Some anti-angiogenic drugs have been found to only be effective in treating tumours at certain stages of development, indicating that its vasculature might change as the tumour develops. Erkki Ruoslahti, Doug Hanahan and colleagues have used a phage-display model to investigate these changes and to identify new therapeutic targets.

In two papers published in the November issue of Cancer Cell, they report using a phage-display system to identify peptides that home to the blood vessels of different tumour types or at different stages of development or progression. Phage libraries can produce more than a billion random peptide sequences. The authors first incubated tumour cells, ex vivo, with phage libraries and isolated the bound phage. These phage were injected into mice for a round of in vivo selection, tumour-binding phage were again isolated and their peptide-encoding DNA inserts were sequenced.

In the first study, Hoffman et al. identified three peptides that specifically bound tumour vessels in a mouse model of epidermal carcinogenesis induced by human papillomavirus 16. One of these recognized the neovasculature in dysplastic skin but not in carcinomas. Its sequence was identical to that found in a loop of kallikrein-9, so it might bind to a substrate of this protease that is specifically expressed in the developing tumour vasculature. Further studies are required to determine the role of this enzyme in tumour vasculogenesis.

In the second article, Joyce et al. searched for vascular markers that are specifically associated with tumours that form in RIP1–Tag2 mice, which are a model of pancreatic cancer. They characterized five peptides that selectively homed to neoplastic lesions in the pancreas but not to islet β-cell tumours that were injected subcutaneously, to xenotransplant tumours from a human cancer cell line, or to squamous-cell tumours of the skin. Three of the peptides homed specifically to angiogenic islets and co-localized with markers that identify endothelial cells or pericytes. Investigation of candidate binding moieties revealed several proteins that have been implicated in some aspect of angiogenesis, including PDGFs, WNTs, collagen XII, FGFR1 and TIE1.

This approach can therefore not only be used to identify new proteins that are involved in tumour angiogenesis but these peptides can be used to target imaging agents or anti-angiogeneic therapies specifically to tumour vessels.