Differential gene expression associated with the tropism between hepatic and pulmonary metastases in colorectal cancers.

Abstract

e21062 Background: In metastatic colorectal cancers tumor cells were already disseminated, prior to surgical resection of the primary tumors, but micrometastases remain dormant until proper colonization mechanisms are activated. Specific aims of this study are, 1) to examine the colonization pathways and genes newly activated in metastatic tumors by longitudinal pair-wise comparisons between primary-to-metastatic tumors and 2) to understand tropism between colon-to-liver and colon-to-lung metastases at gene expression level. Methods: Total 24 tumor samples were prepared as longitudinal pairs from 6 hepatic, and 6 pulmonary cases. In these samples mRNA levels were quantitatively determined for 215 genes that were previously reported to play roles in metastasis, cytokines signaling, or angiogenesis, as provided as RT2 Profiler TM PCR arrays (PAHS-022, 024, 028). Unsupervised hierarchical clustering of Ct values and heat map analyses of DCt values were carried out using web based data analysis program, and 17-gene tropism signature was selected for stratification of the hepatic and the pulmonary metastases. Results: Ct values of 23 duplicated genes and 5 house-keeping genes showed plate-to-plate correlation of 0.92. Unsupervised hierarchical clustering of the Ct values from the Metastasis Arrays revealed that the hepatic metastases were indistinguishable from the primary colorectal cancers (n=5/6), but the lung metastases were highly diversified (n=6/6). Cytokine Array data also showed the divergence of pulmonary metastases from the primary colorectal cancers (n=6/6). Heat map analyses of DCt values from the Metastasis Arrays identified 17-gene tropism signature that was sufficient not only to distinguish the liver and the lung metastases, but also reconstitute the clustering of primary tumors with the hepatic metastases. Conclusions: Intrinsic difference existed between the pulmonary and hepatic metastases of colorectal origins among the tested samples. 17-gene tropism signature was identified, and further genomic and clinical studies are in process to validate their potentials as therapeutic targets to treat pulmonary metastases of colorectal cancers.