AI-05 * IMPACT OF GBM MICROENVIRONMENT ON EXPRESSION PROFILE OF BONE MARROW DERIVED PROGENITOR CELLS

Abstract

We have recently shown that bone marrow derived cells (BMDC) provide a distinct tumor region dependent contribution to glioblastoma multiforme (GBM) neovascularization. The influence of GBM microenvironment on differentiation and modulation of expression factors by BMDC however remains unknown. In this study we establish the differential expression profile of BMDC as a consequence of recruitment and interaction with the GBM microenvironment and in response to radiation (RTx) and anti-angiogenic therapy (AATx). Chimeric mice with reconstituted green-fluorescent bone marrow were used to create intracranial GBM xenografts, by implanting red fluorescent glioma stem cells or U87 into the frontal lobes. Subsequently, BMDC recruited to the GBM were isolated from the GBM cells using FACS during GBM growth, and following treatment (RTx and AATx). RNA was extracted from both FACS-purified BMDC and GBM cells, and mRNA and miRNA array analyses were performed. We compared the expression profiles to systemic BMDC derived from control donor mice. BMDCs were found to exhibit significant plasticity and altered their expression profiles based on stage of GBM growth and in response to therapy. TGFb was significantly upregulated in BMDCs following recruitment to GBMs, with a compensatory increase in expression of IL6,4,8 by GBM cells. BMDC up-regulate cytokines, IFNG, CXCL and TNF pathways, and transcriptional regulators, SMAD2, all of which are able to influence the tumor microenvironment. BMDCs also prove to express angiogenic factors and angioMIRs, with a distinct differential expression pattern based on stage of GBM growth and in response to therapy. We demonstrate that a significant cross-talk exists between BMDC in the tumor microenvironment and GBM cells. There is a distinct angiogenic and invasive profile of BMDC once recruited to the GBM. Furthermore, recruited BMDC provide a source of angiogenic factors, that are differentially expressed based on the stage of GBM growth and in response to therapy.