Global Analysis of Host Tissue Gene Expression in the Invasive Front of Colorectal Liver Metastases

Host cell reactions are a crucial determinant for tumorous invasion. We analysed on a genome wide scale gene expression differences between microdissected tissues taken from unaffected liver tissue of a human colorectal tumor (LS174) growing in the livers of nude mice and tissue from the host part of the invasive front. Due to the low degree of interspecies cross hybridization of 15% as determined on Affymetrix microarrays, our xenograft model allowed for the distinction of genes of murine versus human origin even if the respective tissues could not be isolated separately. With this type of model the reaction of host cells on tumorous invasion can be studied without the common interference of contaminating tumor cells. Using the Gene Ontology classification we were able to determine patterns of up- and down-regulated genes in the liver part of the invasive front. We observed a pronounced overrepresentation e.g. of the GO-terms “extracellular matrix“, “cell communication“, “response to biotic stimulus“, “structural molecule activity“ and “cell growth“, indicating a very pronounced host cell response to tumorous invasion. On the single gene level hepatic stellate cell (HSC) activation markers were overrepresented in the liver part of the invasion front. Immunohistochemistry and qPCR confirmed an activation of HSC as well as an increased number of HSC in the invasive front as compared to the non invaded liver tissue. In summary our data demonstrate the feasibility of an interspecies differential gene expression approach on a genome wide scale.