Finally, we demonstrate that increased CD44 Talatisamine expression is not responsible for the increase in metastatic penetrance the of HT29 LM3 cell line. Importantly, in vivo selection and isolation of liver-tropic CRC metastatic cells allowed us to study the biological mechanisms of CRC cancer metastasis and identify the mechanisms contributing to liver metastasis in CRC. The most devastating aspect of CRC is the emergence of liver metastases, which is responsible for the majority of deaths from this disease. Thus, to understand the molecular mechanisms of metastasis is one of the most important issues in cancer research. According to the concept of tumor cell heterogeneity, highly metastatic cells are present as a sub-population in a primary tumor. At present, it is impossible identify metastatic and non-metastatic cells in the primary tumor. In this study, we utilized an in vivo selection model to identify molecular Mycophenolic acid markers for the prediction of metastatic potential of CRC cells. This model of injecting cancer cells into the spleen, harvesting hepatic metastases, and re-injecting into the spleen, creates highly metastatic cell lines as confirmed by a greater number of lymph and liver metastases. Similarly, our study demonstrated that the cells created through in vivo selection cycle yielded extensive liver metastasis and that aggressive behavior of these cells is associated with alterations in CD44 expression, c-MET activity and increased ability of CRC cells to adhere to endothelial cells. Therefore, the model of in vivo selection for metastatic cells can be a useful tool for studying genetic changes occurring in cells when they acquire the metastatic phenotype. Furthermore, the utilization of this model allows for a better understanding of the mechanisms that drive cancer progression and can be used as a tool to discover and develop potential therapeutic targets for CRC metastasis. c-MET and CD44 are co-expressed in a number of cancers, such as pancreatic cancer and CRC. Pancreatic cancer cells with a high expression of both c-MET and CD44 were shown to have a greater tumorigenic potential. Furthermore, expression of both proteins have been correlated with a shorter patient survival period in CRC, and a recent study from our laboratory showed that CD44 and c-MET activation is associated with an increase in CRC metastasis. Consistent with these findings, the results of our current study demonstrate that an increase in both the expression of CD44 and the activation of cMET correlates with an increase in the metastatic potential of the HT29 LM3 cell line. CD44 and c-MET collaboration, and their interactions on the plasma membrane, lead to the activation of downstream signaling pathways that promote cancer progression. On the other hand, several studies have found that the activation of c-MET is independent of CD44. Our results suggest that in the HT29 LM3 cell line, CD44 and c-MET act independently in the presence or absence of HGF, a c-MET ligand. Discrepancies between studies could be explained by differences in the cell lines used and indicate that the extent of the interaction between CD44 and c-MET may be cell type specific. As both proteins have been associated with a poor prognosis in a multitude of cancers, the further study of their interaction in metastatic cell lines is critically important and may lead to new therapeutic targets. To better understand the role of CD44, we utilized two populations of HT29 derived cells, CD44+ and CD442.