, 1997.
Tuck AB, Park M, Sterns EE, Boag A, Elliott BE. Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma. Am J Pathol 148:225–232, 1996.
Tsao MS, Zhu H, Giaid A, Viallet J, Nakmura T, Park M. Hepatocyte growth factor/scatter factor is an autocrine factor for human bronchial epithelial and lung carcinoma cells. Cell Growth & Differ 4:571–579, 1993.
Wang Y, Selden AC, Morgan N, Stamp GWH, Hodgson HJF. Hepatocyte growth factor/scatter factor expression in human mammary epithelium. Am J Pathol 144:675–682, 1994.
Tamagnone L, Comoglio PM. Control of invasive growth by hepatocyte growth factor (HGF) and related scatter factors. Cytokine Growth Factor Rev 8:129–142, 1997.
Rao UNM, Sonmez-Alpan E, Michalopulos GK. Hepatocyte growth factor and c-Met in benign and malignant peripheral nerve sheath tumors. Hum Pathol 28:1066–1070, 1997.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Papotti, M., Olivero, M., Volante, M. et al. Expression of hepatocyte growth factor (HGF) and its receptor (MET) in medullary carcinoma of the thyroid. Endocr Pathol 11, 19–30 (2000). https://doi.org/10.1385/EP:11:1:19
Issue Date:
DOI: https://doi.org/10.1385/EP:11:1:19