Abstract
Abstract Although Apc mutation is widely considered an initiating event in colorectal cancer, little is known about the earliest stages of tumorigenesis following sporadic Apc loss. Therefore, we have utilized a novel mouse model that facilitated the sporadic inactivation of Apc via frameshift reversion of Cre in single, isolated cells. Our system enables tracking the fates of Apc-deficient intestinal stem cells. Our results suggest that consistent with Apc being a “gatekeeper”, loss of Apc early in life during intestinal growth leads to adenomas or increased crypt fission, manifested by fields of mutant but otherwise normal-appearing crypts. By contrast, later-occurring in life Apc loss has minimal consequences with mutant crypts being less prone to either increased crypt fission or adenoma formation. Using the stem cell specific Lgr5-CreER mouse, in which Apc loss is induced at defined ages and in varying numbers of crypts, we find that Apc-deficient field size again correlates with progression to adenoma. To evaluate this early stage prior to adenoma formation as a therapeutic target, we examined the chemopreventive effects of sulindac on Apc-deficient crypt field formation. We found that sulindac reduces adenomas and inhibits the morphologically occult spread of Apc-deficient crypts. Taken together these results suggest that: 1) A field of Apc-deficient crypts is an important intermediate between loss of Apc and adenoma formation, 2) Earlier Apc loss promotes increased crypt fission and subsequent field formation, and 3) Normal-appearing Apc-deficient crypts are potential unappreciated targets for cancer screening and chemoprevention. Citation Format: Jared M. Fischer, Darryl Shibata, R Michael Liskay. Occult progression by Apc-deficient intestinal crypts as a target for chemoprevention. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr B13.
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