TY - JOUR
T1 - Lectin-deficient TNF mutants display comparable anti-tumour but reduced pro-metastatic potential as compared to the wild-type molecule
AU - Lucas, Rudolf
AU - Montesano, Roberto
AU - Pepper, Michael S.
AU - Hafner, Michael
AU - Sablon, Erwin
AU - Dunant, Yves
AU - Grau, Georges E.
AU - De Baetselier, Patrick
AU - Mnnel, Daniela
AU - Fransen, Lucie
PY - 2001/2/15
Y1 - 2001/2/15
N2 - In this study, we characterised the anti-tumour as well as the pro-metastatic activities of TNF mutants deficient in their lectin-like activity.16,19 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.
AB - In this study, we characterised the anti-tumour as well as the pro-metastatic activities of TNF mutants deficient in their lectin-like activity.16,19 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.
KW - Angiogenesis
KW - Lectin
KW - Metastasis
KW - TNF
KW - Therapy
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U2 - 10.1002/1097-0215(200002)9999:9999<::AID-IJC1090>3.0.CO;2-Y
DO - 10.1002/1097-0215(200002)9999:9999<::AID-IJC1090>3.0.CO;2-Y
M3 - Article
C2 - 11251979
AN - SCOPUS:0035866033
SN - 0020-7136
VL - 91
SP - 543
EP - 549
JO - International Journal of Cancer
JF - International Journal of Cancer
IS - 4
ER -