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Expression of tumor necrosis factor by different tumor cell lines results either in tumor suppression or augmented
Z Qin1, S Krüger-Krasagakes, U Kunzendorf
1Institut für Immunologie, Universitätsklinikum Steglitz, Freie Universität Berlin, Federal Republic of Germany.
Abstract:
Tumor necrosis factor (TNF) produced by tumor cells after gene transfer can effectively suppress the growth of locally growing tumors. We wanted to test the effects of "local" TNF on the growth of a highly metastatic cell line. Therefore, a recombinant retrovirus allowing expression of the TNF gene by the beta-actin promotor has been constructed and used to infect the two tumor cell lines EB and ESB, which grow as solid tumor or metastasize, respectively. Expression of TNF by EB cells resulted in their rapid and dose-dependent rejection. In sharp contrast, mice injected with ESB cells producing similar amounts of TNF showed no signs of tumor suppression, but rather had reduced survival rates that correlated with enhanced hepatic metastases. The accelerated formation of liver metastases by ESB TNF cells could be reversed by an anti-TNF mAb. These results demonstrate the opposite effects TNF may have on tumor growth: suppression of a locally growing tumor and promotion of metastasis formation.
Insights
Tumor necrosis factor (TNF) can suppress local tumor growth but paradoxically promote metastasis. Gene transfer of TNF into metastatic cells accelerated liver metastases, highlighting TNF
Area of Science:
- Oncology
- Immunology
- Gene Therapy
Background:
- Tumor necrosis factor (TNF) gene transfer into tumor cells can inhibit local tumor growth.
- The role of TNF in highly metastatic cancer remains less understood.
Purpose of the Study:
- To investigate the differential effects of locally produced TNF on solid tumor growth versus metastasis.
- To evaluate TNF's impact on a highly metastatic cell line (ESB) compared to a non-metastatic one (EB).
Main Methods:
- Constructed a recombinant retrovirus for beta-actin promoter-driven TNF gene expression.
- Infected EB (solid tumor) and ESB (metastatic) cell lines with the retrovirus.
- Administered infected cells to mice and monitored tumor growth, survival, and metastasis, including using anti-TNF monoclonal antibodies (mAbs).
Main Results:
- TNF expression by EB cells led to rapid, dose-dependent tumor rejection.
- In contrast, ESB cells producing TNF showed no tumor suppression but accelerated hepatic metastases and reduced survival.
- The enhanced liver metastasis in ESB TNF-producing tumors was reversible with anti-TNF mAb treatment.
Conclusions:
- Local TNF production exhibits dichotomous effects on tumor progression: suppression of local growth but promotion of metastasis.
- Targeting TNF may require context-specific strategies, considering its dual role in cancer.
- The study underscores the complex interplay between TNF, tumor cell type, and metastatic potential.