<b>Areas covered</b>: Areas covered in this review include the molecular pathways of angiogenesis in glioblastoma, specifically the overexpression of vascular endothelial growth factor (VEGF) and robust formation of tumor neovasculature.
The chimeric protein toxin was directed toward the neovasculature of cancer cells by fusing a truncated version of Pseudomonas exotoxin A (PE38) to human vascular endothelial growth factor (VEGF) and to the single chain variable fragment (scFv) of anti-Her2/neu.
Further, a significant decrease in the ascites VEGF secretion level was parallel with a drastic reduction in tumoral neovasculature as evidence for angiogenic parameters.
Identification of target molecules specific for angiogenic vascular endothelial cells (VEC), the inner layer of pathological neovasculature, is critical for discovery and development of neovascular-targeting therapy for angiogenesis-dependent human diseases, notably cancer, macular degeneration and endometriosis, in which vascular endothelial growth factor (VEGF) plays a central pathophysiological role.
Here, we show how vaccinia virus-mediated expression of a single-chain antibody targeting VEGF resulted in radiosensitization of the tumor-associated vasculature.
Given that the transient nature of VEGF gene expression provokes instability of neovasculature, we hypothesized that repeated administration would provide efficient tissue protection.
Using a BM transplantation model with GFP(+) transgenic mice as BM donors and nude mice as recipients, we evaluated the effect of SDF-1alpha on the recruitment of BM-derived cells to VEGF(165)-inhibited TC/siVEGF(7-1) tumors, as well as its effect on neovasculature development, vessel morphology and tumor growth.
In the bone marrow transplant mice, double immunofluorescent staining revealed that the combination of CK-induced mobilization and local VEGF-2 gene transfer resulted in a significant increase in the number of bone marrow-derived cells incorporating into the neovasculature, indicating that recruitment and/or retention of bone marrow-derived progenitors was enhanced by mobilization and that local VEGF-2 gene transfer can provide signals for recruitment or incorporation of circulating progenitor cells.
Self-assembling nanoparticles with siRNA were constructed with polyethyleneimine (PEI) that is PEGylated with an Arg-Gly-Asp (RGD) peptide ligand attached at the distal end of the polyethylene glycol (PEG), as a means to target tumor neovasculature expressing integrins and used to deliver siRNA inhibiting vascular endothelial growth factor receptor-2 (VEGF R2) expression and thereby tumor angiogenesis.
Vascular endothelial growth factor (VEGF) is the most potent growth factor of tumor neovasculature, has been shown to be up-regulated in every tumor studied thus far, and is correlated with tumor stage and progression.
A retroviral vector was constructed for gene therapy with VEGF positioned downstream of its 27-amino acid leader sequence, which promoted secretion of a catalytic immunotoxin containing either truncated diphtheria toxin or Pseudomonas exotoxin A. VEGF was chosen on the basis of the expression of VEGF receptor on endothelial cells in the tumor neovasculature.