Abstract B96: Hepatic microenvironment-dependent colon cancer genes: New targets for antimetastatic therapy.

The liver is the first organ where colon cancers deliver their soluble molecules and circulating cancer cells. The effect of colon cancer products results in the “liver prometastatic reaction”, a special microenvironment supporting the experimental hepatic colonization process of colon cancer cells. However, at present it is unclear which genes tumor-activated hepatic cells specifically regulate in colon cancer cells for supporting their intrahepatic growth. We used a microenvironmental approach to the study of genes associated with colon cancer cells9 ability to metastasize to the liver in patients with advanced colon cancer. First we determined by cDNA microarrays and reverse transcription-PCR hepatic metastasis genes not expressed in tumor-unaffected areas of the same liver but expressed in the primary tumors of patients that developed metastases within 5 years of diagnosis. Among identified hepatic metastasis genes, we next selected those that overlapped with genes whose expression level changed in HT-29 human colon carcinoma cells given the conditioned medium from tumor-activated primary cultured human hepatocytes and hepatic stellate cell-derived myofibroblasts. Second, we determined genes co-expressed in hepatic metastases and tumor-unaffected liver tissue, but neither in the primary tumors nor in normal liver. From this gene category we selected those expressed either by cultured HT-29 cells treated with liver cell-conditioned media, or by primary cultured liver cells receiving HT-29-conditioned media. Identified genes suggested that metastatic colon cancer have hepatomimetic properties, and that hepatic tissue expressed colon cancer specific genes under the regulation of tumor-derived factors. A third approach was to determine genes of tumor unaffected areas from livers bearing colon cancer metastasis, not expressed by colon cancer cells. This gene category represented the genetic background of the liver prometastatic reaction induced by colon cancer derived factors, and therefore, genes at the colon cancer metastasis microenvironment. We identified microenvironment-related colon cancer genes whose expression level was regulated by hepatocytes, hepatic myofibroblasts or both. We also identified some genes representing the liver prometastatic reaction whose specific role in the pathogenesis of hepatic metastasis has already been reported. Identified genes may provide a new target context for therapeutic innovation in the cancer metastasis microenvironment of colon cancer patients. On the one hand, by developing drugs able to block liver factors supporting colon cancer metastasis genes and therefore preventing effects of the “liver prometastatic reaction” in colon cancer patients. On the other hand, by developing drugs able to block those factors from colon cancer cells able to induce the prometastatic microenvironment of the liver. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B96.