Topic: NCI Provocative Questions

How does susceptibility of exposure to cancer risk factors change during development?

Background: Cells at various stages of their developmental life cycle will respond differently to risk exposures. A simple well-known example of differential response is seen for cells in early development, which may be more susceptible to exposures that rely on rapid DNA synthesis, than when cells reach mature stages where division is less common. Similarly, exposure risks may be more important when cells are in other stages or under other types of pressures. This Provocative Question seeks experimental approaches that can be used to distinguish when cancer risks are most dangerous and then asks what molecular mechanisms underlie these differences.

Feasibility: Since the measurement of changes induced by cancer risk factor exposure is key to success for this question, it will be essential to identify appropriate systems for study. Longitudinal studies in humans are beyond the scope of this question; therefore, applicants are encouraged to identify other systems where exposure effects can be linked to various outcomes and studied in more detail. Experiments in mice will provide one potential system where both the effect and outcome of exposure can be measured and studied. In addition, some existing human exposure samples may be available to such studies. The goal of these experiments is to move beyond simple observational studies and begin to determine what molecular mechanisms account for the differential responses to risk exposure.

Implications of success: Learning what cellular processes promote and inhibit the effects of exposure will help us understand important variations in the early stages of tumor development. These differences will provide needed insight into how one might identify targets for prevention and early detection. Such information will also help the community prepare better guidance for the management of cancer risk.

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