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).

References

1)

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
2)

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.
3)

Calabrese C, Poppleton H, Kocak M, et al. A perivascular niche for brain tumor stem cells. Cancer Cell. 2007;11(1):69-82.
4)

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.
5)

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.
6)

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.
7)

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 http://www.ncbi.nlm.nih.gov/books/NBK469984/ PubMed PMID: 29251862.
8)

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.

Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma H3 K27M-mutant

Diffuse midline glioma (DMG), H3 K27M-mutant, is a new entity in the World Health Organization Classification of Tumors of the Central Nervous System 2016 grouping together diffuse intrinsic pontine gliomas and infiltrating glial neoplasms of the midline harboring the same canonical mutation at the Lysine 27 of the histone H3 tail.

In the past, pediatric diffuse gliomas were grouped with their adult counterparts, despite known differences in behavior between pediatric and adult gliomas with similar histological appearances. Information on the distinct underlying genetic abnormalities in pediatric diffuse gliomas is beginning to allow the separation of some entities from histologically similar adult counterparts.

One narrowly defined group of tumors primarily occurring in children (but sometimes in adults too) is characterized by K27M mutations in the histone H3 gene H3F3A, or less commonly in the related HIST1H3B gene, a diffuse growth pattern, and a midline location (e.g., thalamus, brain stem, and spinal cord). This newly defined entity is termed diffuse midline glioma, H3 K27M–mutant and includes tumors previously referred to as diffuse intrinsic pontine glioma (DIPG). The identification of this phenotypically and molecularly defined set of tumors provides a rationale for therapies directed against the effects of these mutations.

Epidemiology

Diffuse H3 K27M-mutant gliomas occur primarily in children but can also be encountered in adults.

Diagnosis

see Diffuse midline glioma H3 K27M-mutant diagnosis.

Differential diagnosis

After the start of the era of biopsy, Diffuse intrinsic pontine gliomas (DIPG)s bearing Histone H3K27 mutations have been reclassified into a novel entity, diffuse midline glioma, based on the presence of this molecular alteration. However, it is not well established how clinically diagnosed DIPG overlap with H3 K27-mutated diffuse midline gliomas, and whether rare long-term survivors also belong to this group 1).

Treatment

see Diffuse midline glioma H3 K27M-mutant treatment.

Outcome

Prognosis remains poor, with a 2-year survival of less than 10%

Research

Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study 2).


Eight patient-derived orthotopic xenograft models were obtained after direct stereotactic injection of a mixed cell suspension containing tumor cells and stromal cells in the brainstem or thalamus of nude mice and serially passaged thereafter. In parallel, we developed 6 cell-derived xenograft models after orthotopic injection of tumor-initiating cells cultured from stereotactic biopsies. Cells were modified to express luciferase to enable longitudinal tumor growth monitoring, and fluorescent reporter proteins to trace the tumor cells in the brain.These models do not form a tumor mass, they are invasive, show the H3K27 trimethylation loss in vivo and the tumor type diversity observed in patients in terms of histone H3 mutations and lineage markers. Histological and MRI features at 11.7 Tesla show similarities with treatment naïve human DIPG, and in this respect, both direct and indirect orthotopic xenograft looked alike. These DIPG models will therefore constitute valuable tools for evaluating new therapeutic approaches in this devastating disease 3).

Case series

Diffuse midline glioma H3 K27M-mutant case series.

Case reports

A 36-year-old man presented with subacute progressive cognitive and visual deterioration, and hydrocephalus requiring ventricular shunting. MRI revealed a diffusely infiltrating lesion with a gliomatosis cerebri growth pattern, multiple foci of contrast enhancement, and diffuse leptomeningeal involvement. Suboccipital craniotomy with exploration of the posterior fossa revealed a subtle capsular lesion infiltrating into the choroid plexus. Although histologically low-grade, the tumor was found to have an H3K27 M mutation establishing the diagnosis.

In spite of diverse clinicopathologic characteristics, H3K27M-mutant diffuse midline gliomas are incurable, WHO grade IV lesions with poor prognosis. Yekula et al. discussed the case in the context of a review of published reports of H3K27-mutant diffuse midline gliomas in adults. Findings late in the disease course may mimic inflammatory or infectious pathologies radiographically, and low-grade infiltrative neoplasms histologically.

The diverse clinical, radiographic and molecular features of H3K27M-mutant diffuse midline gliomas in adults remain to be completely characterized. A high index of suspicion is required to avoid missing the diagnosis. Early biopsy and detailed molecular characterization are critical for accurate diagnosis and patient counseling 4).

References

1)

Porkholm M, Raunio A, Vainionpää R, Salonen T, Hernesniemi J, Valanne L, Satopää J, Karppinen A, Oinas M, Tynninen O, Pentikäinen V, Kivivuori SM. Molecular alterations in pediatric brainstem gliomas. Pediatr Blood Cancer. 2017 Aug 9. doi: 10.1002/pbc.26751. [Epub ahead of print] PubMed PMID: 28792659.
2)

Cooney T, Lane A, Bartels U, Bouffet E, Goldman S, Leary SES, Foreman NK, Packer RJ, Broniscer A, Minturn JE, Shih CS, Chintagumpala M, Hassall T, Gottardo NG, Dholaria H, Hoffman L, Chaney B, Baugh J, Doughman R, Leach JL, Jones BV, Fouladi M, Warren KE, Monje M. Contemporary survival endpoints: an International Diffuse Intrinsic Pontine Glioma Registry study. Neuro Oncol. 2017 Sep 1;19(9):1279-1280. doi: 10.1093/neuonc/nox107. PubMed PMID: 28821206.
3)

Plessier A, Dret LL, Varlet P, Beccaria K, Lacombe J, Mériaux S, Geffroy F, Fiette L, Flamant P, Chrétien F, Blauwblomme T, Puget S, Grill J, Debily MA, Castel D. New in vivo avatars of diffuse intrinsic pontine gliomas (DIPG) from stereotactic biopsies performed at diagnosis. Oncotarget. 2017 Feb 2. doi: 10.18632/oncotarget.15002. [Epub ahead of print] PubMed PMID: 28178670.
4)

Yekula A, Gupta M, Coley N, U HS. Adult H3K27M-mutant diffuse midline glioma with gliomatosis cerebri growth pattern: Case report and review of the literature. Int J Surg Case Rep. 2020 Feb 28;68:124-128. doi: 10.1016/j.ijscr.2020.02.046. [Epub ahead of print] PubMed PMID: 32145563.

Glioma

Glioma

The term “glioma” could technically be used to refer to all tumors of any glial lineage (i.e., from glial cells such as oligodendrogliaependymal cells, Schwann cells, microglia…), but in its common usage, “glioma” usually refers only to astrocytic tumors.

Gliomas comprise a heterogeneous group of benign and malignant neoplasms.

The body of glioma-related literature has grown significantly over the past 25 years. Despite this growth in the amount of published research, gliomas remain one of the most intransigent cancers. The purpose of a study was to analyze the landscape of glioma-related research over the past 25 years using machine learning and text analysis.

In April 2019, Feng et al. downloaded glioma-related publications indexed in PubMed between 1994 and 2018. They used Python to extract the title, publication date, MeSH terms, and abstract from the metadata of each publication for bibliometric assessment. Latent Dirichlet allocation (LDA) was applied to the abstracts to identify publications’ research topics with greater specificity.

They identified and analyzed a total of 52,625 publications. They found that research on prognosis and the treatment of glioblastoma increased the most in terms of volume and rate of publications over the past 25 years. However, publications regarding clinical trials accounted for <5% of all publications considered in this study. The current research landscape covers clinical, pre-clinical, biological, and technical aspects of glioblastoma; at present, researchers appear to be less concerned with glioblastoma’s psychological effects or patients’ end-of-life care.

Publication of glioma-related research has expanded rapidly over the past 25 years. Common topics include the disease’s molecular background, patients’ survival, and treatment outcomes; more research needs to be done on the psychological aspects of glioblastoma and end-of-life care 1)


Studies on gliomas suggested that the microenvironment of human gliomas contains both glioma stem cells (GSCs) and glioma associated (GA)-mesenchymal stem cells (MSCs; (GA-MSCs). Also, studies have suggested that nano- sized vesicles, termed exosomes, have been recently observed to contribute towards intercellular communication within the tumor niche 2).

Epidemiology

Gliomas are the second most common primary brain tumors, with an incidence of 4–5/100 000 individuals. Gliomas are the second leading cause of cancer mortality in adults under the age of 35, the fourth leading cause in those under the age of 54, and result in death in approximately 13 770 individuals per year in the United States.

Approximately 89,000 new primary brain tumors are diagnosed in the United States each year, for which 27% are gliomas and 32.8% are malignant glioma3).

The are more frequent among males 4).

Classification

They encompass two principle subgroups: diffuse gliomas and gliomas showing a more circumscribed growth pattern (‘non-diffuse gliomas’). In the revised 4th edition of the World Health Organization Classification of Tumors of the Central Nervous System published in 2016, classification of especially diffuse gliomas has fundamentally changed: for the first time a large subset of these tumours is now defined based on presence/absence of IDH mutation and 1p/19q codeletion. Following this approach, the diagnosis of (anaplastic) oligoastrocytoma can be expected to largely disappear 5).

see Glioma classification.


Sorting and grading of glial tumors by the WHO grade classification provide clinicians with guidance as to the predicted course of the disease and choice of treatment. Nonetheless, histologically identical tumors may have very different outcome and response to treatment. Molecular biomarkers that carry both diagnostic and prognostic information add useful tools to traditional classification by redefining tumor subtypes within each WHO category. Therefore, molecular markers have become an integral part of tumor assessment in modern neurooncology and biomarker status now guides clinical decisions in some subtypes of gliomas. The routine assessment of IDH status improves histological diagnostic accuracy by differentiating diffuse glioma from reactive gliosis. It carries a favorable prognostic implication for all glial tumors and it is predictive for chemotherapeutic response in anaplastic oligodendrogliomas with codeletion of 1p19q chromosomes. Glial tumors that contain chromosomal codeletion of 1p/19q are defined as tumors of oligodendroglial lineage and have favorable prognosis. MGMT promoter methylation is a favorable prognostic marker in astrocytic high-grade gliomas and it is predictive for chemotherapeutic response in anaplastic gliomas with wild-type IDH1/2 and in elderly glioblastoma 6).

Pathogenesis

see Gliomagenesis

Spread

see Glioma spread

Clinical Features

Many gliomas become symptomatic with either seizures or focal neurological deficits and are subsequently detected via MRI.

Diagnosis

see Glioma Diagnosis.

MRI

see MRI for glioma.

Treatment

see Glioma treatment.

Outcome

see Glioma outcome.

Books

see Glioma Books.

Case series

Glioma case series.

References

1)

Feng C, Wu Y, Gao L, Guo X, Wang Z, Xing B. Publication Landscape Analysis on Gliomas: How Much Has Been Done in the Past 25 Years? Front Oncol. 2020 Jan 17;9:1463. doi: 10.3389/fonc.2019.01463. eCollection 2019. PubMed PMID: 32038995; PubMed Central PMCID: PMC6988829.
2)

Xu H, Zhang K, Zong H, Shang M, Li K, He X. Exosomal communication in glioma – a review. J BUON. 2016 Nov-Dec;21(6):1368-1373. PubMed PMID: 28039693.
3)

Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol. 2015 Oct;17 Suppl 4:iv1-iv62. doi: 10.1093/neuonc/nov189. Epub 2015 Oct 27. PubMed PMID: 26511214; PubMed Central PMCID: PMC4623240.
4)

Ohgaki H and Kleihues P (2005) Epidemiology and etiology of gliomas. Acta Neuropathol 109: 93–108.
5)

Wesseling P, Capper D. WHO 2016 Classification of Gliomas. Neuropathol Appl Neurobiol. 2017 Aug 16. doi: 10.1111/nan.12432. [Epub ahead of print] PubMed PMID: 28815663.
6)

Siegal T. Clinical Relevance of Prognostic and Predictive Molecular Markers in Gliomas. Adv Tech Stand Neurosurg. 2016;43:91-108. doi: 10.1007/978-3-319-21359-0_4. PubMed PMID: 26508407.
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