Abstract
BackgroundA crucial step in tumorigenesis is the recruitment of novel vasculature to the site of neoplasia. Currently, a number of high throughput techniques are employed to identify genes, mRNA and proteins that are aberrantly expressed in tumor vasculature. One drawback of such techniques is the lack of functional in vivo data that they provide. Bacteriophage (phage) display has been demonstrated in vivo to select peptides that home to tumors and tumor vasculature. The peptides can be compared to sequences of putative cancer-related proteins, in order to identify novel proteins essential for tumorigenesis.ObjectivesIt was hypothesized that an in vivo selection for phage which targeted human breast cancer xenografts could identify peptides with homology to cancer-related proteins for in vivo imaging of breast cancer.MethodsFollowing four rounds of in vivo selection in human MDA-MB-435 breast cancer xenografted mice, peptide 3-G03 was discovered with significant homology to a putative secreted protein termed EGFL6. Egfl6 mRNA is upregulated in several transcriptomic analyses of human cancer biopsies, and the protein may play a role in tumor vascularization.ResultsEgfl6 mRNA expression was demonstrated in MDA-MB-435 cells and EGFL6 protein was secreted from these cells. Based on homology of 3-G03 to EGFL6, an EGFL6 peptide was synthesized and shown to target MDA-MB-435 cells. EGFL6 peptide was radiolabeled with 111In and analyzed for biodistribution and tumor imaging capabilities. Single photon emission computed tomography imaging revealed uptake of the peptide in a manner consistent with other tumor vasculature targeting agents.
Highlights
Much effort has been placed on identifying the process of human tumor vascularization [1]
Epidermal Like Growth Factor-6 (Egfl6) mRNA expression was demonstrated in MDA-MB-435 cells and EGFL6 protein was secreted from these cells
DOTA-EGFL6 peptide was radiolabeled with 111In and purified peptide was prepared at 1.85 MBq/mL in sterile Phosphate Buffered Saline (PBS)
Summary
Much effort has been placed on identifying the process of human tumor vascularization [1]. The network of blood vessels in each organ, including tumors, is differentiated by tissue specific expression of ligands and receptors [3]. These proteins serve as a molecular address, and in the case of tumorigenesis, may prove effective for delivery of imaging agents or cytotoxic drugs [4]. A number of high throughput techniques are employed to identify genes, mRNA and proteins that are aberrantly expressed in tumor vasculature. One drawback of such techniques is the lack of functional in vivo data that they provide. The peptides can be compared to sequences of putative cancer-related proteins, in order to identify novel proteins essential for tumorigenesis
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