Lack of hypoxic response in uterine leiomyomas despite severe tissue hypoxia.
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.
Institute of Physiology and Pathophysiology, Johannes Gutenberg University, Mainz, Germany. arnmayer@uni-mainz.de
Arnulf
A
Mayer
Michael
M
Höckel
Alexander
A
Wree
Cornelia
C
Leo
Lars-Christian
LC
Horn
Peter
P
Vaupel
D000328:Adult; D000951:Antigens, Neoplasm / Q000378:metabolism; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D049109:Cell Proliferation; D005260:Female; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D007889:Leiomyoma / Q000378:metabolism* / Q000473:pathology; D007890:Leiomyosarcoma / Q000378:metabolism* / Q000473:pathology; D008875:Middle Aged; D009215:Myometrium / Q000378:metabolism / Q000473:pathology; D010100:Oxygen / Q000378:metabolism*; D011446:Prospective Studies; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology; D000099162:Endothelial PAS Domain-Containing Protein 1
D000951:Antigens, Neoplasm; D051792:Basic Helix-Loop-Helix Proteins; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; D051272:Glucose Transporter Type 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010100:Oxygen; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C089226:CA9 protein, human