Abstract B27: Characterization of tumor-host interactions that promote liver metastasis of colorectal cancer

The leading cause of death from colorectal cancer is metastasis. The five year survival rate drops from 95% when the disease is at the localized stage to approximately 12% when metastasis has occurred. Because of its asymptomatic progression, metastasis is often detected at the final stage when little can be done, and little is now regarding the mechanisms that direct the early steps when intervention can potentially have an impact on its progression. In order to elucidate the mechanisms, we developed a mouse model of CRC metastasis to the liver, the frequent target organ of metastasis by cecum implantation of CT26 mouse colon adenocarcinoma cells into immunocompetent host Balb/cByJ mice. This model can recapitulate disease progression from the growth of the primary tumor to establishment of metastatic lesions within a defined time frame. Using this model, we isolated isogenic cell lines that gave rise to a high frequency of spontaneous metastasis to the liver. Implantation of the most highly metastatic CT26-FL3 cell line gave rise to liver metastasis in 90% of host mice, ten-fold higher than the parental CT26 cell line, in as early as 10 days. Initial characterization revealed that these cells expressed elevated levels of genes whose products promoted invasion, migration, and mobilization of bone marrow derived cells (BMDCs) to the pre-metastatic liver. We determined the genetic signatures of the CT26 and CT26-FL3 cells and that of the pre-metastatic and metastatic liver environment by microarray analyses to identify genes that might mediate the crosstalk between the primary tumor and target organ to promote progression of liver metastasis. The results identified genes encoding proteins that might act as potent effectors of the immune response that are induced in the early stage of metastasis. We characterize these proteins and assess their potential as viable biomarkers for early diagnosis of metastatic disease or as targets to deter metastatic progression. Our mouse model, therefore, can be an important platform to characterize metastatic cells and to elucidate tumor-host interactions and mechanisms that drive liver metastasis of CRC. In addition, it can be a valuable tool for pre-clinical evaluation of therapies targeted against metastatic CRC. Citation Format: Maria Marjorette O. Pena, Yu Zhang, Celestia Davis. Characterization of tumor-host interactions that promote liver metastasis of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference: The Translational Impact of Model Organisms in Cancer; Nov 5-8, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(11 Suppl):Abstract nr B27.