Director of Center of Excellence for Stem Cells and Regenerative Medicine Zewail City of Science and Technology October City, Al Jizah, Egypt
Abstract: The secretome of mesenchymal stromal cells (MSCs) is reported to have tissue repair potential and anti-inflammatory effects. However, in the cancer microenvironment, the MSCs secretome was reported to enhance the proliferation and migration of triple-negative breast cancer cells (TNBC). The PI3K pathway is activated in MSCs to secrete the procarcinogen factors CCL5, CCL2, and SDF1. In this work, we investigated the hypothesis that inhibition of the PI3K pathway in MSCs will downregulate the expression of pro-tumorigenic factors, enhance tissue repair, and promote the anti-carcinogenic effects of MSCs secretome. The invasive MDA-MB-231 breast cancer cell line was cultured alone or indirectly with MSCs. Cancer cells and MSCs were treated with PI3K inhibitor and evaluated for regenerative capacities and carcinogenic properties. Our data show that CM of PI3K-inhibited MSCs significantly decreased the proliferation of PI3K-inhibited MDA-MB-231cells (iCM-iMDA). The G2/M phase demonstrated a significant increase to 25.1% and a significant upregulation in the percentage of the polyploidy population to 9.51%. The Ki67 gene expression and protein levels were significantly downregulated. The proportion of viable cells significantly decreased to 74.7%. The proportion of the apoptotic population showed highly significant upregulation to 17.9%. Additionally, the percentage of necrosis demonstrates a significant upregulation to 7.42%. Down-regulation of Bcl2, upregulation of P53 and TNF alpha protein level were detected. There was no significance in the migration of iCM-iMDA group and no change in E-Cadherine. Dual inhibition of PI3K in MSCs and MDA-MB-231 cells diminished the proliferation of MDA-MB-231 cells. Ki67 proliferation marker was downregulated, and apoptosis and necrosis were increased as shown by down-regulation of Bcl2, upregulation of P53 and TNF alpha. The migration ability of MDA-MB-231 cells was not affected. Our data demonstrate that signaling between MSCs and MDA-MB-231 cells through the PI3k pathway supports MDA-MB-231 cells progression, and inhibition of PI3K in the tumor microenvironment may be used as adjuvant therapy for TNBC.
Funding Source: Grant #46721 from the Egyptian Science and Technology Development Fund, Cairo, Egypt Sawiris Foundation scholarship in Stem Cell Research 2024.
