Abstract 2085: Interleukin 33 promotes tumor development, progression, and metastasis in colorectal cancer

Abstract

Abstract Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the United States, and the major cause of death is metastasis which is frequently targeted to the liver. Metastasis progression typically occurs without symptoms, and is often diagnosed at the final stage when little can be done to help the patient. Understanding the genetic and molecular mechanisms at the early stages can lead to the identification of bio-molecular markers that might be useful for early diagnosis or as therapeutic targets to alleviate morbidity and mortality from the disease. To identify factors that promote CRC progression and liver metastasis, we utilized an orthotopic mouse model of CRC metastasis to the liver that we had developed by cecal implantation of CT26 colon adenocarcinoma cells followed by sequential in vivo selection to isolate a highly liver metastatic CRC cell line, CT26-FL3. A whole genome microarray analysis was performed to compare the genetic signature of CT26-FL3 to its isogenic parental cell line CT26. We identified interleukin (IL) 33 a one of the genes that was highly overexpressed in CT26-FL3 as compared to CT26 cells. We found that increased IL-33 expression was associated with advancing stages of CRC in patient samples and that its expression was already elevated in nascent adenomas in the ApcMin/+ mouse, a genetic mouse model of intestinal tumorigenesis. To determine its role in promoting tumor progression, the murine colon cancer cell line MC38 was stably transfected with an Il33-expressing plasmid. We found that overexpression of IL-33 in MC38 cells promoted faster growth of the primary tumor and enhanced its metastasis into the liver. Taken together, the data suggest that IL33 might play an important role in the early development and progression to metastasis of CRC. IL-33 can function as a conventional cytokine or as a transcriptional regulator. It signals through a membrane bound ST2 receptor, as well as a soluble ST2 receptor that can act as a molecular sink to block its signaling pathway. Its potential as a viable marker for diagnosis or as a therapeutic target will be further determined in this study. Citation Format: Yu Zhang, Celestia Davis, Maria Marjorette Pena. Interleukin 33 promotes tumor development, progression, and metastasis in colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2085. doi:10.1158/1538-7445.AM2014-2085