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23 Dec 2011 06:35 AM

Positive Feedback And Tumorigenesis, A Vicious Circle That Promotes Cell Proliferation


Cancer cells are essentially immortal. The acquisition of an unlimited capacity to divide the process of immortalization is a central event in the genesis of tumors. Normally, cells are subject to stringent mechanisms which control their proliferation. Together these ensure that pre-malignant cells are induced to enter a senescent, non-dividing state or to undergo apoptosis, i.e. commit suicide. A research team led by Professor Heiko Hermeking and Dr. Antje Menssen from LMU's Institute of Pathology has now discovered how the regulatory protein c-MYC subverts these controls, thus facilitating the growth of tumors. High levels of c-MYC, which are present in most tumor cells, activate SIRT1, an enzyme that inhibits both senescence and apoptosis. The new results show that the two proteins actually form a positive feedback loop, in that SIRT1 also promotes the activity of c-MYC. Normal cells avoid this vicious circle because they keep the gene that codes for c-MYC turned off, unless they receive growth-promoting signals. In tumor cells, this mechanism no longer functions and the cells can proliferate unchecked. Their latest findings have implications for cancer treatment, as Menssen explains: "Our results indicate that tumor types in which c-MYC plays a crucial role, such as lymphomas and colon or breast cancers, should be especially susceptible to pharmacological inhibitors that interrupt the feedback loop. In particular, combinations of drugs that interact with different components of the loop could provide a new route to effective therapies of these malignancies." (PNAS 19.-23.12)



The c-MYC protein is involved in the control of many basic biological functions, including cell growth and division. It is therefore vital for processes that require cell proliferation, such as embryonic development and the generation of all the cell types in the blood. Overproduction of c-MYC, on the other hand, can have lethal consequences for the organism. Continuous synthesis...
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