Aging has a profound impact on tissue regeneration and cancer incidence. However, the mechanisms of how aging reduces the function of stem cells, alters the transformability of stem cells to beget tumors, or influences tumor progression are poorly understood. Although aging is the single biggest risk factor for cancer in humans and laboratory animals, cancer has been modeled and interrogated solely in young rodent models. Our system for addressing these questions is the mammalian intestine where a majority of intestinal stem cells (ISCs) in the small intestine and colon express Lgr5. Our preliminary studies suggest that ISC numbers are diminished and less proliferative in old mice and humans and that elderly ISCs are less functional in an in vitro organoid (3-D mini-intestinal) assay of stem cell function, indicating that cell autonomous mechanisms contribute to intestinal stem cell aging. Finally, we find that aged mice, like aged humans, develop spontaneous intestinal adenomas and carcinoma; however, the mechanisms of how aging reduces the function of stem cells, alters the transformability of stem cells to give rise to tumors, or influences tumor progression/metastasis are poorly understood. In this proposal, we will study how aging influences the genesis, progression, and treatment response of intestinal adenomas and carcinomas in inducible, genetically defined mouse models of intestinal tumors. Specifically, we will establish aging mouse colonies to interrogate how age- related changes in the tumorigenic potential of intestinal stem and progenitor cells contribute to enhanced tumor incidence in old age (Aim 1); that aging has autonomous and non-autonomous effects on tumor progression (Aim 2), and that aging alters the treatment response of intestinal tumors to chemotherapy or radiation (Aim 3).
Although cancer is mostly a disease of aging, most of our understanding of cancer has been based on pre- clinical studies in young animal models. Here, we will investigate the impact of age on tumor initiation, progression, and response to treatment utilizing established inducible intestinal cancer mouse models and novel genetic engineering approaches. Our proposal will enable the identification of more tolerable cancer treatments for the elderly.