title: HGF/c-met system targeting PI3K/AKT and STAT3/phosphorylated-STAT3 pathways in pituitary adenomas: an immunohistochemical characterization in view of targeted therapies.
abstract: The ligand/receptor hepatocyte growth factor (HGF)/c-met signaling system promotes cellular growth and angiogenesis through PI3K/phosphor-Akt and STAT3/phosphor-STAT3 downstream effectors. In this study, we have evaluated the expression of molecules of the HGF/c-met pathway in pituitary adenomas (PA). The expression of HGF, c-met, PI3K (p85αsubunit) pAkt, STAT3, and pSTAT3 was analyzed by immunohistochemistry in an archival series of 30 PA (12 non-functioning and 18 functioning; 25 macroadenomas and 5 microadenomas). PAs expressed all six proteins in tumor epithelial cells. The proportion of c-met(+ve) cells was greater than HGF(+ve) cells (49 ± 19 vs 34 ± 17 %, P < 0.01), the pAkt(+ve) cells greater than PI3K(+ve) cells (39 ± 16.0 vs 1.3 ± 0.5 %, P < 0.001), and the STAT3(+ve) cells greater than active pSTAT3(+ve) cells (14 ± 8 vs 7 ± 6 %, P < 0.01). Furthermore, endothelial Akt immunostaining was detected on the vascular surface area of 17 PAs, in macroadenomas more frequently than in microadenomas (82 vs 18 %). The percentage of immunostained endothelial cells was greater in macro than in microadenomas (19 ± 7 and 7 ± 3 %; P < 0.05). In conclusion, HGF and c-met are widely expressed in PA, and correlate with pAkt expression. These data, together with the finding of pAkt immunostaining on microvascular areas related to tumor size, suggest a major role of the pAKT signaling in tumor growth and angiogenesis. There might be practical implications for the targeted therapy of PA.
authors.affiliation: Department of Human Pathology, Pad D 4 piano-AOU Policlinico "G. Martino", via Consolare Valeria, 1, 98125, Messina, Italy, mariatrovato@tin.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Trovato
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Torre
authors.forename: Marta
authors.initials: M
authors.lastname: Ragonese
authors.forename: Angela
authors.initials: A
authors.lastname: Simone
authors.forename: Rosy
authors.initials: R
authors.lastname: Scarfì
authors.forename: Valeria
authors.initials: V
authors.lastname: Barresi
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giuffrè
authors.forename: Salvatore
authors.initials: S
authors.lastname: Benvenga
authors.forename: Flavio F
authors.initials: FF
authors.lastname: Angileri
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tuccari
authors.forename: Francesco
authors.initials: F
authors.lastname: Trimarchi
authors.forename: Rosaria Maddalena
authors.initials: RM
authors.lastname: Ruggeri
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cannavò
mesh_terms: D000236:Adenoma / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D000368:Aged; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010911:Pituitary Neoplasms / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*
chemical_list: C066855:HGF protein, human; D050796:STAT3 Transcription Factor; D017228:Hepatocyte Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt