Abstract 415: Human embryonic stem cell-derived endothelial cells as cellular delivery vehicles for targeting therapy of metastatic breast cancer

Abstract

Abstract Recent reports revealed that endothelial progenitor cells (EPCs) isolated from bone marrow, cord blood or embryos have been experimentally utilized to deliver therapeutic agents for cancer treatment. Their potential in cancer therapy highlights the need for a consistent and renewable source of endothelial cells for clinical applications. Moreover, one of the most critical issues for ensuring success of endothelial therapy is the development of technologies for non-invasive monitoring of the distribution of transplanted cells and kinetic of tumor progression or regression. We generated human embryonic stem cell-derived endothelial cells (hESC-ECs) from H9 cell line. The hESC-ECs resemble adult endothelial cells HUVEC in endothelial markers and angiogenesis potential. In vitro study revealed the paracrine effects of hESC-ECs on tumor cells using conditioned medium (EC-CM). After treated with EC-CM, human breast cancer cells MDA-MB-231 proliferated slower and exhibited a higher apoptosis rate in low-serum condition, and the migration ability was impaired. Furthermore, we introduced a multitude of non-invasive, quantitative, functional imaging techniques with reporter gene methods to probe breast cancer model processes, and to track the hESC-ECs for targeting therapy in vivo by firefly luciferase (Fluc)/renilla luciferase (Rluc) imaging. We transduced hESC-ECs with triple fusion (TF) reporter gene containing the herpes simplex virus truncated thymidine kinase (HSV-ttk), renilla luciferase (Rluc) and RFP (RL-RFP-HSV-ttk). The NOD/SCID mice breast cancer metastasis model was established by tail vein injection of 1.5×106 MDA-MB-231 cells, which carry a reporter system encoding the gene of Fluc and GFP. Bioluminescence imaging (BLI) revealed that hESC-ECs can be sequenced in tumor sites for more than 72 hours. When given pro-drug ganciclovir (GCV), targeting HSV-ttk gene, the MDA-MB-231 tumor was inhibited by the indication of Fluc imaging. And immunofluorescence staining also confirmed that hESC-EC can exclusively home to tumor lesions instead of normal lung tissue. Taken together, our results revealed that hESC-ECs can specifically target tumor sites and kill nearby tumor cells by bystander effect when GCV is given. These finds suggest that hESC-ECs are attractive targeting vehicles for cancer therapy, and molecular imaging in small animals is an invaluable part of cancer diagnosis, prediction of tumor response to available therapies and monitoring response to therapy as well as developing drugs prior to clinical translation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 415. doi:1538-7445.AM2012-415