Abstract
Introduction: The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood. Apoptosis and induction of inflammation by tumor released cytokines as tumor escape mechanisms have been proposed to play an important role in colorectal carcinogenesis.Methods: Expression of Tumor necrosis factor-alpha (TNF-α) was analyzed in colorectal cancer specimen and the cancer cell line HT-29 by immunohistochemistry and RT-PCR. TNF-αexpression on protein and mRNA level were correlated with clinical characteristics and impact on survival. TNFR-1 was co-labelled with TNF-αand CD8+ cytotoxic T cells in immunofluorescence double staining experiments.Results: 94% (n=98/104) of the patients with CRC expressed TNF-α. High TNF-αexpression was significantly associated with positive lymph node stage and recurrence of the tumor. Multivariate analysis revealed high TNF-αexpression as an independent prognostic factor. Immunohistochemistry was correlated with RT-PCR results (τ=0.794). Immunofluorescence double staining experiments revealed increased TNFR-1 expression by CD8+ cells.Conclusion: TNF-αexpression by tumor cells may be an efficient immunological escape mechanism by inflammation-enhanced metastases and probably by induction of apoptosis in tumor-infiltrating CD8+ immune cells resulting in a down regulation of the tumoral immune response. Our data support the role of tumor-derived TNF-αexpression as an important promoter of tumoral immune escape mechanisms and malignant progression, and suggest that analysis on either protein (immunohistochemistry) or RNA level (RT-PCR) can be used effectively in this respect. Targeting TNF-αmay be a promising option, especially in cases with high TNF-αexpression and positive lymph node metastases.
Highlights
The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood
The role of lymphadenectomy seemed well established over years, with tumor involvement of lymph nodes clearly recognized as one of the strongest independent prognostic factor, its role with respect to survival benefit has only recently been questioned: One group in Germany around the biostatistician Hölzel [24,25] has suggested from indirect lines of evidence based on epidemiologic data, that lymph node metastases are not able to metastasize
There were significant correlations between the first and the second assessment for intraobserver reliability (TNF-α expression: τ = 0.812, p < 0.0001, 95% CI 0.742– 0.866; Intraclass Correlation Coefficient (ICC) for average measures was 0.9804, 95% CI 0.9700–0.9870) and between two observers (TNFα expression: τ = 0.9593, p < 0.0001, 95% CI 0.9404–0.9722; ICC for average measures was 0.9777; 95% CI 0.9672–0.9849)
Summary
The progressive growth of malignancies is accompanied by a decline in the immune response through mechanisms which are poorly understood. The role of lymphadenectomy seemed well established over years, with tumor involvement of lymph nodes clearly recognized as one of the strongest independent prognostic factor, its role with respect to survival benefit has only recently been questioned: One group in Germany around the biostatistician Hölzel [24,25] has suggested from indirect lines of evidence based on epidemiologic data, that lymph node metastases are not able to metastasize This is merely a hypothesis, there seems surprisingly little evidence in the literature for its ad hoc falsification, extensively stimulating basic research regarding lymphatic spread
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