bims-malgli Biomed News
on Biology of malignant gliomas
Issue of 2022‒07‒17
eleven papers selected by
Oltea Sampetrean
Keio University

  1. Methods Cell Biol. 2022 ;pii: S0091-679X(22)00020-6. [Epub ahead of print]170 1-19
      There is an urgency for identifying effective therapies for glioblastoma (GBM), an incurable and lethal primary malignant brain tumor. Patient-derived xenograft mouse models, in which glioma stem cells, which retain the characteristics of the original tumor, are implanted into the brain of immunocompromised mice, represent a well-suited model for studying GBM. Such models are essential for studies involving the tumor microenvironment and for testing experimental therapeutics for brain tumors. In this chapter, we detail various steps for generating an orthotopic brain tumor model in mice. We provide step-by-step guidance for enrichment and expansion of glioma stem cells for surgical specimens, surgical injection of these cells into the brain of immunocompromised mice, as well as monitoring of tumor growth.
    Keywords:  Glioblastoma; Glioma stem cells; Patient-derived xenograft mouse models
  2. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac082
      Background: Biological differences based on sex have been documented throughout the scientific literature. Glioblastoma (GBM), the most common primary malignant brain tumor in adults, has a male sex incidence bias, however, no clinical trial data examining differential effects of treatment between sexes currently exists.Method: We analyzed genomic data, as well as clinical trials, to delineate the effect of sex on the immune system and GBM outcome following immunotherapy.
    Results: We found that in general females possess enriched immunological signatures on gene set enrichment analysis, which also stratified patient survival when delineated by sex. Female GBM patients treated with immunotherapy had a statistically significant survival advantage at the 1-year compared to males (relative risk [RR] = 1.15; P = .0241). This effect was even more pronounced in vaccine-based immunotherapy (RR = 1.29; P = .0158).
    Conclusions: Our study shows a meaningful difference in the immunobiology between males and females that also influences the overall response to immunotherapy in the setting of GBM.
    Keywords:  glioblastoma; glioma; immunotherapy; sexual dimorphism
  3. Fluids Barriers CNS. 2022 Jul 11. 19(1): 58
      BACKGROUND: Glioblastoma (GBM) is the most aggressive and common type of primary brain tumor in adults. Tumor location plays a role in patient prognosis, with tumors proximal to the lateral ventricles (LVs) presenting with worse overall survival, increased expression of stem cell genes, and increased incidence of distal tumor recurrence. This may be due in part to interaction of GBM with factors of the subventricular zone (SVZ), including those contained within the cerebrospinal fluid (CSF). However, direct interaction of GBM tumors with CSF has not been proved and would be hindered in the presence of an intact ependymal cell layer.METHODS: Here, we investigate the ependymal cell barrier and its derived extracellular matrix (ECM) fractones in the vicinity of a GBM tumor. Patient-derived GBM cells were orthotopically implanted into immunosuppressed athymic mice in locations distal and proximal to the LV. A PBS vehicle injection in the proximal location was included as a control. At four weeks post-xenograft, brain tissue was examined for alterations in ependymal cell health via immunohistochemistry, scanning electron microscopy, and transmission electron microscopy.
    RESULTS: We identified local invading GBM cells within the LV wall and increased influx of CSF into the LV-proximal GBM tumor bulk compared to controls. In addition to the physical disruption of the ependymal cell barrier, we also identified increased signs of compromised ependymal cell health in LV-proximal tumor-bearing mice. These signs include increased accumulation of lipid droplets, decreased cilia length and number, and decreased expression of cell channel proteins. We additionally identified elevated numbers of small fractones in the SVZ within this group, suggesting increased indirect CSF-contained molecule signaling to tumor cells.
    CONCLUSIONS: Our data is the first to show that LV-proximal GBMs physically disrupt the ependymal cell barrier in animal models, resulting in disruptions in ependymal cell biology and increased CSF interaction with the tumor bulk. These findings point to ependymal cell health and CSF-contained molecules as potential axes for therapeutic targeting in the treatment of GBM.
    Keywords:  Cerebrospinal fluid (CSF); Cilia; Glioma; Lateral ventricle; Lipid droplets; Stem cell niche; Subependymal zone
  4. Methods Cell Biol. 2022 ;pii: S0091-679X(22)00021-8. [Epub ahead of print]170 21-30
      Cancer stem cells are defined as low-abundance, quiescent cells and are considered a major cellular source of tumor recurrence following therapy, which identifies these cells as important therapeutic targets for difficult-to-treat cancers, including high-grade gliomas. By contrast to the highly proliferative bulk tumor cells, glioma stem cells (GSC) are slow-cycling, and therefore less sensitive to DNA damaging cytotoxic drugs. GSC are also less reliant on aerobic glycolytic metabolism, leading to inadequate clearing of GSC by chemotherapy and radiotherapy. The definition of GSC is based on the expression of specific stem cell protein markers. This method of GSC isolation is successful in isolating cell populations that can reliably recapitulate the tumor. However, cell populations that lack stem marker expression may also be capable of tumor recapitulation. Therefore, robust, reproducible methods for isolating GSC are required to identify and isolate cells with stem cell characteristics. Here, we provide a comprehensive and reproducible protocol for the isolation of slow-cycling GSC. Using this method, GSC isolated retain key characteristics of the cells in situ, including expression of genes associated with cell quiescence and invasive potential, compared to non-quiescent cell populations. Thus, isolation of GSC gated on cell proliferation offers a reliable alternative method for in vitro GSC identification, that adequately mirrors the physiological properties of GSC seen in vivo.
    Keywords:  GSC; Glioblastoma; Glioma stem cells; Intravital dye; Oregon Green; Quiescent; Slow-cycling
  5. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac080
      Glioblastoma (GBM) is the most common primary adult intracranial malignancy and carries a dismal prognosis despite an aggressive multimodal treatment regimen that consists of surgical resection, radiation, and adjuvant chemotherapy. Radiographic evaluation, largely informed by magnetic resonance imaging (MRI), is a critical component of initial diagnosis, surgical planning, and post-treatment monitoring. However, conventional MRI does not provide information regarding tumor microvasculature, necrosis, or neoangiogenesis. In addition, traditional MRI imaging can be further confounded by treatment-related effects such as pseudoprogression, radiation necrosis, and/or pseudoresponse(s) that preclude clinicians from making fully informed decisions when structuring a therapeutic approach. A myriad of novel imaging modalities have been developed to address these deficits. Herein, we provide a clinically oriented review of standard techniques for imaging GBM and highlight emerging technologies utilized in disease characterization and therapeutic development.
    Keywords:  MRI; PET; glioblastoma (GBM); mass spectrometry; radiographic progression; tumor progression
  6. ACS Nano. 2022 Jul 13.
      M13 bacteriophage (phage) are versatile, genetically tunable nanocarriers that have been recently adapted for use as diagnostic and therapeutic platforms. Applying p3 capsid chlorotoxin fusion with the "inho" circular single-stranded DNA (cssDNA) gene packaging system, we produced miniature chlorotoxin inho (CTX-inho) phage particles with a minimum length of 50 nm that can target intracranial orthotopic patient-derived GBM22 glioblastoma tumors in the brains of mice. Systemically administered indocyanine green conjugated CTX-inho phage accumulated in brain tumors, facilitating shortwave infrared detection. Furthermore, we show that our inho phage can carry cssDNA that are transcriptionally active when delivered to GBM22 glioma cells in vitro. The ability to modulate the capsid display, surface loading, phage length, and cssDNA gene content makes the recombinant M13 phage particle an ideal delivery platform.
    Keywords:  engineered m13 bacteriophage; glioblastoma targeting; materials and gene delivery; nanotheranostic particle; short-wavelength infrared imaging
  7. Sci Rep. 2022 Jul 15. 12(1): 12078
      Glioblastoma is one of the most aggressive types of cancer with success of therapy being hampered by the existence of treatment resistant populations of stem-like Tumour Initiating Cells (TICs) and poor blood-brain barrier drug penetration. Therapies capable of effectively targeting the TIC population are in high demand. Here, we synthesize spherical diketopyrrolopyrrole-based Conjugated Polymer Nanoparticles (CPNs) with an average diameter of 109 nm. CPNs were designed to include fluorescein-conjugated Hyaluronic Acid (HA), a ligand for the CD44 receptor present on one population of TICs. We demonstrate blood-brain barrier permeability of this system and concentration and cell cycle phase-dependent selective uptake of HA-CPNs in CD44 positive GBM-patient derived cultures. Interestingly, we found that uptake alone regulated the levels and signaling activity of the CD44 receptor, decreasing stemness, invasive properties and proliferation of the CD44-TIC populations in vitro and in a patient-derived xenograft zebrafish model. This work proposes a novel, CPN- based, and surface moiety-driven selective way of targeting of TIC populations in brain cancer.
  8. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac096
      Background: The genomic and overall biologic landscape of glioblastoma (GB) has become clearer over the past 2 decades, as predictive and prognostic biomarkers of both de novo and transformed forms of GB have been identified. The oral chemotherapeutic agent temozolomide (TMZ) has been integral to standard-of-care treatment for nearly 2 decades. More recently, the use of non-pharmacologic interventions, such as application of alternating electric fields, called Tumor-Treating Fields (TTFields), has emerged as a complementary treatment option that increases overall survival (OS) in patients with newly diagnosed GB. The genomic factors associated with improved or lack of response to TTFields are unknown.Methods: We performed comprehensive genomic analysis of GB tumors resected from 55 patients who went on to receive treatment using TTFields, and compared results to 57 patients who received standard treatment without TTFields.
    Results: We found that molecular driver alterations in NF1, and wild-type PIK3CA and epidermal growth factor receptor (EGFR), were associated with increased benefit from TTFields as measured by progression-free survival (PFS) and OS. There were no differences when stratified by TP53 status. When NF1, PIK3CA, and EGFR status were combined as a Molecular Survival Score, the combination of the 3 factors significantly correlated with improved OS and PFS in TTFields-treated patients compared to patients not treated with TTFields.
    Conclusions: These results shed light on potential driver and passenger mutations in GB that can be validated as predictive biomarkers of response to TTFields treatment, and provide an objective and testable genomic-based approach to assessing response.
    Keywords:  Tumor-Treating Fields; biomarkers; genomic profiling; glioblastoma; gliomas
  9. Cancer Res. 2022 Jul 15. pii: CAN-22-0507. [Epub ahead of print]
      Glioblastoma (GBM) is a complex ecosystem that includes a heterogeneous tumor population and the tumor immune microenvironment (TIME), prominently containing tumor-associated macrophages (TAMs) and microglia. Here, we demonstrated that β2-microglobulin (B2M), a subunit of the class I major histocompatibility complex (MHC-I), promotes maintenance of stem-like neoplastic populations and reprograms the TIME to an anti-inflammatory, tumor-promoting state. B2M activated PI3K/AKT/mTOR signaling by interacting with PIP5K1A in GBM stem cells (GSCs) and promoting MYC-induced secretion of transforming growth factor-β1 (TGF-β1). Inhibition of B2M attenuated GSC survival, self-renewal, and tumor growth. B2M-induced TGF-β1 secretion activated paracrine SMAD and PI3K/AKT signaling in TAMs and promoted an M2-like macrophage phenotype. These findings reveal tumor promoting functions of B2M and suggest that targeting B2M or its downstream axis may provide an effective approach for treating GBM.
  10. Neurooncol Adv. 2022 Jan-Dec;4(1):4(1): vdac100
      Background: There are no effective treatments for diffuse intrinsic pontine glioma (DIPG); median survival is 11.2 months. Bevacizumab has the potential to improve quality of life (QOL) and survival in DIPG but has never been evaluated systematically. The aim of this review was to assess Bevacizumab's role in the treatment of DIPG.Methods: MEDLINE, EMBASE, Scopus, and Web of Science were searched for relevant studies using terms developed from alternatives for Bevacizumab and DIPG. One reviewer screened titles and abstracts, then two reviewers screened full texts. Data were extracted into tables and quality assessed using methodological index for non-randomized studies and JBI tools.
    Results: Searching revealed 1001 papers; after deduplication 851 remained. After screening of titles and abstracts, then 28 full texts, 11 studies were included. Four studies reported a median overall survival longer than historical data, however, two found no significant impact of Bevacizumab. Five studies reported a radiological response in a proportion of participants and two reported no response. Three studies, evaluating clinical response, reported improvement in a proportion of patients. Three studies, evaluating QOL, reported stability or improvement. Four studies, evaluating steroid use, reported reductions in the proportion of patients receiving steroids. In radiation necrosis treatment, Bevacizumab led to clinical improvement in 6/12 patients in 2 studies and permitted a reduction in steroid use in most patients.
    Conclusions: Insufficient evidence means the role of Bevacizumab in the treatment of DIPG is unclear. However, Bevacizumab may be beneficial to some patients. The review highlights the need for further research in this area.
    Keywords:  Bevacizumab; diffuse intrinsic pontine glioma; quality of life; survival; systematic review
  11. Cancer Res. 2022 Jul 15. pii: CAN-22-0887. [Epub ahead of print]
      Tumor Treating Fields (TTFields), a new modality of cancer treatment, are electric fields transmitted transdermally to tumors. The FDA has approved TTFields for the treatment of glioblastoma multiforme and mesothelioma, and they are currently under study in many other cancer types. While anti-mitotic effects were the first recognized biological anti-cancer activity of TTFields, data have shown that tumor treating fields achieve their anti-cancer effects through multiple mechanisms of action. TTFields therefore have the ability to be useful for many cancer types in combination with many different treatment modalities. Here, we review the current understanding of TTFields and their mechanisms of action.