title: Hypoxia and Prostate Cancer Aggressiveness: A Tale With Many Endings.
abstract: Angiogenesis, increased glycolysis, and cellular adaptation to hypoxic microenvironment are characteristic of solid tumors, including prostate cancer. These representative features are the cornerstone of cancer biology, which are well correlated with invasion, metastasis, and lethality, as well as likely with the success of prostate cancer treatment (eg, tumor hypoxia has been associated with resistance to chemotherapy and radiotherapy). It is well established that prostate cancer cells also metabolically depend on enhanced glucose transport and glycolysis for expansion, whereas growth is contingent with neovascularization to permit diffusion of oxygen and glucose. While hypoxia inducible factor 1 alpha (HIF-1α) remains the central player, the succeeding activated molecules and pathways track distinct branches, all positively correlated with the degree of intratumoral hypoxia. Among these, the vascular endothelial growth factor axis as well as the lysyl oxidase and carbonic anhydrase IX activities are notable in prostate cancer and merit further study. Here, we demonstrate their linkage with HIF-1α as a tentative explanatory mechanism of prostate cancer aggressiveness. Hypoxia drives a tale where HIF-1α-dependent effects lead to many influences in distinct key cancer biology features, rendering targeted therapies toward targets at the endings less efficient. The most appropriate approach will be to inhibit the upstream common driver (HIF-1α) activity. Additional translational and clinical research initiatives in prostate cancer are required to prove its usefulness.
authors.affiliation: Urology Department, Porto Hospital Centre, St António Hospital, Porto, Portugal; ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal; Center for Urological Research, Porto Hospital Centre, Porto, Portugal. Electronic address: avfraga@gmail.com.
authors.forename: Avelino
authors.initials: A
authors.lastname: Fraga
authors.affiliation: Center for Urological Research, Porto Hospital Centre, Porto, Portugal; Molecular Oncology Group, CI, Portuguese Institute of Oncology, Porto, Portugal; Genetics Laboratory, Faculty of Medicine, University of Lisbon, Lisbon, Portugal; Research Department, Portuguese League Against Cancer, North Centre, Porto, Portugal.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Ribeiro
authors.affiliation: Urology Department, Porto Hospital Centre, St António Hospital, Porto, Portugal; Center for Urological Research, Porto Hospital Centre, Porto, Portugal.
authors.forename: Paulo
authors.initials: P
authors.lastname: Príncipe
authors.affiliation: ICBAS, Abel Salazar Biomedical Sciences Institute, University of Porto, Porto, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Lopes
authors.affiliation: Center for Urological Research, Porto Hospital Centre, Porto, Portugal; Molecular Oncology Group, CI, Portuguese Institute of Oncology, Porto, Portugal; Research Department, Portuguese League Against Cancer, North Centre, Porto, Portugal.
authors.forename: Rui
authors.initials: R
authors.lastname: Medeiros
mesh_terms: D015687:Cell Hypoxia; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008297:Male; D009389:Neovascularization, Pathologic; D011471:Prostatic Neoplasms / Q000098:blood supply / Q000378:metabolism / Q000473:pathology*; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: Carbonic anhydrase; Hypoxia; Hypoxia-inducible factor 1; Lysyl oxidase; Prostate cancer; Vascular endothelial growth factor