scfv anti-heparan sulfate antibodies unexpectedly activate endothelial and cancer cells through p38 mapk implications for antibody-based targeting of heparan sulfate proteoglycans in cancer英文论文.pdfVIP

ScFv Anti-Heparan Sulfate Antibodies Unexpectedly Activate Endothelial and Cancer Cells through p38 MAPK: Implications for Antibody-Based Targeting of Heparan Sulfate Proteoglycans in Cancer 1 2 1,3 Helena C. Christianson , Toin H. van Kuppevelt , Mattias Belting * ˚ 1 Department of Clinical Sciences, Section of Oncology, Lund University and Skane University Hospital, Lund, Sweden, 2 Department of Biochemistry, Nijmegen Centre for ˚ Molecular Life Sciences, Nijmegen, The Netherlands, 3 Skane University Hospital and Oncology Clinic, Lund, Sweden Abstract Tumor development requires angiogenesis and anti-angiogenic therapies have been introduced in the treatment of cancer. In this context, heparan sulfate proteoglycans (HSPGs) emerge as interesting targets, owing to their function as co-receptors of major, pro-angiogenic factors. Accordingly, previous studies have suggested anti-tumor effects of heparin, i.e. over- sulfated HS, and various heparin mimetics; however, a significant drawback is their unspecific mechanism of action and potentially serious side-effects related to their anticoagulant properties. Here, we have explored the use of human ScFv anti- HS antibodies (aHS) as a more rational approach to target HSPG function in endothelial cells (ECs). aHS were initially selected for their recognition of HS epitopes localized preferentially to the vasculature of patient glioblastoma tumors, i.e. highly angiogenic brain tumors. Unexpectedly, we found that these aHS exhibited potent pro-angiogenic effects in primary human ECs. aHS were shown to stimulate EC differentiation, which was associated