Abstract A36: Expression profiling reveals characteristics of host-tumor interactions that promote liver metastasis of colorectal cancer
Authors: Zhang Yu , Davis Celestia , Peña Maria Marjorette O. 
Published: August 2014

Colorectal cancer (CRC) is the third most frequent cancer and the third leading cause of cancer deaths in the United States. Metastasis is the major cause of death. When diagnosed at the localized stage, the five-year survival rate is approximately 90%, however, after metastasis has occurred, the survival rate drops to less than 12%. The most frequent target organ is the liver. Successful metastasis depends on productive collaborations between tumor cells and host-derived cells in the tumor microenvironment as well as long distance communication mediated by molecular signals from the primary tumor that stimulate immune cell mobilization between the primary tumor and target organ environments and the hematopoietic compartment. Prior to the arrival of metastatic cells in the secondary organ, signals from the primary tumor direct organ specific mobilization of bone marrow derived cells to prepare a niche that promotes the attachment of cancer cells and their subsequent development into a metastatic lesion. These complex processes occur asymptomatically, thus despite its devastating impact on the patient, metastasis is often diagnosed at the final stage when very little can be done to alleviate its effects.

To understand the mechanisms underlying these processes 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 mouse carcinoma cell line, CT26-FL3, from CT26 colon adenocarcinoma cells. Tumors derived from CT26-FL3 were more proficient in inducing a metastasis-friendly host environment as compared to the parental cell line. We hypothesized that the transition from CT26 to CT26-FL3 was driven by genetic alterations resulting from interactions between tumor cells and host environment, thereby contributing to a higher incidence of liver metastasis from tumors derived from CT26-FL3. We further hypothesized that molecules secreted by the primary tumor can direct genetic changes in the liver microenvironment that promote the creation of a fertile niche for invading cancer cells. By identifying these alterations in both the tumor cells and the host microenvironment, we can begin to understand the mechanisms by which host-tumor interactions promote liver metastasis of CRC.

We therefore carried out microarray analyses to: 1) determine the genetic signatures of the parental CT26 and highly metastatic CT26-FL3 cells, and 2) determine the genetic changes in the liver microenvironment in mice bearing CT26-FL3 tumors prior to metastasis. The results identified a number of genes in signaling, cancer, metabolic, and various signaling pathways that were differentially expressed between CT26 and CT26-FL3, and between liver from tumor-bearing mice and non-tumor bearing mice. More importantly, the results showed that several genes in the chemokine and the cytokine-cytokine receptor pathways were expressed by up to 50-fold or higher in CT26-FL3 cells or in the liver microenvironment of tumor-bearing mice. The products of these genes are likely mediators of the complex cross-talk between the primary tumor and the liver microenvironment. Using our orthotopic mouse model, we examine the kinetics of the changes in gene expression during metastatic progression to assess the potential of these gene products alone or in combination as viable markers in blood serum for early diagnosis of metastasis, or as targets to alleviate metastatic disease.

Citation Format: Yu Zhang, Celestia Davis, Maria Marjorette O. Peña. Expression profiling reveals characteristics of host-tumor interactions that promote liver metastasis of colorectal cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A36.