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See Latest ArticlesExpression and Functional Regulation of Myoglobin in Epithelial Cancers
American Journal of Pathology, 06/23/09
Flonta SE et al. - The study provides evidence that myoglobin, previously thought to be restricted to myocytes, is expressed at high levels by human carcinoma cells. The authors suggest that myoglobin expression is part of a cellular program aimed at coping with changed metabolic and environmental conditions associated with neoplastic growth.
Alberto Bardelli, 06/24/09
| Myoglobin is a multi-functional heme protein thought to be expressed exclusively in myocytes. Its importance in oxygen transport and free radical scavenging has been extensively characterized. We reasoned that myoglobin could also play a role in cancer cells. This hypothesis is supported by several lines of evidence indicating that overcoming hypoxia is a key aspect of tumor progression. Accordingly, the mechanisms by which cancer cells cope with increased hypoxic conditions are a very active and exciting field of research. Current efforts are concentrated on the Hypoxia Inducible Factor-1 alpha (HIF-1 alpha), the master controller of hypoxia-induced transcription and on its regulatory apparatus. However, we noted that muscle cells, that face harsh hypoxic conditions during active myofiber contraction, have adapted to this adverse environmental state by expressing high levels of myoglobin. Myoglobin is a multifunctional heme protein capable of buffering intracellular pO2 and of reducing hypoxia-associated oxidative stress. We reasoned that cancer cells could adopt a similar strategy by expressing proteins specialized in oxygen transport and metabolism. We, therefore, sought to establish whether myoglobin could play a role in the development of solid tumors that are known to face hypoxic conditions during their progression. We started our study by analyzing whether these proteins were expressed in cancer cell lines. To our great surprise we detected, using two independent experimental approaches, high levels of myoglobin transcript and protein in human breast carcinoma cells. We then used an immunohistochemical technique to evaluate myoglobin expression in a comprehensive panel of human breast tumor samples. This analysis showed that breast carcinomas cells -but not normal breast epithelial cells- express high levels of myoglobin from the earliest stages of tumor development. Similar results were obtained by analyzing a number of lung, ovary and colon carcinomas. To assess whether myoglobin’s expression could be functionally modulated we then subjected breast carcinoma cells to a series of stimuli that are associated with tumor progression, including hypoxia, oxidative stress and mitogenic signals. Consistent with a role of myoglobin in O2 transport and ROS/NO scavenging, we found that myoglobin levels could be increased following exposure of cells to low O2 or NO donors. Myoglobin was also transiently but distinctly induced when the cells where treated with the Epidermal Growth Factor (EGF), a well know mitogen. Our data have both immediate and far reaching implications for translational and clinical cancer research and will undoubtedly generate new exciting lines of investigation. For example, Mb expression in epithelial cancer tissues could be used as a tumor marker. In this regard, the measurements of Mb levels in the serum of cancer patients could be attempted with the technologies that are routinely used to monitor Mb expression in acute myocardial infarction. The finding that mice lacking a functional Mb gene are viable, fertile and only display a very mild muscular defect suggests that inhibition of Mb might be feasible in mammals without incurring in serious side effects. It is therefore tempting to speculate that targeting its functions by pharmacological agents or more advanced molecular tools could be feasible and of relevance to cancer therapy. |
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