Mesenchymal stem cells enhance tumorigenic properties of human glioblastoma through independent cell-cell communication mechanisms

// Carolina Oliveira Rodini 1 , Patricia Benites Goncalves da Silva 1 , Amanda Faria Assoni 1, 2 , Valdemir Melechco Carvalho 2 and Oswaldo Keith Okamoto 1, 3 1 Centro de Pesquisa sobre o Genoma Humano e Celulas-Tronco, Departamento de Genetica e Biologia Evolutiva, Instituto de Biociencias, Universidade de Sao Paulo, Cidade Universitaria, Sao Paulo, SP, Brazil 2 Fleury Group, Sao Paulo, Jabaquara, Sao Paulo, SP, Brazil 3 Departamento de Hemoterapia e Terapia Celular, Hospital Israelita Albert Einstein, Sao Paulo, SP, Brazil Correspondence to: Oswaldo Keith Okamoto, email: keith.okamoto@usp.br Keywords: glioblastoma; tumor microenvironment; mesenchymal stem cells; aggressiveness; secretome Received: November 03, 2017      Accepted: April 23, 2018      Published: May 15, 2018 ABSTRACT Mesenchymal stem cells (MSC) display tumor tropism and have been addressed as vehicles for delivery of anti-cancer agents. As cellular components of the tumor microenvironment, MSC also influence tumor progression. However, the contribution of MSC in brain cancer is not well understood since either oncogenic or tumor suppressor effects have been reported for these cells. Here, MSC were found capable of stimulating human Glioblastoma (GBM) cell proliferation through a paracrine effect mediated by TGFB1. Moreover, when in direct cell-cell contact with GBM cells, MSC elicited an increased proliferative and invasive tumor cell behavior under 3D conditions, as well as accelerated tumor development in nude mice, independently of paracrine TGFB1. A secretome profiling of MSC-GBM co-cultures identified 126 differentially expressed proteins and 10 proteins exclusively detected under direct cell-cell contact conditions. Most of these proteins are exosome cargos and are involved in cell motility and tissue development. These results indicate a dynamic interaction between MSC and GBM cells, favoring aggressive tumor cell traits through alternative and independent mechanisms. Overall, these findings indicate that MSC may exert pro-tumorigenic effects when in close contact with tumor cells, which must be carefully considered when employing MSC in targeted cell therapy protocols against cancer.