Hypoxia: The Cornerstone of Glioblastoma

Marta Domènech; Ainhoa Hernández; Andrea Plaja; Eva Martínez-Balibrea; Carmen Balañà

doi:10.3390/ijms222212608

Hypoxia: The Cornerstone of Glioblastoma

International Journal of Molecular Sciences ◽

10.3390/ijms222212608 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12608

Author(s):

Marta Domènech ◽

Ainhoa Hernández ◽

Andrea Plaja ◽

Eva Martínez-Balibrea ◽

Carmen Balañà

Keyword(s):

Tumor Progression ◽

Cell Invasion ◽

Metabolic Reprogramming ◽

High Grade ◽

Treatment Alternative ◽

Oncogenic Signaling ◽

Aggressive Form ◽

Aggressive Tumor ◽

Oncogenic Signaling Pathways ◽

Main Factor

Glioblastoma is the most aggressive form of brain tumor in adults and is characterized by the presence of hypervascularization and necrosis, both caused by a hypoxic microenvironment. In this review, we highlight that hypoxia-induced factor 1 (HIF-1), the main factor activated by hypoxia, is an important driver of tumor progression in GB patients. HIF-1α is a transcription factor regulated by the presence or absence of O2. The expression of HIF-1 has been related to high-grade gliomas and aggressive tumor behavior. HIF-1 promotes tumor progression via the activation of angiogenesis, immunosuppression, and metabolic reprogramming, promoting cell invasion and survival. Moreover, in GB, HIF-1 is not solely modulated by oxygen but also by oncogenic signaling pathways, such as MAPK/ERK, p53, and PI3K/PTEN. Therefore, the inhibition of the hypoxia pathway could represent an important treatment alternative in a disease with very few therapy options. Here, we review the roles of HIF-1 in GB progression and the inhibitors that have been studied thus far, with the aim of shedding light on this devastating disease.

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FOXM1 is a downstream target of LPA and YAP oncogenic signaling pathways in high grade serous ovarian cancer

Oncotarget ◽

10.18632/oncotarget.4280 ◽

2015 ◽

Vol 6 (29) ◽

pp. 27688-27699 ◽

Cited By ~ 21

Author(s):

Qipeng Fan ◽

Qingchun Cai ◽

Yan Xu

Keyword(s):

Ovarian Cancer ◽

Signaling Pathways ◽

High Grade ◽

Serous Ovarian Cancer ◽

Oncogenic Signaling ◽

Downstream Target ◽

Oncogenic Signaling Pathways

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Anti-Angiogenic Effects of Phytochemicals on miRNA Regulating Breast Cancer Progression

Biomolecules ◽

10.3390/biom10020191 ◽

2020 ◽

Vol 10 (2) ◽

pp. 191 ◽

Cited By ~ 16

Author(s):

Elizabeth Varghese ◽

Alena Liskova ◽

Peter Kubatka ◽

Samson Mathews Samuel ◽

Dietrich Büsselberg

Keyword(s):

Breast Cancer ◽

Tumor Growth ◽

Tumor Progression ◽

Cancer Progression ◽

Tumor Angiogenesis ◽

Expression Profiles ◽

Metabolic Reprogramming ◽

Breast Cancers ◽

Oncogenic Signaling ◽

Metabolic Switch

Several phytochemicals have been identified for their role in modifying miRNA regulating tumor progression. miRNAs modulate the expression of several oncogenes and tumor suppressor genes including the genes that regulate tumor angiogenesis. Hypoxia inducible factor-1 alpha (HIF-1α) signaling is a central axis that activates oncogenic signaling and acts as a metabolic switch in endothelial cell (EC) driven tumor angiogenesis. Tumor angiogenesis driven by metabolic reprogramming of EC is crucial for tumor progression and metastasis in many different cancers, including breast cancers, and has been linked to aberrant miRNA expression profiles. In the current article, we identify different miRNAs that regulate tumor angiogenesis in the context of oncogenic signaling and metabolic reprogramming in ECs and review how selected phytochemicals could modulate miRNA levels to induce an anti-angiogenic action in breast cancer. Studies involving genistein, epigallocatechin gallate (EGCG) and resveratrol demonstrate the regulation of miRNA-21, miRNA-221/222 and miRNA-27, which are prognostic markers in triple negative breast cancers (TNBCs). Modulating the metabolic pathway is a novel strategy for controlling tumor angiogenesis and tumor growth. Cardamonin, curcumin and resveratrol exhibit their anti-angiogenic property by targeting the miRNAs that regulate EC metabolism. Here we suggest that using phytochemicals to target miRNAs, which in turn suppresses tumor angiogenesis, should have the potential to inhibit tumor growth, progression, invasion and metastasis and may be developed into an effective therapeutic strategy for the treatment of many different cancers where tumor angiogenesis plays a significant role in tumor growth and progression.

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TMOD-22. LOSS OF PTEN AND TRP53 IN OLIGODENDROCYTE PROGENITORS LEADS TO GLIOMA FORMATION

Neuro-Oncology ◽

10.1093/neuonc/noz175.1121 ◽

2019 ◽

Vol 21 (Supplement_6) ◽

pp. vi267-vi267

Author(s):

Ravinder Verma ◽

Richard Lu

Keyword(s):

Malignant Transformation ◽

Tp53 Gene ◽

Adult Brain ◽

High Grade ◽

Missense Mutations ◽

Oncogenic Signaling ◽

Cooperative Action ◽

Oncogenic Pathways ◽

Cell Sources ◽

Oncogenic Signaling Pathways

Abstract Tumor suppressors PTEN and TP53 are the most commonly mutated anti-oncogenes in human gliomas after TERT mutation. 38% and 17% of total 4023 samples of gliomas in TCGA show TP53 and PTEN mutations respectively. TP53 signaling pathway plays an important role in the suppression of tumor progression PTEN negatively regulates PI3 triphosphate levels and suppresses AKT/PKB pathways. In-frame and missense mutations in PTEN constitutively activates the proliferative pathway and give a survival advantage. Mice with conditional mutation of PTEN and TP53 in neural stem cells directed by hGFAP-Cre develop high-grade gliomas. Our recent study indicates that primitive oligodendrocyte-progenitor intermediates (Pri-OPC) are abundant and hyperproliferative cells and can be progressively reprogrammed towards a stem-like state susceptible to malignant transformation. We hypothesize that mutations in PTEN and TP53 in pri-OPC lineage cells can lead to glioma formation. OPCs distribute across the whole adult brain and exhibit a much higher number than NSCs that are restricted to very small niche areas. Olig1 and Olig2 mark pri-OPC and oligodendrocyte lineage cells. In this study, we inactivated the PTEN/TP53 gene in mouse pri-OPCs using Olig1-Cre or Olig2tva-Cre. The incidence of glioma formation was 100%. Both the tumor formed in these models display multifocal, high-grade, diffuse and infiltrating gliomas. Though tumors are derived from similar cell sources, they vary in the expression and extent of oncogenic pathways. Our transcriptomics profiling at different stages of tumorigenesis reveals that progressive activation of oncogenic signaling pathways establishes a tumorigenic state to promote malignant transformation, suggesting a dynamic process of tumorigenesis caused by the cooperative action of the PTEN and TP53 loss in the pri-OPC lineage.

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Glutathione Peroxidase 8 (GPX8)-IL6 axis is essential in maintaining breast cancer mesenchymal stem-like state and aggressive phenotype

10.1101/818245 ◽

2019 ◽

Cited By ~ 1

Author(s):

Anees Khatib ◽

Solaimuthu Balakrishnan ◽

Michal Ben-Yosef ◽

Gidi Oren ◽

Areej Abu Rmaileh ◽

...

Keyword(s):

Glutathione Peroxidase ◽

Signaling Pathway ◽

Cancer Cell ◽

A549 Cells ◽

Metabolic Reprogramming ◽

Metabolic Enzyme ◽

Oncogenic Signaling ◽

Stat3 Signaling Pathway ◽

Cancer Aggressiveness ◽

Oncogenic Signaling Pathways

AbstractMetabolic reprogramming as a downstream result of oncogenic signaling pathways has been described as a hallmark of cancer. Here, we describe a reverse scenario in which a metabolic enzyme regulates cancer cell behavior by triggering a signaling pathway. We find that glutathione peroxidase 8 (GPX8), a poorly characterized redox enzyme that resides in the endoplasmic reticulum, is upregulated during the epithelial-to-mesenchymal (EMT) program in HMLE and A549 cells. In cancer patients, high tumor levels of GPX8 correlate with mesenchymal markers and poor patient outcome. Strikingly, GPX8 knockout in mesenchymal-like cells results in an epithelial-like morphology, downregulation of EMT characteristics, loss of cancer stemness features, and impeded tumor initiation in mice. We determine the mechanism governing this reduction in cancer aggressiveness is through the repression of crucial autocrine factors, in particular, interleukin-6 (IL-6). Specifically, GPX8 knockout impairs IL-6-driven activation of the JAK-STAT3 signaling pathway, a critical regulator of a cancer-aggressive state. Altogether, we uncover the GPX8-IL-6 axis as a novel metabolic-inflammatory pathway that acts as a robust EMT activator and program to induce aggressive cancer cell characteristics.

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The Role of the BH4 Cofactor in Nitric Oxide Synthase Activity and Cancer Progression: Two Sides of the Same Coin

International Journal of Molecular Sciences ◽

10.3390/ijms22179546 ◽

2021 ◽

Vol 22 (17) ◽

pp. 9546

Author(s):

Diego Assis Gonçalves ◽

Miriam Galvonas Jasiulionis ◽

Fabiana Henriques Machado de Melo

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Tumor Progression ◽

Cancer Progression ◽

Control Cell ◽

Metabolic Reprogramming ◽

Main Function ◽

Oncogenic Signaling ◽

Oxide Synthase

Cancer development is associated with abnormal proliferation, genetic instability, cell death resistance, metabolic reprogramming, immunity evasion, and metastasis. These alterations are triggered by genetic and epigenetic alterations in genes that control cell homeostasis. Increased reactive oxygen and nitrogen species (ROS, RNS) induced by different enzymes and reactions with distinct molecules contribute to malignant transformation and tumor progression by modifying DNA, proteins, and lipids, altering their activities. Nitric oxide synthase plays a central role in oncogenic signaling modulation and redox landscape. Overexpression of the three NOS isoforms has been found in innumerous types of cancer contributing to tumor growth and development. Although the main function of NOS is the production of nitric oxide (NO), it can be a source of ROS in some pathological conditions. Decreased tetrahydrobiopterin (BH4) cofactor availability is involved in NOS dysfunction, leading to ROS production and reduced levels of NO. The regulation of NOSs by BH4 in cancer is controversial since BH4 has been reported as a pro-tumoral or an antitumoral molecule. Therefore, in this review, the role of BH4 in the control of NOS activity and its involvement in the capabilities acquired along tumor progression of different cancers was described.

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MALAT1 as a Versatile Regulator of Cancer: Overview of the updates from Predatory role as Competitive Endogenous RNA to Mechanistic In-sights

Current Cancer Drug Targets ◽

10.2174/1568009620999200730183110 ◽

2020 ◽

Vol 20 ◽

Author(s):

Ammad Ahmad Farooqi ◽

Evangelia Legaki ◽

Maria Gazouli ◽

Silvia Rinaldi ◽

Rossana Berardi

Keyword(s):

Molecular Biology ◽

Detailed Analysis ◽

Signaling Pathways ◽

Individualized Medicine ◽

Signaling Cascades ◽

Oncogenic Signaling ◽

Non Coding Rnas ◽

Oncogenic Signaling Pathways ◽

Competitive Endogenous Rna

: Central dogma of molecular biology has remained cornerstone of classical molecular biology but serendipitous discovery of microRNAs (miRNAs) in nematodes paradigmatically shifted our current understanding of the intricate mech-anisms which occur during transitions from transcription to translation. Discovery of miRNA captured tremendous attention and appreciation and we had witnessed an explosion in the field of non-coding RNAs. Ground-breaking discoveries in the field of non-coding RNAs have helped in better characterization of microRNAs and long non-coding RNAs (LncRNAs). There is an ever-increasing list of miRNA targets which are regulated by MALAT1 to stimulate or repress expression of tar-get genes. However, in this review our main focus is to summarize mechanistic insights related to MALAT1-mediated regu-lation of oncogenic signaling pathways. We have discussed how MALAT1 modulated TGF/SMAD and Hippo pathways in various cancers. We have also comprehensively summarized how JAK/STAT and Wnt/β-catenin pathways stimulated MALAT1 expression and consequentially how MALAT1 potentiated these signaling cascades to promote cancer. MALAT1 research has undergone substantial broadening however, there is still a need to identify additional mechanisms. MALAT1 is involved in multi-layered regulation of multiple transduction cascades and detailed analysis of different pathways will be helpful in getting a step closer to individualized medicine.

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The m6A RNA methylation regulates oncogenic signaling pathways driving cell malignant transformation and carcinogenesis

Molecular Cancer ◽

10.1186/s12943-021-01356-0 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Mohammad Burhan Uddin ◽

Zhishan Wang ◽

Chengfeng Yang

Keyword(s):

Signaling Pathways ◽

Malignant Transformation ◽

Noncoding Rna ◽

Rna Modification ◽

Oncogenic Signaling ◽

Aberrant Expression ◽

Rna Methylation ◽

Rna Molecules ◽

M6a Rna Methylation ◽

Oncogenic Signaling Pathways

AbstractThe m6A RNA methylation is the most prevalent internal modification in mammalian mRNAs which plays critical biological roles by regulating vital cellular processes. Dysregulations of the m6A modification due to aberrant expression of its regulatory proteins are frequently observed in many pathological conditions, particularly in cancer. Normal cells undergo malignant transformation via activation or modulation of different oncogenic signaling pathways through complex mechanisms. Accumulating evidence showing regulation of oncogenic signaling pathways at the epitranscriptomic level has added an extra layer of the complexity. In particular, recent studies demonstrated that, in many types of cancers various oncogenic signaling pathways are modulated by the m6A modification in the target mRNAs as well as noncoding RNA transcripts. m6A modifications in these RNA molecules control their fate and metabolism by regulating their stability, translation or subcellular localizations. In this review we discussed recent exciting studies on oncogenic signaling pathways that are modulated by the m6A RNA modification and/or their regulators in cancer and provided perspectives for further studies. The regulation of oncogenic signaling pathways by the m6A modification and its regulators also render them as potential druggable targets for the treatment of cancer.

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Whole-exome mutational landscape of neuroendocrine carcinomas of the gallbladder

Signal Transduction and Targeted Therapy ◽

10.1038/s41392-020-00412-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Fatao Liu ◽

Yongsheng Li ◽

Dongjian Ying ◽

Shimei Qiu ◽

Yong He ◽

...

Keyword(s):

Gene Mutations ◽

Large Cell ◽

Molecular Signatures ◽

Single Nucleotide Variants ◽

Oncogenic Signaling ◽

Single Nucleotide ◽

Whole Exome ◽

Deadly Disease ◽

Oncogenic Signaling Pathways ◽

Neuroendocrine Carcinomas

AbstractNeuroendocrine carcinoma (NEC) of the gallbladder (GB-NEC) is a rare but extremely malignant subtype of gallbladder cancer (GBC). The genetic and molecular signatures of GB-NEC are poorly understood; thus, molecular targeting is currently unavailable. In the present study, we applied whole-exome sequencing (WES) technology to detect gene mutations and predicted somatic single-nucleotide variants (SNVs) in 15 cases of GB-NEC and 22 cases of general GBC. In 15 GB-NECs, the C > T mutation was predominant among the 6 types of SNVs. TP53 showed the highest mutation frequency (73%, 11/15). Compared with neuroendocrine carcinomas of other organs, significantly mutated genes (SMGs) in GB-NECs were more similar to those in pulmonary large-cell neuroendocrine carcinomas (LCNECs), with driver roles for TP53 and RB1. In the COSMIC database of cancer-related genes, 211 genes were mutated. Strikingly, RB1 (4/15, 27%) and NAB2 (3/15, 20%) mutations were found specifically in GB-NECs; in contrast, mutations in 29 genes, including ERBB2 and ERBB3, were identified exclusively in GBC. Mutations in RB1 and NAB2 were significantly related to downregulation of the RB1 and NAB2 proteins, respectively, according to immunohistochemical (IHC) data (p values = 0.0453 and 0.0303). Clinically actionable genes indicated 23 mutated genes, including ALK, BRCA1, and BRCA2. In addition, potential somatic SNVs predicted by ISOWN and SomVarIUS constituted 6 primary COSMIC mutation signatures (1, 3, 30, 6, 7, and 13) in GB-NEC. Genes carrying somatic SNVs were enriched mainly in oncogenic signaling pathways involving the Notch, WNT, Hippo, and RTK-RAS pathways. In summary, we have systematically identified the mutation landscape of GB-NEC, and these findings may provide mechanistic insights into the specific pathogenesis of this deadly disease.

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Protein Acetylation at the Interface of Genetics, Epigenetics and Environment in Cancer

Metabolites ◽

10.3390/metabo11040216 ◽

2021 ◽

Vol 11 (4) ◽

pp. 216

Author(s):

Mio Harachi ◽

Kenta Masui ◽

Webster K. Cavenee ◽

Paul S. Mischel ◽

Noriyuki Shibata

Keyword(s):

Cancer Cells ◽

Intracellular Signaling ◽

Cancer Biology ◽

High Resolution Mass Spectrometry ◽

Metabolic Reprogramming ◽

Protein Acetylation ◽

Protein Activity ◽

Oncogenic Signaling ◽

Intermediary Metabolites ◽

Novel Therapeutic Strategies

Metabolic reprogramming is an emerging hallmark of cancer and is driven by abnormalities of oncogenes and tumor suppressors. Accelerated metabolism causes cancer cell aggression through the dysregulation of rate-limiting metabolic enzymes as well as by facilitating the production of intermediary metabolites. However, the mechanisms by which a shift in the metabolic landscape reshapes the intracellular signaling to promote the survival of cancer cells remain to be clarified. Recent high-resolution mass spectrometry-based proteomic analyses have spotlighted that, unexpectedly, lysine residues of numerous cytosolic as well as nuclear proteins are acetylated and that this modification modulates protein activity, sublocalization and stability, with profound impact on cellular function. More importantly, cancer cells exploit acetylation as a post-translational protein for microenvironmental adaptation, nominating it as a means for dynamic modulation of the phenotypes of cancer cells at the interface between genetics and environments. The objectives of this review were to describe the functional implications of protein lysine acetylation in cancer biology by examining recent evidence that implicates oncogenic signaling as a strong driver of protein acetylation, which might be exploitable for novel therapeutic strategies against cancer.

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