Abstract C9: MACC1 enhances intestinal tumorigenesis in ApcMin mice.

Abstract

Abstract Colorectal cancer is one of the most frequently occurring malignancies worldwide. Although about 50% of the patients with colorectal cancer can be cured by surgery and multimodal treatment, the successful outcome of CRC patients is seriously affected by the metastatic dissemination of primary tumors. We have previously identified a novel gene termed MACC1 (metastasis-associated in colon cancer 1), which has a strong prognostic value for colon cancer metastasis, enhancing the metastatic potential of colon cancer cells both in vitro and in vivo. To further understand the role of MACC1 on colorectal carcinogenesis, we generated a transgenic mouse model with intestine-specific overexpression of MACC1 (vil-MACC1). Additionally, we crossed these animals with ApcMin mice to create vil-MACC1/ApcMin mice. Four vil-MACC1 founder lines showed MACC1 transgene mRNA and protein expression in the small intestine and colon, but not in other organs including liver, lung, and kidney. Although the villin promoter drove MACC1 expression through the whole vertical (crypt-villus) and horizontal (duodenum-colon) intestinal axes, higher levels of transgenic MACC1 were detected in the small intestine as compared with the colon, and in the villi as compared with the crypts. Histopathological analysis of the intestine of 3-months old vil-MACC1 mice showed no abnormalities as compared with age-matched wild-type littermate controls. Similar analysis is currently being performed in older animals (≥ 1 year old). In line with what we observed in the vil-MACC1 animals, the vil-MACC1/ApcMin mice displayed a similar pattern of MACC1 mRNA and protein expression throughout the whole small intestine and colon. Remarkably, transgenic overexpression of MACC1 in the intestine of vil-MACC1/ApcMin mice significantly increased the total number of adenomas, as compared with ApcMin littermate controls (P = 0.0146). Moreover, the small intestine of vil-MACC1/ApcMin mice displayed an increased number of large-sized adenomas (diameter ≥ 3 mm; P = 0.0033). Additionally, we also observed a slight increase in spleen size in vil-MACC1/ApcMin mice, as compared with ApcMin controls. Despite the increased tumor burden on vil-MACC1/ApcMin mice, we didn't observe a significant difference on survival between the two animal groups. We report here for the first time the generation of a mouse model with genetically engineered MACC1 expression. More importantly, our current findings demonstrate that MACC1 is instrumental for intestinal adenoma formation and development in vivo. These results further strengthen the importance of MACC1 for intestinal tumorigenesis and metastasis, underlying its potential as a new target for colorectal cancer treatment. Funded by the Alexander von Humboldt Foundation, the Wilhelm Sander Foundation, the Preclinical Comprehensive Cancer Center and the German Cancer Consortium Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C9. Citation Format: Clara Lemos, Cynthia Voss, Boris Jerchow, Wolfram Haider, Ulrike Stein. MACC1 enhances intestinal tumorigenesis in ApcMin mice. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C9.