期刊
JOURNAL OF PATHOLOGY
卷 253, 期 2, 页码 160-173出版社
WILEY
DOI: 10.1002/path.5569
关键词
GBM; tumor microenvironment; tumor angiogenesis; microglia; macrophages; granulocytes; CXCL2; CD45; CSF
资金
- German Research Foundation (DFG) [SPP1190, SFB TRR43]
- Berliner Krebsgesellschaft (BKG)
- BKG
The study identified two distinct myeloid cell populations in human glioblastoma, which play a role in tumor escape mechanisms by expressing alternative proangiogenic factors. Limited efficacy of anti-angiogenic therapy may be due to tumor-infiltrating myeloid cells bypassing VEGF-mediated pathways through expression of alternative proangiogenic factors.
Myeloid cells are an inherent part of the microenvironment of glioblastoma multiforme (GBM). There is growing evidence for their participation in mechanisms of tumor escape, especially in the development of resistance following initially promising anti-VEGF/VEGFR treatment. Thus, we sought to define the capability of myeloid cells to contribute to the expression of proangiogenic molecules in human GBM. We investigated GBM specimens in comparison with anaplastic astrocytoma (WHO grade III) and epilepsy patient samples freshly obtained from surgery. Flow cytometric analyses revealed two distinct CD11b(+)CD45(+) cell populations in GBM tissues, which were identified as microglia/macrophages and granulocytes. Due to varied granulocyte influx, GBM samples were subdivided into groups with low (GBM-lPMNL) and high (GBM-hPMNL) numbers of granulocytes (polymorphonuclear leukocytes; PMNL), which were related to activation of the microglia/macrophage population. Microglia/macrophages of the GBM-lPMNL group were similar to those of astrocytoma specimens, but those of GBM-hPMNL tissues revealed an altered phenotype by expressing high levels of CD163, TIE2, HIF1 alpha, VEGF, CXCL2 and CD13. Although microglia/macrophages represented the main source of alternative proangiogenic factors, additionally granulocytes participated by production of IL8 and CD13. Moreover, microglia/macrophages of the GBM-hPMNL specimens were highly associated with tumor blood vessels, accompanied by remodeling of the vascular structure. Our data emphasize that tumor-infiltrating myeloid cells might play a crucial role for limited efficacy of anti-angiogenic therapy bypassing VEGF-mediated pathways through expression of alternative proangiogenic factors. (c) 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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