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Quantitative Immunohistochemistry of the Cellular Microenvironment in Patient Glioblastoma Resections
Published on: July 31, 2017
Interactions and communications in the glioblastoma microenvironment: potential targets for chemo-/radiotherapy
Qamar Abuhassan1, Hamzeh J Al-Ameer2, Subbulakshmi Ganesan3
1Department of Pharmaceutics and Pharmaceutical Technology, School of Pharmacy, University of Jordan, 11942, Amman, Jordan.
Abstract:
Glioblastoma therapy remains constrained by a highly interactive tumor microenvironment (TME) that stimulates invasion, resistance, and immune suppression. The glioblastoma TME comprises malignant astrocytic and stem-like tumor cells, resident microglia, infiltrating immune cells, endothelial cells, and a modified extracellular matrix (ECM) that together establish an immunosuppressive tumor stroma. Communication among these elements proceeds through cytokines, chemokines, growth factors, extracellular vesicles, metabolic exchange, and direct cell-matrix contacts. These interactions modulate DNA damage responses (DDRs); remodel immune responses by immunosuppressive and antitumor immune cells; alter the activity of stromal cells; and change angiogenesis, metastasis, and cell survival pathways-which in turn induce resistance to chemo-/radiotherapy. Chemotherapy and radiotherapy induce acute and chronic changes in the TME, including the recruitment of immunosuppressive cells, upregulation of survival signaling in perivascular niches, vascular remodeling, and hypoxia/metabolism rewiring that diminishes the efficacy of chemo-/radiotherapy. Preclinical and early clinical interventions show that targeting cells and their secretions in the TME can be suggested for reprogramming the glioblastoma TME and the subsequent resistance to chemo-/radiotherapy. The focus of this review is to provide mechanistic evidence linking TME communication networks to chemo-/radiotherapy resistance. Strategies that target these interactions to identify translational pathways for combination therapies are reviewed.
Insights
Glioblastoma therapy is hindered by its tumor microenvironment (TME), which promotes resistance and immune suppression. Targeting TME communication networks offers new strategies to overcome chemo/radiotherapy resistance.
Area of Science:
- Neuro-oncology
- Cancer Immunology
- Tumor Microenvironment Biology
Background:
- Glioblastoma therapy is limited by a complex tumor microenvironment (TME) that fosters tumor cell invasion, treatment resistance, and immune evasion.
- The glioblastoma TME consists of tumor cells, immune cells, endothelial cells, and extracellular matrix, creating an immunosuppressive stroma.
- Interactions within the TME, mediated by various signaling molecules and cell contacts, influence DNA damage responses, immune cell activity, and angiogenesis, ultimately driving resistance to therapy.
Purpose of the Study:
- To provide mechanistic insights into how glioblastoma tumor microenvironment (TME) communication networks contribute to chemo/radiotherapy resistance.
- To review strategies targeting TME interactions for potential combination therapies against glioblastoma.
Main Methods:
- Review of preclinical and early clinical data on glioblastoma TME composition and function.
- Analysis of communication pathways within the TME, including cytokines, chemokines, growth factors, extracellular vesicles, and metabolic exchange.
- Examination of how chemo/radiotherapy alters the TME and contributes to treatment failure.
Main Results:
- Chemo/radiotherapy induces significant changes in the TME, such as immune cell recruitment, altered signaling, vascular remodeling, and metabolic rewiring, which diminish treatment efficacy.
- Targeting cellular and secreted components within the TME shows promise for reprogramming the glioblastoma TME and overcoming resistance.
- Specific TME communication networks are mechanistically linked to resistance against standard glioblastoma treatments.
Conclusions:
- Understanding the intricate communication networks within the glioblastoma TME is crucial for developing effective therapeutic strategies.
- Targeting TME interactions represents a promising avenue for overcoming chemo/radiotherapy resistance in glioblastoma.
- Further research into translational pathways for combination therapies that modulate the TME is warranted.
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