Evaluation of immunological escape mechanisms in a mouse model of colorectal liver metastases.
BACKGROUND
The local and systemic activation and regulation of the immune system by malignant cells during carcinogenesis is highly complex with involvement of the innate and acquired immune system. Despite the fact that malignant cells do have antigenic properties their immunogenic effects are minor suggesting tumor induced mechanisms to circumvent cancer immunosurveillance. The aim of this study is the analysis of tumor immune escape mechanisms in a colorectal liver metastases mouse model at different points in time during tumor growth.


METHODS
CT26.WT murine colon carcinoma cells were injected intraportally in Balb/c mice after median laparotomy using a standardized injection technique. Metastatic tumor growth in the liver was examined by standard histological procedures at defined points in time during metastatic growth. Liver tissue with metastases was additionally analyzed for cytokines, T cell markers and Fas/Fas-L expression using immunohistochemistry, immunofluorescence and RT-PCR. Comparisons were performed by analysis of variance or paired and unpaired t test when appropriate.


RESULTS
Intraportal injection of colon carcinoma cells resulted in a gradual and time dependent metastatic growth. T cells of regulatory phenotype (CD4+CD25+Foxp3+) which might play a role in protumoral immune response were found to infiltrate peritumoral tissue increasingly during carcinogenesis. Expression of cytokines IL-10, TGF-beta and TNF-alpha were increased during tumor growth whereas IFN-gamma showed a decrease of the expression from day 10 on following an initial increase. Moreover, liver metastases of murine colon carcinoma show an up-regulation of FAS-L on tumor cell surface with a decreased expression of FAS from day 10 on. CD8+ T cells express FAS and show an increased rate of apoptosis at perimetastatic location.


CONCLUSIONS
This study describes cellular and macromolecular changes contributing to immunological escape mechanisms during metastatic growth in a colorectal liver metastases mouse model simulating the situation in human cancer.
Grimm
Martin
M
Department of General Surgery, Molecular Oncology and Immunology, University of Wuerzburg Hospital, Germany.
Gasser
Martin
M
Bueter
Marco
M
Strehl
Johanna
J
Wang
Johann
J
Nichiporuk
Ekaterina
E
Meyer
Detlef
D
Germer
Christoph T
CT
Waaga-Gasser
Ana M
AM
Thalheimer
Andreas
A
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D015179:Colorectal Neoplasms / Q000276:immunology / Q000473:pathology*; D004195:Disease Models, Animal; D053222:Fas Ligand Protein / Q000096:biosynthesis; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008113:Liver Neoplasms / Q000276:immunology / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D010641:Phenotype; D019014:fas Receptor / Q000096:biosynthesis
D015704:CD4 Antigens; C505661:FASLG protein, human; C418974:FOXP3 protein, human; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D019014:fas Receptor