Related Experiment Videos
Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the
R Lucas1, R Montesano, M S Pepper
1Department of Pharmacology, University Medical Center, Geneva, Switzerland. rudolf.lucas@uni-konstanz.de
Abstract:
In this study, we characterised the anti-tumour as well as the pro-metastatic activities of TNF mutants deficient in their lectin-like activity.1619 We report that, despite reduced systemic toxicity as compared to wild-type (wt) mTNF, a (T104A) and a (T104A-E106A-E109A) mTNF mutant (triple mTNF) retained most of their necrotic and tumouristatic activities, as measured in a CFS-1 fibrosarcoma and a B16BL6 melanoma tumour model, respectively. These mutants also conserved their anti-angiogenic activity, as measured in an in vitro endothelial morphogenesis assay.26 In contrast, the pro-metastatic activity of the T104A and the triple mTNF mutants in the CFS-1 fibrosarcoma and the 3LL-R Lewis lung carcinoma tumour model was significantly lower than that of the wt molecule. These results thus indicate that the lectin-like domain of TNF is not implicated in its necrotic, tumouristatic and anti-angiogenic activities, but that it can contribute to the pro-metastatic effect of the cytokine. In conclusion, in view of their reduced systemic toxicity and pro-metastatic capacity, but their retained anti-tumour activities, lectin-deficient TNF mutants might prove to be therapeutically interesting alternatives to wt TNF.
Insights
Tumor necrosis factor (TNF) mutants lacking lectin-like activity retain anti-tumor effects but show reduced metastasis. These findings suggest potential therapeutic applications for these modified TNF variants.
Area of Science:
- Immunology
- Cancer Biology
- Molecular Biology
Background:
- Tumor necrosis factor (TNF) is a key cytokine involved in inflammation and immunity.
- TNF exhibits both anti-tumor and pro-metastatic activities, making its therapeutic use complex.
- The lectin-like domain of TNF has been implicated in its various biological functions.
Purpose of the Study:
- To investigate the role of the lectin-like domain of TNF in its anti-tumor and pro-metastatic activities.
- To characterize TNF mutants deficient in lectin-like activity.
- To evaluate the therapeutic potential of these modified TNF mutants.
Main Methods:
- Characterization of TNF mutants (T104A and triple mTNF) lacking lectin-like activity.
- Assessment of necrotic and tumoristatic activities in CFS-1 fibrosarcoma and B16BL6 melanoma models.
- Evaluation of anti-angiogenic activity using an in vitro endothelial morphogenesis assay.
- Analysis of pro-metastatic activity in CFS-1 fibrosarcoma and 3LL-R Lewis lung carcinoma models.
Main Results:
- TNF mutants showed reduced systemic toxicity compared to wild-type (wt) mTNF.
- Mutants retained significant necrotic and tumoristatic activities.
- Anti-angiogenic activity was conserved in the lectin-deficient TNF mutants.
- Pro-metastatic activity was significantly lower in TNF mutants compared to wt TNF.
Conclusions:
- The lectin-like domain of TNF is not essential for its necrotic, tumoristatic, and anti-angiogenic functions.
- The lectin-like domain contributes to the pro-metastatic effect of TNF.
- Lectin-deficient TNF mutants offer a promising therapeutic alternative due to retained anti-tumor efficacy and reduced toxicity and metastatic potential.