Abstract 3888: Host-tumor interactions that promote liver metastasis of colorectal cancer.

Abstract

Abstract Colorectal cancer (CRC) is the third most frequent cancer in the United States. Metastases is the major cause of death, reducing the five-year survival to less than 12%, with liver as the frequent target organ. Metastasis occurs due to productive collaborations between tumor cells and host-derived cells in the tumor microenvironment. Molecular signals from the primary tumor mediate long distance communication with the hematopoietic compartment and stimulate immune cell mobilization to the primary tumor and target organ environments. These interactions promote invasiveness of tumor cells in the primary lesion and the establishment of a pre-metastatic niche in the distant organ where cancer cells can attach and develop into a metastatic lesion. Therefore, understanding these interactions can provide us with valuable opportunities for early diagnosis of metastasis or blocking its progression by disengaging the cancer cells from their metastasis promoting networks. To understand these interactions and identify the molecular regulators, particularly at the early stages, we established an orthotopic mouse model of liver metastasis of CRC that can recapitulate all stages of tumor growth and metastasis. We used in vivo selection to isolate a highly metastatic cell line, CT26-FL3, from CT26 colon adenocarcinoma cells. Tumors derived from CT26-FL3 were more proficient in inducing a metastasis-friendly host environment compared to CT26 cells. These suggest that transition from CT26 to CT26-FL3 might be due to genetic alterations resulting from interactions between tumor cells and the host environment. We hypothesized that molecules secreted by the primary tumor can direct genetic changes in the liver microenvironment creating a fertile niche for invading cancer cells. Identifying these alterations in both the tumor cells and the host microenvironment, will allow us to understand the mechanisms by which host-tumor interactions promote liver metastasis of CRC. We carried out microarray analyses to determine the genetic signatures of the parental CT26 and highly metastatic CT26-FL3 cells, and to determine the genetic changes in the liver microenvironment in mice bearing CT26-FL3 tumors prior to metastasis. The results identified genes in signaling, cancer, metabolic, and various pathways that were differentially expressed between CT26 and CT26-FL3, and between liver from tumor-bearing and non-tumor bearing mice. More importantly, several genes in the chemokine and the cytokine-cytokine receptor pathways were expressed up to 50-fold or higher in CT26-FL3 cells or in the liver microenvironment of tumor-bearing mice. The gene products are likely mediators of the complex cross-talk between the primary tumor and the liver microenvironment. Using our orthotopic mouse model, we will assess their potential alone or in combination as viable markers for early diagnosis or as therapeutic targets to alleviate metastatic disease. Citation Format: Yu Zhang, Celestia Davis, Maria Marjorette Pena. Host-tumor interactions that promote liver metastasis of colorectal cancer. [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 3888. doi:10.1158/1538-7445.AM2013-3888