Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the wild-type molecule.
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.
Lucas
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Department of Pharmacology, University Medical Center, Geneva, Switzerland. rudolf.lucas@uni-konstanz.de
Montesano
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Pepper
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Hafner
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Sablon
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Dunant
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Grau
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De Baetselier
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Männel
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Fransen
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D000818:Animals; D018827:Carcinoma, Lewis Lung; D002417:Cattle; D002448:Cell Adhesion; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D005260:Female; D005354:Fibrosarcoma / Q000235:genetics / Q000378:metabolism; D037102:Lectins / Q000378:metabolism*; D008168:Lung / Q000378:metabolism; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009154:Mutation; D009336:Necrosis; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000378:metabolism; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000737:chemistry* / Q000235:genetics* / Q000627:therapeutic use
D037102:Lectins; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D003094:Collagen