Abstract 816: Persistent effects of radiation on intestinal stem cells: implications for colorectal carcinogenesis

Abstract

Abstract Adult stem cells, similar to somatic cells, are also subject to a similar array of insults and are therefore presumed to accrue radiation damage. Unlike somatic cells, however, lesions arising in the stem cell compartment are propagated both to daughter stem cells and to downstream lineages through the processes of self-renewal and differentiation. The impact of damage accrued in individual stem cells can thus have major ramifications for all levels of the developmental hierarchy leading to cancer initiation and promotion in human as well as in animal models of human colorectal cancer (CRC) such as in APCMin/+. Differentiation of intestinal stem cell (ISC) and ordered migration of differentiated cells along crypt-villus axis is essential for maintenance of intestinal homeostasis and provides a model system to study stem cell alterations after radiation. Furthermore, considering that tumors in animal models of CRC almost exclusively develop in the small intestine and increased intestinal tumor frequency was radiation quality dependent, we investigated persistent effects of radiation quality on ISC as well as on differentiated intestinal epithelial cells in mice. Mice (6 to 8 week; C57BL/6J) were exposed to γ (0.5 and 2 Gy) and 56-Fe (0.5 and 1.6 Gy) radiation, samples were collected 7 d and 2 m after radiation exposure, and carcinogenic precursor events such as persistent oxidative stress and DNA damage were assessed. Higher persistently increased oxidative stress and oxidative DNA damage was observed after 56-Fe relative to γ radiation. However, increased oxidative stress did not increase cell death implying that the oxidative stress was sub-lethal. Autophagy, a self-cannibalistic process of cell involved in removing damaged cell and cell constituents, was consistently downregulated in a radiation quality dependent manner even 2 m after exposure suggesting persistence of damage-bearing cells. We believe radiation-induced autophagy downregulation and sub-lethal oxidative stress is working in tandem to trigger proliferative signaling such as PI3K/Akt and mTOR in intestinal cells. Taken together our results provide insight into radiation quality dependent persistent cancer-related molecular events, which could have altered phenotypic behavior of ISC such as proliferation, differentiation, and migration. Note: This abstract was not presented at the meeting. Citation Format: Kamal Datta, Shubhankar Suman, Santosh Kumar, Albert J. Fornace. Persistent effects of radiation on intestinal stem cells: implications for colorectal carcinogenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 816. doi:10.1158/1538-7445.AM2015-816