Journal
NEURO-ONCOLOGY ADVANCES
Volume 4, Issue 1, Pages -Publisher
OXFORD UNIV PRESS
DOI: 10.1093/noajnl/vdac166
Keywords
glioblastoma; organic anion transporting polypeptides; OATP; tumor microenvironment
Categories
Funding
- Neurosurgical team at Auckland hospital
- Neurological Foundation of New Zealand
- Auckland Cancer Society Research Centre
- Cancer Research Trust [CRTNZ 2013 RPG]
- Maurice Phyllis Paykel Trust [203123]
- Cure Kids [3915]
- Health Research Council
- School of Medicine Foundation
- (Neurosurgical Research Unit)
- New Zealand Brain Tumor Trust
- Hugh Green Foundation
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This study demonstrates, for the first time, the expression of four OATP isoforms in human GBM tissue, with upregulation within the tumor microenvironment by myeloid cells and tumor vasculature, as well as isoform-specific upregulation within hypoxic niches.
Background Glioblastoma (GBM) is the most common and aggressive primary brain tumor in adults. Whilst the role of the efflux transporters are well established in GBM, the expression and function of uptake transporters, such as the organic anion transporting polypeptide (OATP) family, are not well understood. OATPs possess broad substrate specificity that includes anti-cancer agents; therefore, we sought to investigate the expression of four OATP isoforms in human GBM cell types using patient tumor tissue. Methods We used fluorescent immunohistochemical labeling of paraffin-embedded surgically resected tissues and single-cell image analysis methods to explore the expression of the OATP isoforms in different tumor cell types through co-labeling with cell-type specific markers, such as IBA1 (pan-myeloid), GFAP (tumor cell), PDGFR beta (stromal cell), and UEA-1-lectin (endothelial). Results We found significant over-expression of all the OATP isoforms (OATP1A2, 2B1, 1C1 and 4A1) in GBM tumor sections when compared to non-neoplastic brain. A single-cell image analysis revealed that OATPs were significantly upregulated throughout the tumor parenchyma, with significantly higher expression found on lectin-positive blood vessels and IBA1-positive myeloid cells in GBM compared to non-tumor brain tissue. Qualitative analysis of the four OATP isoforms demonstrated greater expression of OATP4A1 in peri-necrotic regions of GBM tissue, which correlated with hypoxia-related markers within the Ivy GAP RNAseq dataset. Conclusion Here, we demonstrate, for the first time, the protein expression of four OATPs in human GBM tissue, including upregulation within the tumor microenvironment by myeloid cells and tumor vasculature, and isoform-specific upregulation within hypoxic niches.
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