Abstract SY37-03: Targeting developmental pathways in colon cancer cells and stem cells

Abstract

Abstract The small intestine epithelium renews every 2 to 5 days, making it one of the most regenerative mammalian tissues. Genetic inducible fate mapping studies have identified two principal epithelial stem cell pools in this tissue. One pool consists of columnar Lgr5-expressing cells that cycle rapidly and are present predominantly at the crypt base. The other pool consists of Bmi1-expressing cells that largely reside above the crypt base. In the absence of Lgr5-expressing cells, progeny production by Bmi1-expressing cells increased, indicating that Bmi1-expressing stem cells compensate for the loss of Lgr5-expressing cells. Interestingly, both stem cell compartments can serve as cell of origin for the development of colorectal cancer in mice. The Pathways that regulate self-renewal, commitment as well as the interplay between these two populations remain to be clearly defined but are likely to involve Wnt Notch Hedgehog. The Notch, Wnt and Hedgehog signaling pathways play critical roles during embryonic development. These factors modulate proliferation or differentiation of numerous cell types and are also involved in the regulation of the self-renewal and/or differentiation of embryonic and adult stem cells. It is however becoming increasingly clear that these pathways are involved in tumorigenesis when reactivated in adult tissues through mutations or overexpression of pathway components. Aberrant reactivation of the Hedgehog (Hh) pathway in adult tissues can lead for example to the development of cancers such as basal cell carcinoma (BCC) and medulloblastoma is often the result of inactivating mutations in PATCHED (PTCH) or activating SMOOTHENED (SMO) mutations. Notch1 mutations are found in most T-cell acute lymphoblastic leukemias and activation of the Wnt pathway, often through APC (adenomatous polyposis coli) gene mutations, is observed in a majority of colon adenocarcinomas. However all 3 pathways play a role in normal gut homeostasis and may be involved in some aspect of colon tumorigenesis. In addition to the development of agents targeting these pathways in tumors where they are mutated we will discuss the effect on inhibiting Wnt, Notch and Hedgehog signaling on stem cells in the normal intestine and in tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY37-03. doi:1538-7445.AM2012-SY37-03