OP0018 mi-RNA-150 and seven regulators of mesenchymal stem cells action on colon cancer inflammatory tumour microenvironment

Abstract

Background This study is the first step toward use of mesenchymal stem cells (MSCs) in therapy to alleviate the effects of radiation exposure in patients. MSCs improve repair in various organs and tissues, in particular after irradiation. However, before using MSCs in a cancer environment, for instance after radiotherapy, it must be established that MSC injections do not promote malignant cells proliferation. Methods A rat model of colorectal carcinogenesis close to human cancer was used as preclinical model. The carcinogen N-methyl-N ′ -nitro-N-nitroso-guanidine (MNNG) was instilled in rats by four intrarectal deposits within 2 weeks, and two MSC injections (10 7 cells per rat) 2 and 4 weeks after the end of carcinogen treatment. Tumours were then examined 32 and 52 weeks after initiating MNNG treatment. Another cohort of rats entered a survival experiment. Findings MSC treatment reduced cancer significantly, lowering the number of adenomas and adenocarcinomas and extending the lifespan of rats. The anti-cancer effect of MSCs was mediated by their immunological properties. In adenocarcinoma of MSC-treated rats, CD68+ monocyte/macrophage infiltration was lowered and CD3+ lymphocytes increased. MSCs induce macrophages to turn into regulatory cells involved in phagocytosis, inhibiting the production of proinflammatory cytokines. MSCs decrease NK cells and rTh17 cell activities, Treg recruitment, CD8+ lymphocytes, and endothelial cell number and restore Th17 cell activity. MiRNA mi-150 and miRNA-7 are the key effectors. Mi-150 inhibits tumour invasion and mi-RNA-7 negatively regulates the EGFR/AKT pathway, promoting cell death. Interpretation MSC infusion has a durable action on colon cancer development by modulating the immune component of the tumour microenvironment. For the first time, two mi-RNA were identified as responsible for the anti-cancer effect of MSCs. We propose that in this model of colorectal cancer early bone-marrow-derived MSC injections, by a long-term effect, reoriented tumour immune response and induced regression of colonic carcinogenesis.