Abstract 253: IMP1 mediates tumor size and dissemination into the blood in colorectal cancer cell xenografts.

Introduction Colorectal cancer (CRC) remains amongst the top causes of cancer-related deaths in the United Sates, with nearly 60,000 deaths per year. Despite significant emphasis placed on improving early detection, only 40% of new CRC cases are diagnosed with localized-stage disease, which nonetheless is associated with a 5-year survival rate of 90%. However, the 5-year survival rate for regional and distal metastases is 68% and 11%, respectively, underscoring the importance of elucidating the underlying mechanisms for these invasive processes. Several recent studies support the emerging paradigm that the same factors that promote “stemness” in embryonic or adult stem cells may also play a critical role in tumorigenesis. We hypothesize that Insulin-like growth factor II mRNA binding protein 1 (IMP1) may be such a factor in the intestine. Imp1 −/ − mice exhibit dwarfism and increased perinatal lethality due to impaired gut formation, suggesting a potential role in stem cell maintenance in the intestine. Our previous data demonstrate that IMP1 loss decreases proliferation and anchorage-independent growth, and increases apoptosis in CRC cell lines. We hypothesize that IMP1 modulates tumor growth in vivo, and its overexpression may enhance disease progression. Methods In the current study, we generated stable CRC cell lines with IMP-1 overexpression and performed xenograft experiments. Furthermore, because IMP-1 overexpression in human CRC tumors correlates with increased metastasis, we used FACS to assess tumor dissemination into the blood. Finally, in order to determine mechanisms attributable to IMP1 and enhanced metastasis, we examined whether IMP1 modulates a tumor-initiating cell phenotype. Results Both control and IMP1 overexpressing tumors exhibited features of poorly differentiated carcinoma, and IMP1 overexpressing cells grew larger tumors. Mice harboring IMP1 overexpressing tumors had more tumor cells circulating in the blood at sacrifice. We did not observe gross metastases within the 8-week time course of xenograft tumor growth, however we cannot discount the possibility of establishment of micro-metastases. IMP1 overexpression led to a dramatic increase in CD24+CD44+ cells in vitro, suggesting that IMP1 may promote a tumor-initiating cell phenotype. Conclusions Our data suggest that IMP1 may play an important role in regulating primary tumor size as well as the ability of tumor cells to disseminate into the blood, possibly through the pro-survival advantage imparted by enhancing a tumor-initiating cell phenotype. Future studies will be required to assess whether the IMP1-mediated increase in tumor-initiating cells alone promotes metastasis, or whether additional factors are needed to establish tumor cells in distal sites. Funding: NIH F32 DK093207-01, NIH R01 DK056645-12, NIH U01 DK007066 Citation Format: Kathryn E. Hamilton, Prateek S. Katti, Christopher M. Hahn, Sonya R. Davey, Emma T. Lundsmith, Andrew D. Rhim, Anil K. Rustgi. IMP1 mediates tumor size and dissemination into the blood in colorectal cancer cell xenografts. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 253. doi:10.1158/1538-7445.AM2013-253