Abstract
Inhibiting the growth of tumor vasculature represents one of the relevant strategies against tumor progression. Between all the different pro-angiogenic molecular targets, plasma membrane glycosphingolipids have been under-investigated. In this present study, we explore the anti-angiogenic therapeutic advantage of a tumor immunotherapy targeting the globotriaosylceramide Gb3. In this purpose, a monoclonal antibody against Gb3, named 3E2 was developed and characterized. We first demonstrate that Gb3 is over-expressed in proliferative endothelial cells relative to quiescent cells. Then, we demonstrate that 3E2 inhibits endothelial cell proliferation in vitro by slowing endothelial cell proliferation and by increasing mitosis duration. Antibody 3E2 is further effective in inhibiting ex vivo angiogenesis in aorta ring assays. Moreover, 3E2 treatment inhibits NXS2 neuroblastoma development and liver metastases spreading in A/J mice. Immunohistology examination of the NXS2 metastases shows that only endothelial cells, but not cancer cells express Gb3. Finally, 3E2 treatment diminishes tumor vessels density, proving a specific therapeutic action of our monoclonal antibody to tumor vasculature. Our study demonstrates that Gb3 is a viable alternative target for immunotherapy and angiogenesis inhibition.
Highlights
Anti-angiogenic therapy, including monoclonal antibodies and small molecule inhibitors, is considered a relevant approach that limits tumor progression by inhibiting tumor vasculature development [1]
The anti-angiogenesis therapies mainly focus on blocking growth cytokines or related receptors, or over-expressed proteins anchored in the endothelial cell membrane
We demonstrated by FACS the exclusive binding of 3E2 to Gb3expressing cell lines, HMEC-1 (3E2-positive cells: 68.2%; mean of fluorescence (MF): 568.3; Fig. 1B) and RAJI (3E2-positive cells: 87.9%; MF: 423.8), compared to the Gb3-negative cell line, NXS2 (2.9% of 3E2-positive cells; MF: 156.5)
Summary
Anti-angiogenic therapy, including monoclonal antibodies (mAbs) and small molecule inhibitors, is considered a relevant approach that limits tumor progression by inhibiting tumor vasculature development [1]. The anti-angiogenesis therapies mainly focus on blocking growth cytokines or related receptors, or over-expressed proteins anchored in the endothelial cell membrane. GSLs are expressed mainly at the outer leaflet of the plasma membrane [4] They consist of a hydrophobic ceramide membrane anchor and a hydrophilic cell surface-exposed oligosaccharide chain, accessible to cell surface recognition molecules, making them candidate targets for oncological applications [3]. Gb3 is expressed in tumor cells, and in the vasculature surrounding and within the tumor [15] This latter finding may reflect an overexpression of Gb3, especially in angiogenic endothelial cells, which could be targeted by an anti-cancer agent
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
