Institute of Physiology and Pathophysiology, University Medical Center, Mainz, Germany.
Adv Exp Med Biol. 2010;662:399-405. doi: 10.1007/978-1-4419-1241-1_58.
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.
我们实验室的结果对宫颈癌中肿瘤缺氧与 HIF 介导的蛋白表达之间是否存在直接定量关系提出了质疑。在本研究中，通过免疫组织化学、Western blot 和 RT-PCR 分析良性肿瘤实体——子宫肌瘤中的 HIF 相关标志物表达，进一步探讨了这一问题。通过术中极谱针电极测量评估了 17 个子宫肌瘤的氧合状态。结果表明，这些肿瘤严重且均匀缺氧，但不会诱导 HIF-1alpha、HIF-2alpha、葡萄糖转运蛋白 (GLUT)-1 或碳酸酐酶 (CA)IX。此外，HIF 系统的下调不是由缺氧诱导的脯氨酰羟化酶结构域蛋白 (PHD)2 和 3 的过表达引起的。与正常子宫肌层相比，子宫肌瘤的血管化程度也较差。相反，平滑肌肉瘤尽管具有相似的微血管密度，但仍表现出丰富的 HIF 相关标志物表达。总之，这些结果表明，在实体恶性肿瘤中观察到的 HIF 系统的强烈激活可能与其转化表型有关，而不是在病理环境中激活的生理反应。
