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| Oncogenesis: A twist in the tale
Dean Felsher and colleagues show that by briefly inactivating c-MYC, a cell's response changes from promoting life to promoting death. Every good tale has a twist, and the fascinating story of c-MYC is no different. Dean Felsher and colleagues, reporting in the 5 July issue of Science, show that by briefly inactivating c-MYC, the cell's response changes from promoting life to promoting death, which has important implications for therapeutic strategies that target c-MYC.
Inactivating oncogenes would seem to be a sensible approach for treating cancer, but the toxicity that is associated with this can be high because most oncogenes are also essential for the growth of normal cells. Inactivating oncogenes for just a short period of time could solve the toxicity problem, but would tumours regrow following oncogene reactivation? The authors investigated this question by expressing c-MYC in mice lymphocytes behind the regulatable tetracycline promoter. This mouse model has recently been shown to induce osteogenic sarcomas — apparently c-MYC is also expressed in immature osteoblasts — which share features with human osteogenic sarcomas, such as frequent metastasis. Switching off c-MYC by administering doxycycline caused the tumours to regress and the cells to differentiate into bone. Culturing the osteogenic sarcoma cells in vitro allowed further analysis of the effects of switching off c-MYC. As expected, doxycycline treatment resulted in a rapid decrease in cell division; however, on removal of doxycycline and reactivation of c-MYC, cell division did not resume. Instead, cells underwent apoptosis — another event that is induced by c-MYC. So does apoptosis also occur in vivo? Both primary tumours and osteogenic sarcomas that were transplanted subcutaneously into mice were investigated; doxycycline was administered after the tumours had reached a certain size. As expected, the tumour cells differentiated into osteocytes — mature bone cells. Reactivating c-MYC by removing doxycycline after 10 days resulted in a decrease in the number of cells by 14 days, and TUNEL staining confirmed that this was due to apoptosis. The tumours did not regrow. Other reports have recently shown that the decision to live or die in response to c-MYC is determined by other genetic lesions — such as mutation of the apoptosis inhibitor Bcl-xL — so the ability of c-MYC alone to switch responses from proliferation to apoptosis is surprising and might be dependent on the cell type. Alternatively, the authors propose that inactivation of c-MYC, and the subsequent differentiation, might change the epigenetic context of the tumour cells, so that they are unable to evoke the proliferative response when c-MYC is reactivated. So, a therapeutic strategy that temporarily inactivates oncogenes such as c-MYC might be both effective and have low toxicity. Whether this also works for different tumour types, metastatic tumours and even human tumours remains to be determined. Emma Greenwood References
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