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-1α, HIF-2α, 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.