Abstract 3562: Exosomes secreted by AC133+/CD34+cells harbor invasion potentiating miRNAs
Authors: Rahoma Ghada Ben , Maniyar Rachana , Chakraborty Sanjukta , Singh Sarnath , Srinivasan Anitha , Mittelman Abraham , Geliebter Jan , Tiwari Raj K. 
Published: August 2019

Despite the exciting progresses in the treatment of breast cancer, the effectiveness of the current therapeutic modalities is still restricted by drug toxicity, resistance, and lack of predictive and prognostic biomarkers. Breast cancer continues to be the second leading cause of cancer death among women in the U.S. Therefore, the development of new therapeutic targets and further understanding of the tumor microenvironment is extremely critical for accelerating the progress against breast cancer. Human AC133+/CD34+ stem cells are a highly promising and novel therapeutic option for targeting tumor angiogenesis. We and others have described the incorporation of bone marrow derived AC133+/CD34+/KDR+ cells in the neovasculature around implanted tumors supporting their growth and metastasis. Many mediators have been involved in the cross talk between AC133+/CD34+ cells, endothelial cells, and the tumor cells, but most of these have insufficient clinical benefits as reported by several trials. In this study, we evaluated the secretome of the AC133+/CD34+ stem cells that were isolated by positive selection from human umbilical cord blood and their role in breast cancer progression. Using flow cytometry, we show that the high proliferative AC133+/CD34+ stem cells maintain their capacity to differentiate in to AC133+/CD34+/KDR+ endothelial progenitor cells even after long period of in vitro expansion. In order to evaluate the effect of AC133+/CD34+ stem cells on breast cancer cells, a proliferation (XTT) assay was performed using conditioned medium (CM) from AC133+/CD34+ stem cells and examined on MCF-7 and MDA-MB-231 proliferation. As anticipated, CM significantly induced breast cancer cells proliferation. This effect was in part due to the high expression of a large range of proinflammatory and proangiogenic cytokines in the CM of the AC133+/CD34+ cells. In particular, angiogenin, GRO, IL-8, MCP, and TIMP2. Next, we examined if exosomes, a component of paracrine secretion are involved in the paracrine effect of the AC133+/CD34+ stem cells. Surprisingly, exosomes from AC133+/CD34+ stem cells significantly increased MCF-7 and MDA-MB-231 proliferation at a comparable level as the CM. Further analysis of the exosomes using miRNA array screen reveals that exosomes of AC133+/CD34 cells are highly enriched with oncogenic miRNAs including miR-21-5p, miR-142-3p, and miR-223-3p. These miRNAs are up-regulated in breast cancer. Several studies have confirmed their role in mediating breast cancer cells invasiveness. However, miR-142-3p and miR-223-3p are exclusively expressed in hematopoietic cells. Therefore, we propose that shuttling of the exosomes between AC133+/CD34+cells and breast cancer cells induces breast cancer invasiveness. The analysis of the paracrine interactive mediators between breast cancer cells and AC133+/CD34+ cells is likely to yield viable novel clinically translatable therapeutic targets.

Citation Format: Ghada Ben Rahoma, Rachana Maniyar, Sanjukta Chakraborty, Sarnath Singh, Anitha Srinivasan, Abraham Mittelman, Jan Geliebter, Raj K. Tiwari. Exosomes secreted by AC133+/CD34+cells harbor invasion potentiating miRNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3562.