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  • Title: Chronic systemic hypoxia promotes LNCaP prostate cancer growth in vivo.
    Author: Terraneo L, Bianciardi P, Caretti A, Ronchi R, Samaja M.
    Journal: Prostate; 2010 Aug; 70(11):1243-54. PubMed ID: 20333700.
    Abstract:
    OBJECTIVE: Solid tumors contain underperfused regions where hypoxia-inducible factor-1alpha (HIF-1alpha) over-expression induces hypoxia adaptation and cell proliferation. We test the hypothesis that systemic hypoxia promotes prostate cancer growth in vivo and examine HIF-1alpha centrality in this effect. METHODS: Male athymic mice were xenografted with 3 x 10(6) LNCaP cells per each flank and exposed for 28 days to either chronic hypoxia (CH, 10% O(2)) or CH with reoxygenation (CHReox, 3 times/week for 1 hr), with normoxia as control (n = 17, 9, and 20, respectively). At the end of the observation, mice were euthanized and tumors harvested for analyses. RESULTS: The successful xenografts grew faster in CH and CHReox than in normoxia (first-order rate constants 0.15 +/- 0.01, 0.18 +/- 0.03, and 0.09 +/- 0.01 day(-1), P < 0.05, n = 18, 15, and 25, respectively). Furthermore, the tumor masses at the end were 4.09 +/- 0.58, 3.42 +/- 0.55, and 1.86 +/- 0.25 mg/g bw (P < 0.05), respectively. HIF-1alpha, assayed by Western blot and immunofluorescence, was slightly increased in CH with respect to normoxia, but markedly over-expressed (5-10 times) in CHReox (P < 0.001). The tumor hemoglobin content, higher in CH and CHReox than in normoxia, reflected the higher blood hemoglobin concentration, not neovascularization, as supported by similar expression levels of vascular endothelial growth factor (VEGF) in the three groups. By contrast, protein kinase B (Akt) was more phosphorylated in both hypoxic groups than in normoxia (P < 0.01). CONCLUSION: In vivo systemic hypoxia promotes prostate cancer growth regardless of HIF-1alpha expression level and neovascularization, suggesting an important role for hypoxia-dependent pathways that do not involve HIF-1alpha, as the phosphatidyl inositol-3-phosphate signaling cascade.
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