title: Tubulocystic renal cell carcinoma: is there a rational reason for targeted therapy using angiogenic inhibition? Analysis of seven cases.
abstract: Generally, patients with renal cell carcinoma (RCC) are viewed as potential candidates for antiangiogenic targeted therapy. Tubulocystic RCC (TCRC) is a recently described entity which may behave aggressively, and the rationale for antiangiogenic therapy in this group of renal tumors has yet to be determined. Seven TCRCs and five non-tumor tissue samples from seven patients were subjected to relative expression analysis of mRNA levels of 16 genes involved in three angiogenic signal pathways: (1) VHL/HIF, (2) RTK/mitogen-activated protein kinase (MAPK), and (3) PI3K/Akt/mTOR. Two of them, pathways (2) and (3), are often targeted by antiangiogenic agents. We also determined the mutation and methylation status of the VHL gene. Finally, the levels of vascular endothelial growth factor A (VEGFA), HIF-1α, HIF-2α proteins, and phosphorylated mTOR protein were also determined. The comparison of tumor and control samples revealed no changes of mRNA levels of the following genes: VHL, HIF-1α, HIF-2α, PTEN, Akt2, Akt3, mTOR, VEGFA, KDR, HRas, C-Jun, EGFR, and FGF2. Significantly elevated mRNA level of TP53 was found, while the mRNA levels of FLT1 and C-FOS were reduced in tumor samples. No mutations or methylation in the VHL gene were found. Changes in levels of studied proteins VEGFA, HIF-1α, HIF-2α, and increased phosphorylation of mTOR protein were not found. Three studied angiogenic pathways (VHL/HIF, RTK/MAPK, and PI3K/Akt/mTOR) seem not to be upregulated in TCRC samples, so there appears to be no rationale for a general recommendation of antiangiogenic targeted therapeutic protocols for patients with these tumors.
authors.affiliation: Department of Pathology, Faculty of Medicine Plzen, Charles University Prague, Alej Svobody 80, 304 60 Pilsen, Czech Republic.
authors.forename: Petr
authors.initials: P
authors.lastname: Steiner
authors.forename: Milan
authors.initials: M
authors.lastname: Hora
authors.forename: Jan
authors.initials: J
authors.lastname: Stehlik
authors.forename: Petr
authors.initials: P
authors.lastname: Martinek
authors.forename: Tomas
authors.initials: T
authors.lastname: Vanecek
authors.forename: Fredrik
authors.initials: F
authors.lastname: Petersson
authors.forename: Michal
authors.initials: M
authors.lastname: Michal
authors.forename: Marie
authors.initials: M
authors.lastname: Korabecna
authors.forename: Ivan
authors.initials: I
authors.lastname: Travnicek
authors.forename: Ondrej
authors.initials: O
authors.lastname: Hes
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007680:Kidney Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy / Q000379:methods*; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000235:genetics; D010766:Phosphorylation; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D020533:Angiogenesis Inhibitors; D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C467484:VEGFA protein, human; C546842:MTOR protein, human; C497446:VHL protein, human