Novel Association and Therapeutic Targeting of Neuropilin-1 and MUC1 in Pancreatic Cancer.

摘要

We hypothesized that MUC1, a transmembrane glycoprotein that is overexpressed in greater than 80% of pancreatic ductal adenocarcinoma induces a pro-angiogenic tumor microenvironment by increasing the level of NRP1 and VEGF thereby enhancing angiogenesis and metastasis. We report that MUC1hi PC cells and tumors in vitro and in vivo not only express higher levels of NRP1 but also express higher levels of VEGFR2 and its phosphorylation forms as well as secrete higher levels of VEGF than MUC1low PC cells. This enables the MUC1hi/NRP1hi cells to induce endothelial cell tube formation and generate long ectopic blood vessels and enhanced distant metastasis. In the proposal, we also hypothesized that blocking the interaction between VEGF165 and NRP1 within the tumor microenvironment will lead to therapeutic benefit. Indeed, in vivo blocking NRP1 significantly reduces tumor burden in the MUC1hi mouse and human tumors. For the in vivo MUC1-specific tumor targeting, we demonstrate that our antibody TAB004 binds MUC+ve tumors in vitro and in vivo by section staining or live animal imaging. Thus, we conclude that NRP1 may be a promising target for MUC1hi PC and in the future conjugating to the MUC1 antibody for targeted delivery may enhance its potency.