Cross-species comparison of biological themes and underlying genes on a global gene expression scale in a mouse model of colorectal liver metastasis and in clinical specimens.
BACKGROUND
Invasion-related genes over-expressed by tumor cells as well as by reacting host cells represent promising drug targets for anti-cancer therapy. Such candidate genes need to be validated in appropriate animal models.


RESULTS
This study examined the suitability of a murine model (CT26/Balb/C) of colorectal liver metastasis to represent clinical liver metastasis specimens using a global gene expression approach. Cross-species similarity was examined between pure liver, liver invasion, tumor invasion and pure tumor compartments through overlap of up-regulated genes and gene ontology (GO)-based biological themes on the level of single GO-terms and of condensed GO-term families. Three out of four GO-term families were conserved in a compartment-specific way between the species: secondary metabolism (liver), invasion (invasion front), and immune response (invasion front and liver). Among the individual GO-terms over-represented in the invasion compartments in both species were "extracellular matrix", "cell motility", "cell adhesion" and "antigen presentation" indicating that typical invasion related processes are operating in both species. This was reflected on the single gene level as well, as cross-species overlap of potential target genes over-expressed in the combined invasion front compartments reached up to 36.5%. Generally, histopathology and gene expression correlated well as the highest single gene overlap was found to be 44% in syn-compartmental comparisons (liver versus liver) whereas cross-compartmental overlaps were much lower (e.g. liver versus tumor: 9.7%). However, single gene overlap was surprisingly high in some cross-compartmental comparisons (e.g. human liver invasion compartment and murine tumor invasion compartment: 9.0%) despite little histolopathologic similarity indicating that invasion relevant genes are not necessarily confined to histologically defined compartments.


CONCLUSIONS
In summary, cross-species comparison on a global gene expression scale suggests the validity of an animal model representing the human situation. The actual yield of potential target genes depends on several variables including the animal model, choice of inclusion criteria, inherent species differences and histologic assessment.
Bandapalli
Obul Reddy
OR
Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220/1, 69120 Heidelberg, Germany. reddy.bandapalli@med.uni-heidelberg.de
Kahlert
Christoph
C
Hellstern
Victoria
V
Galindo
Luis
L
Schirmacher
Peter
P
Weitz
Jürgen
J
Brand
Karsten
K
D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology*; D015536:Down-Regulation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D023421:Models, Animal; D013045:Species Specificity