Abstract 1330: A reliable mouse model for hepatic metastasis of colorectal cancer
Authors: Zhang Yu , Davis Celestia , Peña Maria Marjorette O. 
Published: August 2012

Colorectal cancer (CRC) is the second leading cause of cancer deaths in the United States and most deaths occur due to metastasis. Metastasis is the spread of cancer cells from the primary tumor to distant organs and is the final most devastating step of the disease. When colon cancer is diagnosed prior to metastasis, the five-year survival rate is approximately 90%, however, after metastasis has occurred, the survival rate drops to less than 10%. Metastasis is a complex multistep process that occurs through multiple interactions between cells in the primary tumor and host derived cells in the primary tumor and target organ microenvironment. The early stages provide an opportunity for early diagnosis and therapeutic intervention to block its progression, however they occur silently and undetected in the patient. Because of this, little is known regarding the genetic and molecular events that direct these steps and metastasis is often diagnosed at the final stage when little can be done for the patient. To understand the mechanisms of the early stages, it is important to develop a mouse model that can faithfully recapitulate the progression of CRC from the growth of primary tumor to liver metastasis, the frequent target organ. Current models utilize splenic or portal vein injection which by-pass the early stages of the disease. We established a mouse model of CRC with a high frequency of spontaneous liver metastasis by cecal implantation of a highly metastatic mouse carcinoma cell line, isolated by in vivo education of CT26 colon carcinoma cells, into immunocompetent Balb/c mice. When injected into the cecum of Balb/c mice, these cells give rise to liver metastasis with a ten-fold higher frequency compared to the parental cell line. They proliferate at a higher rate in vivo when injected into Balb/c mice as compared to ex vivo in cell culture. They are more invasive than CT26 cells in wound healing, matrigel invasion, and migration assays. Analyses of blood sera from tumor bearing mice by immunoblotting suggest that they can induce an in vivo microenvironment with a higher metastatic potential compared to CT26 cells. We labeled these cells with mCherry fluorescent protein and firefly luciferase to allow analyses of metastatic progression by in vivo imaging, confocal microscopy, and flow cytometry. We combined this model with transplantation of bone marrow cells expressing the green fluorescent protein to begin to decipher the complex interactions between tumor and bone marrow derived cells (BMDCs) necessary to promote metastasis. Analysis of the liver in tumor bearing mice showed that BMDCs are recruited into the liver prior to the arrival of metastatic cells. Therefore, this model recapitulates all stages of CRC growth and progression to liver metastasis and will facilitate the elucidation of the genetic, molecular, and cellular mechanisms that mediate the crosstalk between the primary tumor and target organ microenvironment to promote hepatic metastasis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1330. doi:1538-7445.AM2012-1330