title: Activation of the hepatocyte growth factor (HGF)-Met system in papillary thyroid cancer: biological effects of HGF in thyroid cancer cells depend on Met expression levels.
abstract: Met, the receptor for hepatocyte growth factor (HGF), is overexpressed in approximately 90% papillary thyroid carcinomas. To investigate the role of the HGF-Met system in these tumors, we examined HGF and Met expression in a variety of primary cultures, normal or malignant thyroid cells, and tissue specimens and analyzed the different HGF effects (promotion of mitogenesis, branching morphogenesis, and cell motility and invasion). In cancer specimens, HGF was produced at high levels by tumor stromal cells, and Met was constitutively phosphorylated in malignant cells. No HGF production was found in a panel of malignant thyroid cancer cells. Biological effects of HGF were examined in papillary cancer cell cultures with either high or low Met expression. High-Met cells were more sensitive to the growth effect of HGF (ED50 = 3-5 ng/ml and 10-15 ng/ml in high- or low-Met cells, respectively). Moreover, only high-Met cells underwent branching morphogenesis in response to HGF. In contrast, high-Met cells showed a reduced migration. Met down-regulation by small interfering RNAs resulted in enhanced cell migration and abrogation of branching morphogenesis in response to HGF. Conversely, Met overexpression impaired cell migration while favoring branching morphogenesis and cell adherence to substrate. These data suggest that both Met and HGF are overexpressed in papillary thyroid carcinomas, that Met is frequently activated in these carcinomas and may favor tumor growth, and that the abundance of Met expression may differently regulate cell growth, morphogenesis, and migration in response to HGF.
authors.affiliation: Dipartimento di Medicina Sperimentale e Clinica, Policlinico Mater Domini, University of Catanzaro Magna Graecia, via Tommaso Campanella 115, 88100 Catanzaro, Italy.
authors.forename: Rossana
authors.initials: R
authors.lastname: Mineo
authors.forename: Angela
authors.initials: A
authors.lastname: Costantino
authors.forename: Franco
authors.initials: F
authors.lastname: Frasca
authors.forename: Laura
authors.initials: L
authors.lastname: Sciacca
authors.forename: Simona
authors.initials: S
authors.lastname: Russo
authors.forename: Riccardo
authors.initials: R
authors.lastname: Vigneri
authors.forename: Antonino
authors.initials: A
authors.lastname: Belfiore
mesh_terms: D002291:Carcinoma, Papillary / Q000503:physiopathology*; D045744:Cell Line, Tumor; D015536:Down-Regulation; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000503:physiopathology*; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: D011518:Proto-Oncogene Proteins; D017228:Hepatocyte Growth Factor; D011505:Protein-Tyrosine Kinases; D019859:Proto-Oncogene Proteins c-met; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases