J Pharm Pharmacogn Res 2(Suppl. 1): S6, 2014
Special supplement with the abstract book of LATINFARMA 2013
CO 010: NEOPLASTIC TRANSFORMATION OF HUMAN MESENCHYMAL STEM CELLS CONCERTS IMMUNE-EVASION AND PRO-INFLAMMATORY PROGRAMS IN THE ABSENCE OF IMMUNE-EDITION MEDIATED PREASSURE
Miranda-Rodríguez A1, Sánchez-Castellanos N1, Funes-Quesada JM2, Pérez-Rodríguez R1, de León-Delgado J1.
Introduction: The presence of altered molecular pathways associated with oncogenes and tumor suppressor genes as cancer hallmark not only support the self-sufficiency on tumor cells proliferation but also determine the interaction of neoplastic cells with the host, allowing cells to escape from homeostatic control mechanisms.
The aim of this research is to assess the direct impact of cancer progression driven by genetic alterations over immune-surveillance evasion and tumor related inflammation, in a context independent on immune-edition mediated pressure. We took advantage of a model based on in vitro step-wise neoplastic transformation induced on human mesenchymal stem cells (hMSC). The genetic lesions introduced to transform hMSC included hTERT, c-Myc and H-Ras activity while p53 and pRb expression were reduced.
Methods: MSC immunogenicity was evaluated by HLA-ABC gene and protein expression. In vitro co-culture experiments were performed to determine hMSC inhibitory capacity on T cells proliferation. Immunesuppressive mediators, pro-inflammatory molecules and IFNγ signaling were assessed on hMSCby qPCR, western blot, flow cytometry, ELISA, gene micro-array and immune-fluorescence assays. Neoplastic hMSC with reduced expression of IL-beta were obtained by lentiviral infection encoding shRNA targeting IL-beta mRNA. Anchorage independent growth in soft agar was assayed as surrogate of cells tumorigenicity. In vivo tumorigenicity was evaluated by xenogenic transplantation in athymic nude mice.
Results: In vitro step-wise neoplastic transformation reduces hMSC immunogenicity and progressively increases the inhibitory capacity of hMSC on T cell proliferation, whereas a modification in the immunesuppressive mechanism is detected. Transformation leads to the generation of a pro-inflammatory phenotype characterized by increased expression of IL-beta, a mediator that concert tumorigenic and immune-suppressive potential of fully transformed cells.
Conclusions: Overall results suggest that neoplastic transformation can stimulate oncogenic inflammation and immune-surveillance evasion as an intrinsic feature of cancer cells, even in the absence of the immune-edition pressure exerted at tumor microenvironment.