title: Targeting the NG2/CSPG4 proteoglycan retards tumour growth and angiogenesis in preclinical models of GBM and melanoma.
abstract: Aberrant expression of the progenitor marker Neuron-glia 2 (NG2/CSPG4) or melanoma proteoglycan on cancer cells and angiogenic vasculature is associated with an aggressive disease course in several malignancies including glioblastoma multiforme (GBM) and melanoma. Thus, we investigated the mechanism of NG2 mediated malignant progression and its potential as a therapeutic target in clinically relevant GBM and melanoma animal models. Xenografting NG2 overexpressing GBM cell lines resulted in increased growth rate, angiogenesis and vascular permeability compared to control, NG2 negative tumours. The effect of abrogating NG2 function was investigated after intracerebral delivery of lentivirally encoded shRNAs targeting NG2 in patient GBM xenografts as well as in established subcutaneous A375 melanoma tumours. NG2 knockdown reduced melanoma proliferation and increased apoptosis and necrosis. Targeting NG2 in two heterogeneous GBM xenografts significantly reduced tumour growth and oedema levels, angiogenesis and normalised vascular function. Vascular normalisation resulted in increased tumour invasion and decreased apoptosis and necrosis. We conclude that NG2 promotes tumour progression by multiple mechanisms and represents an amenable target for cancer molecular therapy.
authors.affiliation: Translational Cancer Research Group, Department of Biomedicine, University of Bergen, Bergen, Norway.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Agnete
authors.initials: A
authors.lastname: Svendsen
authors.forename: Justyna
authors.initials: J
authors.lastname: Kmiecik
authors.forename: Heike
authors.initials: H
authors.lastname: Immervoll
authors.forename: Kai Ove
authors.initials: KO
authors.lastname: Skaftnesmo
authors.forename: Jesús
authors.initials: J
authors.lastname: Planagumà
authors.forename: Rolf Kåre
authors.initials: RK
authors.lastname: Reed
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Per Øyvind
authors.initials: PØ
authors.lastname: Enger
authors.forename: Cecilie Brekke
authors.initials: CB
authors.lastname: Rygh
authors.forename: Martha
authors.initials: M
authors.lastname: Chekenya
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D006801:Humans; D007124:Immunoenzyme Techniques; D008279:Magnetic Resonance Imaging; D008545:Melanoma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D011509:Proteoglycans / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D011923:Rats, Nude; D019076:Transgenes / Q000502:physiology; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D011509:Proteoglycans; D034741:RNA, Small Interfering; D000099216:Chondroitin Sulfate Proteoglycan 4