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ADAM8 affects glioblastoma progression through microglia/macrophage by regulating osteopontin-mediated angiogenesis
This cumulative dissertation summarizes two peer-reviewed publications addressing the role of a Disintegrin and Metalloproteases 8 (ADAM8) in Glioblastoma multiforme (GBM) cells and in the GBM tumor microenvironment. The first publication entitled “Molecular profiling of the tumor microenvironment...
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| Format: | Dissertation |
| Sprache: | Englisch |
| Veröffentlicht: |
Philipps-Universität Marburg
2023
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| Zusammenfassung: | This cumulative dissertation summarizes two peer-reviewed publications addressing the role of a Disintegrin and Metalloproteases 8 (ADAM8) in Glioblastoma multiforme (GBM) cells and in the GBM tumor microenvironment.
The first publication entitled “Molecular profiling of the tumor microenvironment in glioblastoma patients: correlation of microglia/macrophage polarization state with metalloprotease expression profiles and survival”. In this study, we investigated the molecular profile of glioma-associated macrophages/microglia (GAMMs) in correlation with patient prognosis by exploiting M1/M2-like polarization markers in a cohort of 20 GBM patients. Using quantitative PCR (qPCR), the markers CXCL10 (M1) and CCL13 (M2) were validated in human macrophages and applied to a global analysis of GBM tissue. Furthermore, proteinase genes, known to be associated with GBM progression (ADAM8, MMP9, MMP14, ADAM10, ADAM17), were analyzed in correlation to M1/M2 markers. Our data showed that the M2-like macrophage marker CCL13 showed significantly higher expression levels than all M1-like macrophage markers. Genes for MMP9 and MMP14 are significantly associated with an M2-like phenotype and association to impaired prognosis in the GBM patient cohort. A high expression in MMP9 and MMP14 is significantly correlated (P<0.001) with high expression of ADAM8 in GBM.
The second publication entitled “ADAM8 affects glioblastoma progression by regulating osteopontin-mediated angiogenesis” investigated the functional impact of ADAM8 on GBM progression in vivo by stereotactic injection of ADAM8-deficient glioma cells into the brains of nude mice (nu/nu). Our results provide evidence for a significant contribution of ADAM8 during tumor angiogenesis, as demonstrated in vivo and in vitro by functional analysis of ADAM8-deficient U87 glioma cells and by analyzing primary macrophages isolated from Adam8 knockout mice. Notably, mice lacking ADAM8 have no evident developmental or pathological defects as confirmed by phenotyping report of ADAM8 knockout mouse (Kelly, Hutchinson et al. 2005), which suggests ADAM8 as a potential candidate target protein for GBM therapy with minor expected side effects.
In our study, we initially found in GBM tissue that ADAM8 is widely expressed both in neoplastic glioblastoma cells as well as in tumor-associated cells in the tumor microenvironment. We investigated the impact of ADAM8 on GBM progression in vivo by stereotactic injection of ADAM8 deficient glioma cells in the brain of nude mice. Our results suggest a significant contribution of ADAM8 during tumor angiogenesis, as demonstrated in vivo and in vitro by functional analysis of ADAM8 deficient U87 glioma cells and by analyzing primary macrophages isolated from ADAM8 knockout mice.
We found that the angiogenic potential of ADAM8 in GBM cells and in primary macrophages is mediated by the regulation of osteopontin (OPN), an important inducer of tumor angiogenesis. By in vitro cell signaling analyses, we demonstrate that ADAM8 regulates OPN via JAK/STAT3 pathway in U87 cells and in primary macrophages. As ADAM8 is a dispensable protease for physiological homeostasis, we conclude that ADAM8 could be a tractable target to modulate angiogenesis in GBM with minor side-effects. |
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| DOI: | 10.17192/z2023.0355 |