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The Molecular Basis of Therapeutic Resistance of Brain Tumor

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (15 May 2021) | Viewed by 43255

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Special Issue Editor

Prof. Dr. BuHyun Youn

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Guest Editor

Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea
Interests: brain tumor; glioblastoma; therapeutic resistance; cancer metabolism; signaling transduction; oncogene; radiotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Brain tumor is one of the formidable tumor types due to its unique spatial and physiological features. The preferred treatment for the brain tumor is surgical elimination, which is usually followed by chemo- and radiotherapy to prevent recurrence. Therefore, therapeutic resistance is a major obstruction to achieving successful control of brain tumors. Although related studies have been performed over several decades, there has been little remarkable advance in brain tumor treatment—especially absence in malignant brain tumor. Currently, wide-ranging screening and analytical techniques help investigators to discover novel therapeutic targets with reliable molecular mechanisms in various types of tumors. Furthermore, the combination of target inhibitors with classical therapies could marginally elevate therapeutic efficacy. In the context of brain tumors, recent studies have underscored the alterations in cellular signaling transduction, metabolic pathways, oncogenic gene expressions, and microenvironments, leading to the acquisition of therapeutic resistance and malignancy. Therefore, a deeper investigation about the molecular mechanisms of these events is prompted to suggest ways to overcome the contemporary limitations of treatments.

In this Special Issue, we shall discuss the recent advances in molecular mechanisms around the therapeutic resistance of brain tumors derived from genetic/epigenetic, metabolic, and microenvironmental alterations for next-generation therapeutic strategies. The types of research invited include basic/translational research and reviews.

Prof. BuHyun Youn
Guest Editor

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Keywords

Brain tumor
Therapeutic resistance
Molecular mechanisms
Signaling transduction
Cancer metabolism
Oncogene
Microenvironments
Epigenetics

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Published Papers (11 papers)

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Research

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21 pages, 5843 KiB

Open AccessArticle

Comprehensive Assessment of Secreted Immuno-Modulatory Cytokines by Serum-Differentiated and Stem-like Glioblastoma Cells Reveals Distinct Differences between Glioblastoma Phenotypes

by Laverne D. Robilliard, Jane Yu, Akshata Anchan, Graeme Finlay, Catherine E. Angel and E Scott Graham

Int. J. Mol. Sci. 2022, 23(22), 14164; https://doi.org/10.3390/ijms232214164 - 16 Nov 2022

Cited by 2 | Viewed by 1806

Abstract

Glioblastoma is refractory to therapy and presents a significant oncological challenge. Promising immunotherapies have not shown the promise observed in other aggressive cancers. The reasons for this include the highly immuno-suppressive tumour microenvironment controlled by the glioblastoma cells and heterogeneous phenotype of the glioblastoma cells. Here, we wanted to better understand which glioblastoma phenotypes produced the regulatory cytokines, particularly those that are implicated in shaping the immune microenvironment. In this study, we employed nanoString analysis of the glioblastoma transcriptome, and proteomic analysis (proteome profiler arrays and cytokine profiling) of secreted cytokines by different glioblastoma phenotypes. These phenotypes were cultured to reflect a spectrum of glioblastoma cells present in tumours, by culturing an enhanced stem-like phenotype of glioblastoma cells or a more differentiated phenotype following culture with serum. Extensive secretome profiling reveals that there is considerable heterogeneity in secretion patterns between serum-derived and glioblastoma stem-like cells, as well as between individuals. Generally, however, the serum-derived phenotypes appear to be the primary producers of cytokines associated with immune cell recruitment into the tumour microenvironment. Therefore, these glioblastoma cells have considerable importance in shaping the immune landscape in glioblastoma and represent a valuable therapeutic target that should not be ignored. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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16 pages, 2385 KiB

Open AccessCommunication

Metabolome Shift in Both Metastatic Breast Cancer Cells and Astrocytes Which May Contribute to the Tumor Microenvironment

by Hiromi Sato, Ayaka Shimizu, Toya Okawa, Miaki Uzu, Momoko Goto and Akihiro Hisaka

Int. J. Mol. Sci. 2021, 22(14), 7430; https://doi.org/10.3390/ijms22147430 - 11 Jul 2021

Cited by 2 | Viewed by 3151

Abstract

The role of astrocytes in the periphery of metastatic brain tumors is unclear. Since astrocytes regulate central nervous metabolism, we hypothesized that changes in astrocytes induced by contact with cancer cells would appear in the metabolome of both cells and contribute to malignant transformation. Coculture of astrocytes with breast cancer cell supernatants altered glutamate (Glu)-centered arginine–proline metabolism. Similarly, the metabolome of cancer cells was also altered by astrocyte culture supernatants, and the changes were further amplified in astrocytes exposed to Glu. Inhibition of Glu uptake in astrocytes reduces the variability in cancer cells. Principal component analysis of the cancer cells revealed that all these changes were in the first principal component (PC1) axis, where the responsible metabolites were involved in the metabolism of the arginine–proline, pyrimidine, and pentose phosphate pathways. The contribution of these changes to the tumor microenvironment needs to be further pursued. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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14 pages, 2632 KiB

Open AccessArticle

Lomeguatrib Increases the Radiosensitivity of MGMT Unmethylated Human Glioblastoma Multiforme Cell Lines

by Anna Kirstein, Daniela Schilling, Stephanie E. Combs and Thomas E. Schmid

Int. J. Mol. Sci. 2021, 22(13), 6781; https://doi.org/10.3390/ijms22136781 - 24 Jun 2021

Cited by 9 | Viewed by 2438

Abstract

Background: Treatment resistance of glioblastoma multiforme to chemo- and radiotherapy remains a challenge yet to overcome. In particular, the O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter unmethylated patients have only little benefit from chemotherapy treatment using temozolomide since MGMT counteracts its therapeutic efficacy. Therefore, new treatment options in radiotherapy need to be developed to inhibit MGMT and increase radiotherapy response. Methods: Lomeguatrib, a highly specific MGMT inhibitor, was used to inactivate MGMT protein in vitro. Radiosensitivity of established human glioblastoma multiforme cell lines in combination with lomeguatrib was investigated using the clonogenic survival assay. Inhibition of MGMT was analyzed using Western Blot. Cell cycle distribution and apoptosis were investigated to determine the effects of lomeguatrib alone as well as in combination with ionizing radiation. Results: Lomeguatrib significantly decreased MGMT protein and reduced radiation-induced G2/M arrest. A radiosensitizing effect of lomeguatrib was observed when administered at 1 µM and increased radioresistance at 20 µM. Conclusion: Low concentrations of lomeguatrib elicit radiosensitization, while high concentrations mediate a radioprotective effect. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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13 pages, 2802 KiB

Open AccessArticle

Evaluation of Haptoglobin and Its Proteoforms as Glioblastoma Markers

by Stanislav Naryzhny, Natalia Ronzhina, Elena Zorina, Fedor Kabachenko, Maria Zavialova, Viktor Zgoda, Nikolai Klopov, Olga Legina and Rimma Pantina

Int. J. Mol. Sci. 2021, 22(12), 6533; https://doi.org/10.3390/ijms22126533 - 18 Jun 2021

Cited by 17 | Viewed by 2481

Abstract

Haptoglobin (Hp) is a blood plasma glycoprotein that plays a critical role in tissue protection and the prevention of oxidative damage. Haptoglobin is an acute-phase protein, its concentration in plasma changes in pathology, and the test for its concentration is part of normal clinical practice. Haptoglobin is a conservative protein and is the subject of research as a potential biomarker of many diseases, including malignant neoplasms. The Human Hp gene is polymorphic and controls the synthesis of three major phenotypes—homozygous Hp1-1 and Hp2-2, and heterozygous Hp2-1, determined by a combination of allelic variants that are inherited. Numerous studies indicate that the phenotype of haptoglobin can be used to judge the individual’s predisposition to various diseases. In addition, Hp undergoes various post-translational modifications (PTMs). Glioblastoma multiform (GBM) is the most malignant primary brain tumor. In our study, we have analyzed the state of Hp proteoforms in plasma and cells using 1D (SDS-PAGE) and 2D electrophoresis (2DE) with the following mass spectrometry (LC ES-MS/MS) or Western blotting. We found that the levels of α2- and β-chain proteoforms are up-regulated in the plasma of GBM patients. An unprocessed form of Hp2-2 (PreHp2-2, zonulin) with unusual biophysical parameters (pI/Mw) was also detected in the plasma of GBM patients and glioblastoma cells. Altogether, this data shows the possibility to use proteoforms of haptoglobin as a potential GBM-specific plasma biomarker. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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18 pages, 7430 KiB

Open AccessArticle

Involvement of PI3K Pathway in Glioma Cell Resistance to Temozolomide Treatment

by Adrian Zając, Joanna Sumorek-Wiadro, Ewa Langner, Iwona Wertel, Aleksandra Maciejczyk, Bożena Pawlikowska-Pawlęga, Jarosław Pawelec, Magdalena Wasiak, Monika Hułas-Stasiak, Dorota Bądziul, Wojciech Rzeski, Michał Reichert and Joanna Jakubowicz-Gil

Int. J. Mol. Sci. 2021, 22(10), 5155; https://doi.org/10.3390/ijms22105155 - 13 May 2021

Cited by 24 | Viewed by 3312

Abstract

The aim of the study was to investigate the anticancer potential of LY294002 (PI3K inhibitor) and temozolomide using glioblastoma multiforme (T98G) and anaplastic astrocytoma (MOGGCCM) cells. Apoptosis, autophagy, necrosis, and granules in the cytoplasm were identified microscopically (fluorescence and electron microscopes). The mitochondrial membrane potential was studied by flow cytometry. The activity of caspases 3, 8, and 9 and Akt was evaluated fluorometrically, while the expression of Beclin 1, PI3K, Akt, mTOR, caspase 12, and Hsp27 was determined by immunoblotting. SiRNA was used to block Hsp27 and PI3K expression. Cell migration and localization of Hsp27 were tested with the wound healing assay and immunocytochemistry, respectively. LY294002 effectively diminished the migratory potential and increased programmed death of T98G and MOGGCCM. Autophagy was dominant in MOGGCCM, while apoptosis was dominant in T98G. LY294002 with temozolomide did not potentiate cell death but redirected autophagy toward apoptosis, which was correlated with ER stress. A similar effect was observed after blocking PI3K expression with siRNA. Transfection with Hsp27 siRNA significantly increased apoptosis related to ER stress. Our results indicate that inhibition of the PI3K/Akt/mTOR pathway sensitizes glioma cells to apoptosis upon temozolomide treatment, which was correlated with ER stress. Hsp27 increases the resistance of glioma cells to cell death upon temozolomide treatment. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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16 pages, 6524 KiB

Open AccessArticle

Dual Specificity Kinase DYRK3 Promotes Aggressiveness of Glioblastoma by Altering Mitochondrial Morphology and Function

by Kyeongmin Kim, Sungmin Lee, Hyunkoo Kang, Eunguk Shin, Hae Yu Kim, HyeSook Youn and BuHyun Youn

Int. J. Mol. Sci. 2021, 22(6), 2982; https://doi.org/10.3390/ijms22062982 - 15 Mar 2021

Cited by 16 | Viewed by 3176

Abstract

Glioblastoma multiforme (GBM) is a malignant primary brain tumor with poor patient prognosis. Although the standard treatment of GBM is surgery followed by chemotherapy and radiotherapy, often a small portion of surviving tumor cells acquire therapeutic resistance and become more aggressive. Recently, altered kinase expression and activity have been shown to determine metabolic flux in tumor cells and metabolic reprogramming has emerged as a tumor progression regulatory mechanism. Here we investigated novel kinase-mediated metabolic alterations that lead to acquired GBM radioresistance and malignancy. We utilized transcriptomic analyses within a radioresistant GBM orthotopic xenograft mouse model that overexpresses the dual specificity tyrosine-phosphorylation-regulated kinase 3 (DYRK3). We find that within GBM cells, radiation exposure induces DYRK3 expression and DYRK3 regulates mammalian target of rapamycin complex 1 (mTORC1) activity through phosphorylation of proline-rich AKT1 substrate 1 (PRAS40). We also find that DYRK3 knockdown inhibits dynamin-related protein 1 (DRP1)-mediated mitochondrial fission, leading to increased oxidative phosphorylation (OXPHOS) and reduced glycolysis. Importantly, enforced DYRK3 downregulation following irradiation significantly impaired GBM cell migration and invasion. Collectively, we suggest DYRK3 suppression may be a novel strategy for preventing GBM malignancy through regulating mitochondrial metabolism. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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Review

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14 pages, 308 KiB

Open AccessReview

WNT Signaling as a Therapeutic Target for Glioblastoma

by Michael Latour, Nam-Gu Her, Santosh Kesari and Elmar Nurmemmedov

Int. J. Mol. Sci. 2021, 22(16), 8428; https://doi.org/10.3390/ijms22168428 - 5 Aug 2021

Cited by 42 | Viewed by 4154

Abstract

The WNT (Wingless/Integrated) signaling pathway is implicated in various stages of glioblastoma, which is an aggressive brain tumor for which therapeutic options are limited. WNT has been recognized as a hallmark of therapeutic challenge due to its context-dependent role and critical function in healthy tissue homeostasis. In this review, we deeply scrutinize the WNT signaling pathway and its involvement in the genesis of glioblastoma as well as its acquired therapy resistance. We also provide an analysis of the WNT pathway in terms of its therapeutic importance in addition to an overview of the current targeted therapies under clinical investigation. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

13 pages, 707 KiB

Open AccessReview

The Roles Played by Long Non-Coding RNAs in Glioma Resistance

by Yeonsoo Chae, Jungwook Roh and Wanyeon Kim

Int. J. Mol. Sci. 2021, 22(13), 6834; https://doi.org/10.3390/ijms22136834 - 25 Jun 2021

Cited by 20 | Viewed by 4362

Abstract

Glioma originates in the central nervous system and is classified based on both histological features and molecular genetic characteristics. Long non-coding RNAs (lncRNAs) are longer than 200 nucleotides and are known to regulate tumorigenesis and tumor progression, and even confer therapeutic resistance to glioma cells. Since oncogenic lncRNAs have been frequently upregulated to promote cell proliferation, migration, and invasion in glioma cells, while tumor-suppressive lncRNAs responsible for the inhibition of apoptosis and decrease in therapeutic sensitivity in glioma cells have been generally downregulated, the dysregulation of lncRNAs affects many features of glioma patients, and the expression profiles associated with these lncRNAs are needed to diagnose the disease stage and to determine suitable therapeutic strategies. Accumulating studies show that the orchestrations of oncogenic lncRNAs and tumor-suppressive lncRNAs in glioma cells result in signaling pathways that influence the pathogenesis and progression of glioma. Furthermore, several lncRNAs are related to the regulation of therapeutic sensitivity in existing anticancer therapies, including radiotherapy, chemotherapy and immunotherapy. Consequently, we undertook this review to improve the understanding of signaling pathways influenced by lncRNAs in glioma and how lncRNAs affect therapeutic resistance. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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15 pages, 806 KiB

Open AccessReview

Molecular Mechanisms of Drug Resistance in Glioblastoma

by Maya A. Dymova, Elena V. Kuligina and Vladimir A. Richter

Int. J. Mol. Sci. 2021, 22(12), 6385; https://doi.org/10.3390/ijms22126385 - 15 Jun 2021

Cited by 56 | Viewed by 9628

Abstract

Glioblastoma multiforme (GBM) is the most common and fatal primary brain tumor, is highly resistant to conventional radiation and chemotherapy, and is not amenable to effective surgical resection. The present review summarizes recent advances in our understanding of the molecular mechanisms of therapeutic resistance of GBM to already known drugs, the molecular characteristics of glioblastoma cells, and the barriers in the brain that underlie drug resistance. We also discuss the progress that has been made in the development of new targeted drugs for glioblastoma, as well as advances in drug delivery across the blood–brain barrier (BBB) and blood–brain tumor barrier (BBTB). Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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23 pages, 466 KiB

Open AccessReview

Multidiscipline Immunotherapy-Based Rational Combinations for Robust and Durable Efficacy in Brain Metastases from Renal Cell Carcinoma

by Hye-Won Lee

Int. J. Mol. Sci. 2021, 22(12), 6290; https://doi.org/10.3390/ijms22126290 - 11 Jun 2021

Cited by 5 | Viewed by 2888

Abstract

Advanced imaging techniques for diagnosis have increased awareness on the benefits of brain screening, facilitated effective control of extracranial disease, and prolonged life expectancy of metastatic renal cell carcinoma (mRCC) patients. Brain metastasis (BM) in patients with mRCC (RCC-BM) is associated with grave prognoses, a high degree of morbidity, dedicated assessment, and unresponsiveness to conventional systemic therapeutics. The therapeutic landscape of RCC-BM is rapidly changing; however, survival outcomes remain poor despite standard surgery and radiation, highlighting the unmet medical needs and the requisite for advancement in systemic therapies. Immune checkpoint inhibitors (ICIs) are one of the most promising strategies to treat RCC-BM. Understanding the role of brain-specific tumor immune microenvironment (TIME) is important for developing rationale-driven ICI-based combination strategies that circumvent tumor intrinsic and extrinsic factors and complex positive feedback loops associated with resistance to ICIs in RCC-BM via combination with ICIs involving other immunological pathways, anti-antiangiogenic multiple tyrosine kinase inhibitors, and radiotherapy; therefore, novel combination approaches are being developed for synergistic potential against RCC-BM; however, further prospective investigations with longer follow-up periods are required to improve the efficacy and safety of combination treatments and to elucidate dynamic predictive biomarkers depending on the interactions in the brain TIME. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

20 pages, 3796 KiB

Open AccessReview

Revisiting Platinum-Based Anticancer Drugs to Overcome Gliomas

by Jaewan Jeon, Sungmin Lee, Hyunwoo Kim, Hyunkoo Kang, HyeSook Youn, Sunmi Jo, BuHyun Youn and Hae Yu Kim

Int. J. Mol. Sci. 2021, 22(10), 5111; https://doi.org/10.3390/ijms22105111 - 12 May 2021

Cited by 23 | Viewed by 4763

Abstract

Although there are many patients with brain tumors worldwide, there are numerous difficulties in overcoming brain tumors. Among brain tumors, glioblastoma, with a 5-year survival rate of 5.1%, is the most malignant. In addition to surgical operations, chemotherapy and radiotherapy are generally performed, but the patients have very limited options. Temozolomide is the most commonly prescribed drug for patients with glioblastoma. However, it is difficult to completely remove the tumor with this drug alone. Therefore, it is necessary to discuss the potential of anticancer drugs, other than temozolomide, against glioblastomas. Since the discovery of cisplatin, platinum-based drugs have become one of the leading chemotherapeutic drugs. Although many studies have reported the efficacy of platinum-based anticancer drugs against various carcinomas, studies on their effectiveness against brain tumors are insufficient. In this review, we elucidated the anticancer effects and advantages of platinum-based drugs used in brain tumors. In addition, the cases and limitations of the clinical application of platinum-based drugs are summarized. As a solution to overcome these obstacles, we emphasized the potential of a novel approach to increase the effectiveness of platinum-based drugs. Full article

(This article belongs to the Special Issue The Molecular Basis of Therapeutic Resistance of Brain Tumor)

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