A team of researchers headed by Professor Roland Stauber of Mainz University's ENT clinic has identified a molecular mechanism used by cancer cells to "defend" themselves against chemotherapeutics in an attempt to ensure their own survival. Both the messenger substance nitrogen monoxide (NO) and the protein survivin play a role in this.
The results of the study, carried out in patients with head-neck tumors, recently appeared in the International Journal of Cancer (Fetz et al., 2008). In another publication in the journal Cancer Research (Engels et al., 2008), which appeared in the summer of this year, researchers had already reported the discovery of a similar mechanism in ovarian cancer. This raises the possibility that the "NO/survivin axis" may be a common denominator that plays a role in a large number of different types of cancer.
Every year, at least 10,000 people develop malignant cancer of the head-neck region. Despite a positive outcome after surgery, radiotherapy, and/or chemotherapy, the majority of these patients suffer a relapse after initial treatment, with the development of distant metastases being a frequent complication. The molecular causes of the development and progression of head-neck cancers and their response to treatment are still not yet adequately understood.
In the recent comprehensive study, researchers from the University Hospital of Johannes Gutenberg University Mainz were for the first time able to identify the molecular mechanism by which the messenger substance nitrogen monoxide (NO) contributes towards the growth and the resistance to treatment of head-neck cancers. NO plays a role in numerous physiological but also pathological processes: Thus, for example, most cancer cells produce increased amounts of NO and in result appear to gain a survival advantage. Until recently, it was not clear how they do this. The researchers in Mainz have now managed to demonstrate that NO or the NO-producing protein - known as iNOS in medical jargon - induces the synthesis of another protein called survivin.
The name survivin is derived from the verb "to survive", which also offers a clue to its function: survivin was only recently identified by researchers as one of the central factors important with regard to the occurrence of relapses and the resistance of head-neck cancers to treatment, as it prevents the programmed death (apoptosis) of cancerous cells. (Engels et al., 2007) The increased formation of iNOS - and therefore the messenger substance NO - results in activation of certain signal pathways in the cancer cells, which ultimately leads to an increase in the production of survivin. Its properties as an inhibitor of programmed cell death are in turn exploited by the cancer cells to protect themselves against attack by chemo- or radiotherapy so that cancer cells employ, as it were, the "iNOS/survivin" axis as a survival aid.
"This new molecular understanding of the defense mechanisms of cancer cells now allows us to focus on these defensive mechanisms," reports Professor Roland Stauber, head of the Department of Molecular and Cellular Oncology. The results of tests conducted on cultured cancer cells within the framework of this study have been promising, as they have shown that the combined use of chemical iNOS inhibitors and a blockade of survivin synthesis can efficiently kill off tumor cells.
The researchers are even one step ahead: "We already managed to demonstrate earlier this year that this is a mechanism that is not simply restricted to head-neck cancers when we discovered the significance of the iNOS/survivin axis in ovarian cancer," explained Professor Stauber. "These results confirm our multidisciplinary approach, in which we conduct basic research to identify mechanisms the effects of which can then be verified in a range of tumor entities in close co-operation with various medical disciplines. This also allows us to quickly and effectively identify mechanisms that are not restricted to a specific indication. This ultimately benefits patients, as the results of the initial research benefit them sooner."
The challenge for the clinicians and researchers now lies in testing the efficacy and safety of this strategy in tumor models, thus better enabling them to assess the potential clinical benefits of the approach. "These complex investigations can, however, only be carried out with the help of national sponsors," pointed out Professor Stauber. "We therefore hope that we will continue to receive support for our indication-overlapping research strategy in the future."
- Engels et al. NO Signaling Confers Cytoprotectivity through the Survivin Network in Ovarian Carcinomas. Cancer Research, 2008; 68 (13): 5159 DOI: 10.1158/0008-5472.CAN-08-0406
- Engels et al. Dynamic intracellular survivin in oral squamous cell carcinoma: underlying molecular mechanism and potential as an early prognostic marker. The Journal of Pathology, 2007; 211 (5): 532 DOI: 10.1002/path.2134
- Fetz, V., Bier, C., Habtemichael, N., Schuon, R., Schweitzer, A., Kunkel, M., Engels, K., Kovacs, A. F., Schneider, S., Mann, W., Stauber, R. H., and Knauer, S. K. Survivin-mediated chemoresistance is modulated by iNOS in head and neck cancer cells. International Journal of Cancer, DOI: 10.1002/ijc.24182
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