1. Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia.
- Author
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Mayer A, Höckel M, Wree A, Leo C, Horn LC, and Vaupel P
- Subjects
- Adult, Antigens, Neoplasm metabolism, Apoptosis, Basic Helix-Loop-Helix Transcription Factors metabolism, Carbonic Anhydrase IX, Carbonic Anhydrases metabolism, Cell Proliferation, Female, Glucose Transporter Type 1 metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Immunoenzyme Techniques, In Situ Nick-End Labeling, Leiomyoma pathology, Leiomyosarcoma pathology, Middle Aged, Myometrium metabolism, Myometrium pathology, Prospective Studies, Uterine Cervical Neoplasms pathology, Hypoxia metabolism, Leiomyoma metabolism, Leiomyosarcoma metabolism, Oxygen metabolism, Uterine Cervical Neoplasms metabolism
- Abstract
Hypoxia is now established as a key factor influencing the pathophysiology of malignant growth. Among other effects, hypoxia modulates the expression of a multitude of genes through the induction of hypoxia-inducible transcription factors. This differential gene expression favors angiogenesis, cell survival, an invasive/metastatic phenotype, and resistance to anticancer therapies. Because benign tumors do not exhibit these traits, one might expect these entities to be neither hypoxic nor to induce the genetic hypoxia response program. To test this hypothesis, an investigation of the oxygenation status of 17 leiomyomas and 1 leiomyosarcoma of the uterus using polarographic needle electrodes (Eppendorf pO(2) sensor) and the expression of hypoxia-related markers in biopsy specimens of the same tumors was carried out. Marker expression in eight additional archival leiomyosarcomas was also assessed. Leiomyoma tissue was generally found to be severely hypoxic, with median oxygen (O(2)) partial pressure values ranging from 1 to 5 mm Hg. In contrast, none of the hypoxia-related markers hypoxia-inducible factor (HIF)-1alpha, HIF-2alpha, glucose transporter-1, or carbonic anhydrase IX were expressed in any leiomyoma. Larger intercapillary distances were correlated with a poorer oxygenation status. Conversely, the expression of hypoxia-related markers was abundant in the leiomyosarcomas and they also exhibited a high-turnover phenotype (significantly increased proliferation and apoptosis). Uterine leiomyoma might therefore represent a state of oxygen-limited proliferation. Malignancy in the same organ system is associated with growth and metabolism beyond tissue-inherent limitations leading to the induction of hypoxia-related markers, thereby contributing to a self-perpetuating aggressive phenotype.
- Published
- 2008
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