AUTHOR=Hudson Amanda L. , Parker Nicole R. , Khong Peter , Parkinson Jonathon F. , Dwight Trisha , Ikin Rowan J. , Zhu Ying , Chen Jason , Wheeler Helen R. , Howell Viive M. 

TITLE=Glioblastoma Recurrence Correlates With Increased APE1 and Polarization Toward an Immuno-Suppressive Microenvironment

JOURNAL=Frontiers in Oncology

VOLUME=8

YEAR=2018

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2018.00314

DOI=10.3389/fonc.2018.00314

ISSN=2234-943X

ABSTRACT=<p>While treatment with surgery, radiotherapy and/or chemotherapy may prolong life for patients with glioblastoma, recurrence is inevitable. What is still being discovered is how much these treatments and recurrence of disease affect the molecular profiles of these tumors and how these tumors adapt to withstand these treatment pressures. Understanding such changes will uncover pathways used by the tumor to evade destruction and will elucidate new targets for treatment development. Nineteen matched pre-treatment and post-treatment glioblastoma tumors were subjected to gene expression profiling (Fluidigm, TaqMan assays), <italic>MGMT</italic> promoter methylation analysis (pyrosequencing) and protein expression analysis of the DNA repair pathways, known to be involved in temozolomide resistance (immunohistochemistry). Gene expression profiling to molecularly subtype tumors revealed that 26% of recurrent post-treatment specimens did not match their primary diagnostic specimen subtype. Post-treatment specimens had molecular changes which correlated with known resistance mechanisms including increased expression of APEX1 (<italic>p</italic> &lt; 0.05) and altered <italic>MGMT</italic> methylation status. In addition, genes associated with immune suppression, invasion and aggression (<italic>GPNMB, CCL5, and KLRC1</italic>) and polarization toward an M2 phenotype (<italic>CD163</italic> and <italic>MSR1</italic>) were up-regulated in post-treatment tumors, demonstrating an overall change in the tumor microenvironment favoring aggressive tumor growth and disease recurrence. This was confirmed by <italic>in vitro</italic> studies that determined that glioma cell migration was enhanced in the presence of M2 polarized macrophage conditioned media. Further, M2 macrophage-modulated migration was markedly enhanced in post-treatment (temozolomide resistant) glioma cells. These findings highlight the ability of glioblastomas to evade not only the toxic onslaught of therapy but also to evade the immune system suggesting that immune-altering therapies may be of value in treating this terrible disease.</p>