Abstract 2053: Exosomes from AC133+/CD34+ stem cells mediate a paracrine effect in breast cancer cells

Abstract

Abstract Exciting advances in the treatment of breast cancer have occurred over the past decade. However, the efficacy of the current therapeutic modalities is still limited by drug toxicity, resistance, and lack of predictive and prognostic biomarkers. Breast cancer remains the second leading cause of cancer death among women in the U.S. Thus, the development of new therapeutic targets and further understanding of the tumor microenvironment is extremely crucial for accelerating the progress against breast cancer. Human AC133+/CD34+ stem cells serve as a highly promising and novel therapeutic option for targeting tumor angiogenesis. We and others have demonstrated the incorporation of bone marrow-derived AC133+/CD34+/KDR+ endothelial progenitor cells in the neovasculature around implanted tumors supporting their growth and spread. Many mediators have been implicated in the crosstalk between AC133+/CD34+/KDR+ endothelial progenitor cells, endothelial cells, and the tumor cells, but most of these have limited clinical benefits as reported by several trials. In this study, we analyzed the secretome of the AC133+/CD34+ stem cells that were isolated by positive selection from human umbilical cord blood and evaluated their role in breast cancer progression. Our results show that AC133+/CD34+ stem cells exhibited significant growth potential that was manifested as seventy-five fold increase in cell number after 10 days in culture. Flow cytometry demonstrated that AC133+/CD34+ stem cells preserve their capacity to differentiate into AC133+/CD34+/KDR+ endothelial progenitor cells even after long term in vitro expansion. In order to evaluate the effect of AC133+/CD34+ stem cells on breast cancer cells, we performed a simple proliferation (XTT) assay using conditioned medium (CM) from AC133+/CD34+ stem cells and tested on MCF-7 and MDA-MB-231 proliferation. As expected, CM significantly induced proliferation of breast cancer cells. This effect was in part due to the high expression of a repertoire of proinflammatory and proangiogenic cytokines in the CM of the AC133+/CD34+ stem cells. In particular, angiogenin, GRO, IL-8, MCP, PDGF.BB, TIMP2. Further, we examined if exosomes, a component of paracrine secretion are involved in the paracrine effect of the AC133+/CD34+ stem cells. Interestingly, exosomes from AC133+/CD34+ stem cells significantly enhanced MCF-7 and MDA-MB-231 proliferation at a comparable level as the CM. Further analysis of the exosomes reveals that the pro-proliferative miR-141-3p, miR-182-5p, miR-200b-3p, and miR-203a are highly expressed in AC133+/CD34+ exosomes. The analysis of the paracrine interactive mediators between breast cancer cells, AC133+/CD34+ stem cells, and AC133+/CD34+/KDR+ endothelial progenitor cells is likely to yield viable novel clinically translatable therapeutic targets. Citation Format: Ghada Ben Rahoma, Neha Tuli, Rachana Maniyar, Sanjukta Chakraborty, Sarnath Singh, Abraham Mittelman, Jan Gelibter, Raj K. Tiwari. Exosomes from AC133+/CD34+ stem cells mediate a paracrine effect in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2053.