PQD - 4 What properties of cells in a pre-malignant or pre-invasive field—sometimes described as the result of a cancer field effect—can be used to design treatments for a tumor that has emerged from this field or to block the appearance of future tumors? Background: Several lines of experimentation have shown that the cells that surround solid tumors often carry mutations or epigenetic changes characteristic of the tumor itself. These cells appear either normal or at least more like normal cells than the tumor, but their genetic changes suggest that they may be derived from the same precursor cell that led to the tumor. Early carcinogenesis studies developed the concept of the cancer field, essentially arguing that early carcinogenic events initiated a pre-malignant event that led to the expansion of a precursor lesion. An individual cell within this field later would suffer other tumorigenic events that led to full carcinogenesis. More recent sequencing and other –“omic” work has shown that seemingly normal cells adjacent to the tumor often carry a subset of alterations that are found in the tumor. These findings also have led to the hypothesis that the surrounding cells in the cancer field may be derived from a precursor to the tumor. In both these examples, it is suggested that the changes found in the surrounding cells may harbor early changes that are essential for the tumor precursor and thus for the derived tumor itself. This Provocative Question expands on these models and asks for experimental approaches that might use the changes seen in surrounding cells as potential targets to treat the tumor or to prevent the appearance of secondary tumors from these fields. Feasibility: Investigators will need to identify a useful tumor development model to study these types of changes. These could be in the mouse or there may be specific tumor and nearby non-tumor samples available for some human tissues. Comparison of –“omic” style studies would be the most likely source for the identification of potential differences in tumor and surrounding cells. These then could be used to build and test hypotheses about new targets for treatment or prevention of secondary tumor development. Implications of success: The results from these studies will provide a useful tumor development model for the identification of early stage lesions. Comparison of responses with drugs targeting early stage lesions versus late stage lesions will help us understand the importance of choosing among various targets based on their stage of appearance. In addition, such studies might suggest diagnostic steps that could identify early lesions and thus might help prioritize target selection. Similarly it may be possible to design trials to block the future development of secondary tumors based on the identification of the earliest lesions. Finally, the classification of lesions as either early or late stage promises to help us understand the development pattern of certain tumor mutations. |
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