Glioma tumor microenvironment

Glioma tumor microenvironment

In a study, both U118 cell and GSC23 cell exhibited good printability and cell proliferation. Compared with 3D-U118, 3D-GSC23 had a greater ability to form cell spheroids, to secrete VEGFA, and to form tubule-like structures in vitro. More importantly, 3D-GSC23 cells had a greater power to transdifferentiate into functional endothelial cells, and blood vessels composed of tumor cells with an abnormal endothelial phenotype was observed in vivo. In summary, 3D bioprinted hydrogel scaffold provided a suitable tumor microenvironment (TME) for glioma cells and GSCs. This bioprinted model supported a novel TME for the research of glioma cells, especially GSCs in glioma vascularization and therapeutic targeting of tumor angiogenesis 1).

Important advances have been made in deciphering the microenvironment of GBMs, but its association with existing molecular subtypes and its potential prognostic role remain elusive. Jeanmougin et al. investigated the abundance of infiltrating immune and stromal cellin silico, from gene expression profiles. Two cohorts, including in-house normal brain and glioma samples (n=70) and a large sample set from The Cancer Genome Atlas (TCGA)(n=393), were combined into a single exploratory dataset. A third independent cohort (n=124) was used for validation. Tumors were clustered based on their microenvironment infiltration profiles, and associations with known GBM molecular subtypes and patient outcome were tested a posteriori in a multivariable setting. Jeanmougin et al. identified a subset of GBM samples with significantly higher abundances of most immune and stromal cell populations. This subset showed increased expression of both immune suppressor and immune effector genes compared to other GBMs and was enriched for the mesenchymal molecular subtype. Survival analyses suggested that the tumor microenvironment infiltration pattern was an independent prognostic factor for GBM patients. Among all, patients with the mesenchymal subtype with low immune and stromal infiltration had the poorest survival. By combining molecular subtyping with gene expression measures of tumor infiltration, the present work contributes to improving prognostic models in GBM 2).

Tumor-associated microglia and macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) are potent immunosuppressors in the glioma tumor microenvironment (TME). Their infiltration is associated with tumor grade, progression and therapy resistance.

This resiliency of glioma stem cells (GSCs) is, in part, due to self-remodeling of their supportive niche also known as the tumor microenvironment 3) 4) 5) 6).

The tumor and the surrounding microenvironment are closely related and interact constantly. Tumors can influence the microenvironment by releasing extracellular signals, promoting tumor angiogenesis and inducing peripheral immune tolerance, while the immune cells in the microenvironment can affect the growth and evolution of cancerous cells.

The tumor microenvironment contributes to tumour heterogeneity.

Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms.

Solid cancers develop in dynamically modified microenvironments in which they seem to hijack resident and infiltrating nontumor cells, and exploit existing extracellular matrices and interstitial fluids for their own benefit. Glioblastoma (GBM), the most malignant intrinsic glial brain tumor, hardly colonizes niches outside the central nervous system (CNS). It seems to need the unique composition of cranial microenvironment for growth and invasion as the incidence of extracranial metastasis of GBM is as low as 0.5%. Different nontumor cells (both infiltrating and resident), structures and substances constitute a semiprotected environment, partially behind the well-known blood–brain barrier, benefitting from the relatively immune privileged state of the CNS. This imposes a particular challenge on researchers and clinicians who try to tackle this disease and desire to penetrate efficiently into this shielded environment to weaken the GBM cells and cut them off from the Hinterland they are addicted to. In this chapter, we focus on how GBM interacts with the different components of its tumor microenvironment (TME), how we can target this TME as a useful contribution to the existing treatments, how we could make further progress in our understanding and interaction with this environment as a crucial step toward a better disease control in the future, and what efforts have already been taken thus far 7).

To characterize the glioma tumor microenvironment, a mixed collective of nine glioma patients underwent [18F]DPA-714-PET-MRI in addition to [18F]FET-PET-MRI. Image-guided biopsy samples were immuno-phenotyped by multiparameter flow cytometry and immunohistochemistry. In vitro autoradiography was performed for image validation and assessment of tracer binding specificity.

They found a strong relationship (r = 0.84, p = 0.009) between the [18F]DPA-714 uptake and the number and activation level of glioma-associated myeloid cells (GAMs). TSPO expression was mainly restricted to HLA-DR+ activated GAMs, particularly to tumor-infiltrating HLA-DR+ MDSCs and TAMs. [18F]DPA-714-positive tissue volumes exceeded [18F]FET-positive volumes and showed a differential spatial distribution.

[18F]DPA-714-PET may be used to non-invasively image the glioma-associated immunosuppressive TME in vivo. This imaging paradigm may also help to characterize the heterogeneity of the glioma TME with respect to the degree of myeloid cell infiltration at various disease stages. [18F]DPA-714 may also facilitate the development of new image-guided therapies targeting the myeloid-derived TME. 8).



Wang X, Li X, Ding J, et al. 3D bioprinted glioma microenvironment for glioma vascularization [published online ahead of print, 2020 Aug 10]. J Biomed Mater Res A. 2020;10.1002/jbm.a.37082. doi:10.1002/jbm.a.37082

Jeanmougin M, Håvik AB, Cekaite L, Brandal P, Sveen A, Meling TR, Ågesen TH, Scheie D, Heim S, Lothe RA, Lind GE. Improved prognostication of glioblastoma beyond molecular subtyping by transcriptional profiling of the tumor microenvironment. Mol Oncol. 2020 Mar 14. doi: 10.1002/1878-0261.12668. [Epub ahead of print] PubMed PMID: 32171051.

Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69-82.

Cheng L, Huang Z, Zhou W, et al. Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell. 2013;153(1):139- 152.

Lathia JD, Heddleston JM, Venere M, et al. Deadly teamwork: neural cancer stem cells and the tumor microenvironment. Cell Stem Cell. 2011;8(5):482- 485.

Wang L, Rahn JJ, Lun X, et al. Gamma-secretase represents a therapeutic target for the treatment of invasive glioma mediated by the p75 neurotrophin receptor. PLoS Biol. 2008;6(11):e289.

De Vleeschouwer S, Bergers G. Glioblastoma: To Target the Tumor Cell or the Microenvironment? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 16. Available from PubMed PMID: 29251862.

Zinnhardt B, Müther M, Roll W, Backhaus P, Jeibmann A, Foray C, Barca C, Döring C, Tavitian B, Dollé F, Weckesser M, Winkeler A, Hermann S, Wagner S, Wiendl H, Stummer W, Jacobs AH, Schäfers M, Grauer OM. TSPO imaging-guided characterization of the immunosuppressive myeloid tumor microenvironment in patients with malignant glioma. Neuro Oncol. 2020 Feb 12. pii: noaa023. doi: 10.1093/neuonc/noaa023. [Epub ahead of print] PubMed PMID: 32047908.

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