title: HIF-mediated hypoxic response is missing in severely hypoxic uterine leiomyomas.
abstract: Results from our laboratory have put a question mark on the existence of a direct quantitative relationship between tumor hypoxia and HIF-mediated protein expression in cancers of the uterine cervix. In the present study, this subject has been further explored by the analysis of HIF-related marker expression in a benign tumor entity - uterine leiomyomas - using immunohistochemistry, western blotting and RT-PCR. The oxygenation status of 17 leiomyomas was assessed by means of intraoperative polarographic needle electrode measurements. Results show that these tumors are severely and uniformly hypoxic, but do not induce HIF-1alpha, HIF-2alpha, glucose transporter (GLUT)-1 or carbonic anhydrase (CA) IX. Furthermore, this downregulation of the HIF-system was not caused by an overexpression of the hypoxia-inducible prolyl hydroxylase domain proteins (PHDs) 2 and 3. Compared with normal myometrium, leiomyomas also show a poorer vascularization. Conversely, leiomyosarcomas show abundant expression of HIF-related markers despite a similar microvascular density. In conclusion, these results indicate that the strong activation of the HIF system observed in solid malignant tumors may be mechanistically linked to their transformed phenotype, rather than being a physiological reaction activated in a pathological context.
authors.affiliation: Institute of Physiology and Pathophysiology, University Medical Center, Mainz, Germany. arnmayer@uni-mainz.de
authors.forename: Arnulf
authors.initials: A
authors.lastname: Mayer
authors.forename: Michael
authors.initials: M
authors.lastname: Hoeckel
authors.forename: Angelika
authors.initials: A
authors.lastname: von Wallbrunn
authors.forename: Lars-Christian
authors.initials: LC
authors.lastname: Horn
authors.forename: Alexander
authors.initials: A
authors.lastname: Wree
authors.forename: Peter
authors.initials: P
authors.lastname: Vaupel
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology*; D014594:Uterine Neoplasms / Q000378:metabolism* / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000099162:Endothelial PAS Domain-Containing Protein 1