Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth

Abstract

Tumor-associated macrophages (TAMs) are enriched in glioblastoma (GBM) that contains glioma stem cells (GSCs) at the apex of its cellular hierarchy. The correlation between TAM density and glioma grade suggests a supportive role of TAMs in tumor progression. Here we interrogated the molecular link between GSCs and TAM recruitment in GBMs and demonstrated that GSCs secrete Periostin (POSTN) to recruit TAMs. TAM density correlates with POSTN levels in human GBMs. Silencing POSTN in GSCs markedly reduced TAM density, inhibited tumor growth, and increased survival of mice bearing GSC-derived xenografts. We found that TAMs in GBMs are not brain-resident microglia, but mainly monocyte-derived macrophages from peripheral blood. Disrupting POSTN specifically attenuated the tumor supportive M2 type of TAMs in xenografts. POSTN recruits TAMs through integrin αvβ3 as blocking this signaling by an RGD peptide inhibited TAM recruitment. Our findings highlight the possibility of improving GBM treatment by targeting POSTN-mediated TAM recruitment.

Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

“…GSCs and matched NSTCs were isolated from GBM surgical specimens or patient-derived GBM xenografts using Papain Dissociation System as previously reported. 3,7,8,22,42 T4121 xenograft was derived from an adult GBM tumor (WHO grade IV), 22 and D456 (D456-MG) xenograft was derived from a pediatric GBM. 43 To isolate total glioma cells from GBM tumors, subcutaneous xenografts were collected and cut into small pieces and then were isolated using the Papain Dissociation System (Worthington Biochemical, Lakewood, NJ, USA) according to the manufacturer's instructions.…”

“…The cancer stem cell property of GSCs was confirmed by functional analyses (including in vitro limiting dilution assay, cell differentiation assay and in vivo tumorigenic assay) to assess the self-renewal potential, multi-lineage differentiation potency and in vivo tumor formation capacity of GSCs as described previously. 3,7,8,22,42 Preferential expressions of GSC markers SOX2, OLIG2, L1CAM, CD15 and CD133 in GSC populations were validated. The enriched GSCs were constantly maintained as GBM xenografts and were only dissociated, sorted and cultured in vitro for functional experiments.…”

“…Immunoblot analyses were performed as previously described. 8,44 The primary antibodies used in this study include the following: anti-CD9 (sc- Ubiquitination assay. Ubiquitination assay was performed as previously described.…”

“…6,7 The potent capacity of GSCs in promoting tumor progression may be a result of their extensive potential to maintain cell proliferation and to support malignant behaviors such as cancer invasion, tumor angiogenesis, vascular pericyte generation and immune evasion. 5,8 GSCs have been found to be enriched in GBMs after radiation and chemotherapy, and contribute to therapeutic resistance and tumor re-initiation. 3,9 The pivotal role of GSCs in promoting malignant progression and tumor recurrence in GBMs indicate that targeting GSCs may significantly improve GBM treatment and overcome the therapeutic resistance.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…CD163, a common maker of tumor associated myeloid cells (TAMs), 17 functions as a hemoglobin-haptoglobin scavenger receptor, and is up-regulated on the surface of macrophages, monocytes, and microglia in response to anti-inflammatory cytokines such as IL-10, 18,19 and glucocorticoids such as Dex. 20-22 A recent study evaluating grades II-IV astrocytomas demonstrates that CD163 mRNA expression increases with increasing grade of astrocytoma, and that CD163+ cells produce IL-10 in the GBM tumor microenvironment.…”