title: Prostatic angiogenic responses in late life: antiangiogenic therapy influences and relation with the glandular microenvironment in the transgenic adenocarcinoma of mouse prostate (TRAMP) model.
abstract: BACKGROUND
  Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model.
  
  
  METHODS
  Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count.
  
  
  RESULTS
  Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride.
  
  
  CONCLUSIONS
  Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy.
authors.affiliation: Department of Structural and Functional Biology, Institute of Biology, University of Campinas (UNICAMP), São Paulo, Brazil.
authors.forename: Fabio
authors.initials: F
authors.lastname: Montico
authors.forename: Larissa Akemi
authors.initials: LA
authors.lastname: Kido
authors.forename: Amanda Cia
authors.initials: AC
authors.lastname: Hetzl
authors.forename: Valéria Helena Alves
authors.initials: VH
authors.lastname: Cagnon
mesh_terms: D058891:5-alpha Reductase Inhibitors / Q000494:pharmacology; D000230:Adenocarcinoma / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D015153:Blotting, Western; D003510:Cyclohexanes / Q000627:therapeutic use; D004195:Disease Models, Animal; D043169:Endostatins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D018120:Finasteride / Q000494:pharmacology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D007211:Indoles / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D011758:Pyrroles / Q000627:therapeutic use; D012717:Sesquiterpenes / Q000627:therapeutic use; D059016:Tumor Microenvironment; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
chemical_list: D058891:5-alpha Reductase Inhibitors; D020533:Angiogenesis Inhibitors; D003510:Cyclohexanes; D043169:Endostatins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007211:Indoles; D011758:Pyrroles; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D016222:Fibroblast Growth Factor 2; D018120:Finasteride; C116890:Semaxinib; D000077609:O-(Chloroacetylcarbamoyl)fumagillol