Hypoxia in the tumorigenesis of gliomas and as a potential target for therapeutic measures

✓ In this article, the author provides a brief description of the role of hypoxia in the tumorigenesis of gliomas and suggests potential ways of exploiting this role to design treatment modalities. Tumor hypoxia predicts the likelihood of metastases, tumor recurrence, resistance to chemotherapy and radiation therapy, invasive potential, and decreased patient survival for many human malignancies. Various methods of measurement of tumor hypoxia are discussed, including direct measurement and imaging methods. The role of hypoxia-responsive molecules, especially hypoxia-inducible factor-1 (HIF-1), in glioma tumorigenesis is explored. Treatment modalities regulated by hypoxia are proposed and some potential strategies reviewed. The progression of a low-grade astrocytoma to a glioblastoma multiforme may be mediated by hypoxia-induced phenotypic changes and subsequent clonal selection of cells that overexpress hypoxia-responsive molecules, such as HIF-1. In this model, intratumoral hypoxia causes genetic changes that produce a microenvironment that selects for cells of a more aggressive phenotype.

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TAp73 opposes tumor angiogenesis by promoting hypoxia-inducible factor 1α degradation

10.31234/osf.io/v24zc ◽

2020 ◽

Author(s):

Lungwani Muungo

Keyword(s):

Cancer Progression ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Human Lung Cancer ◽

Regulatory Subunit ◽

Patients With Cancer ◽

Hypoxia Inducible Factor 1 ◽

Chemically Induced ◽

Induced Tumors ◽

Patient Prognosis

Tumor hypoxia and hypoxia-inducible factor 1 (HIF-1) activationare associated with cancer progression. Here, we demonstrate thatthe transcription factor TAp73 opposes HIF-1 activity through anontranscriptional mechanism, thus affecting tumor angiogenesis.TAp73-deficient mice have an increased incidence of spontaneousand chemically induced tumors that also display enhanced vascularization.Mechanistically, TAp73 interacts with the regulatory subunit(α) of HIF-1 and recruits mouse double minute 2 homolog intothe protein complex, thus promoting HIF-1α polyubiquitination andconsequent proteasomal degradation in an oxygen-independentmanner. In human lung cancer datasets, TAp73 strongly predictsgood patient prognosis, and its expression is associated with lowHIF-1 activation and angiogenesis. Our findings, supported by invivo and clinical evidence, demonstrate a mechanism for oxygenindependentHIF-1 regulation, which has important implicationsfor individualizing therapies in patients with cancer.

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Anticancer Activity of Natural Flavonoids: Inhibition of HIF-1α Signaling Pathway

Current Organic Chemistry ◽

10.2174/1385272823666191203122030 ◽

2020 ◽

Vol 23 (26) ◽

pp. 2945-2959 ◽

Cited By ~ 1

Author(s):

Xiangping Deng ◽

Yijiao Peng ◽

Jingduo Zhao ◽

Xiaoyong Lei ◽

Xing Zheng ◽

...

Keyword(s):

Transcription Factor ◽

Secondary Metabolites ◽

Anticancer Agents ◽

Hypoxia Inducible Factor ◽

Tumor Hypoxia ◽

Pharmacological Activities ◽

Hypoxia Inducible Factor 1 ◽

The Past ◽

Low Toxicity ◽

Tumor Blood Vessels

Rapid tumor growth is dependent on the capability of tumor blood vessels and glycolysis to provide oxygen and nutrients. Tumor hypoxia is a common characteristic of many solid tumors, and it essentially happens when the growth of the tumor exceeds the concomitant angiogenesis. Hypoxia-inducible factor 1 (HIF-1) as the critical transcription factor in hypoxia regulation is activated to adapt to this hypoxia situation. Flavonoids, widely distributed in plants, comprise many polyphenolic secondary metabolites, possessing broadspectrum pharmacological activities, including their potentiality as anticancer agents. Due to their low toxicity, intense efforts have been made for investigating natural flavonoids and their derivatives that can be used as HIF-1α inhibitors for cancer therapy during the past few decades. In this review, we sum up the findings concerning the inhibition of HIF-1α by natural flavonoids in the last few years and propose the idea of designing tumor vascular and glycolytic multi-target inhibitors with HIF-1α as one of the targets.

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The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Cellular and Molecular Neurobiology ◽

10.1007/s10571-016-0440-6 ◽

2016 ◽

Vol 37 (6) ◽

pp. 969-977 ◽

Cited By ~ 12

Author(s):

Osigbemhe Iyalomhe ◽

Sabina Swierczek ◽

Ngozi Enwerem ◽

Yuanxiu Chen ◽

Monica O. Adedeji ◽

...

Keyword(s):

Cognitive Impairment ◽

Mild Cognitive Impairment ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1

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Schistosomiasis: from established diagnostic assays to emerging micro/nanotechnology-based rapid field testing for clinical management and epidemiology

Precision Nanomedicine ◽

10.33218/prnano3(1).191205.1 ◽

2019 ◽

Vol 3 (1) ◽

pp. 439-458 ◽

Cited By ~ 1

Author(s):

Maurice Mutro Nigo ◽

Georgette Salieb-Beugelaar ◽

Manuel Battegay ◽

Peter Odermatt ◽

Patrick Hunziker

Keyword(s):

Point Of Care ◽

Field Testing ◽

Detection Methods ◽

Low Grade ◽

Analytical Strategy ◽

Diagnostic Assays ◽

And Control ◽

Analytical Platforms ◽

Selection Of

Schistosomiasis is a neglected invasive worm disease with a huge disease burden in developing countries, particularly in children, and is seen increasingly in non-endemic regions through transfer by travellers, expatriates, and refugees. Undetected and untreated infections may be responsible for the persistence of transmission. Rapid and accurate diagnosis is the key to treatment and control. So far, parasitological detection methods remain the cornerstone of Schistosoma infection diagnosis in endemic regions, but conventional tests have limited sensitivity, in particular in low-grade infection. Recent advances contribute to improved detection in clinical and field settings. The recent progress in micro- and nanotechnologies opens a road by enabling the design of new miniaturized point-of-care devices and analytical platforms, which can be used for the rapid detection of these infections. This review starts with an overview of currently available laboratory tests and their performance and then discusses emerging rapid and micro/nanotechnologies-based tools. The epidemiological and clinical setting of testing is then discussed as an important determinant for the selection of the best analytical strategy in patients suspected to suffer from Schistosoma infection. Finally, it discusses the potential role of advanced technologies in the setting near to disease eradication is examined.

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Hypoxia-inducible factor–1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma

Neurosurgical FOCUS ◽

10.3171/2014.9.focus14496 ◽

2014 ◽

Vol 37 (6) ◽

pp. E8 ◽

Cited By ~ 18

Author(s):

Matthew Womeldorff ◽

David Gillespie ◽

Randy L. Jensen

Keyword(s):

Cellular Response ◽

Treatment Options ◽

Hypoxia Inducible Factor ◽

Hypoxia Inducible Factor 1 ◽

Poor Patient ◽

Growth Development ◽

The Relationship ◽

Insight Into ◽

Upstream Regulators

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1–regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.

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Normoxic Tumour Extracellular Vesicles Modulate the Response of Hypoxic Cancer and Stromal Cells to Doxorubicin In Vitro

International Journal of Molecular Sciences ◽

10.3390/ijms21175951 ◽

2020 ◽

Vol 21 (17) ◽

pp. 5951

Author(s):

Laura Patras ◽

Marcel H. A. M. Fens ◽

Pieter Vader ◽

Arjan Barendrecht ◽

Alina Sesarman ◽

...

Keyword(s):

Drug Resistance ◽

Extracellular Vesicles ◽

Hypoxia Inducible Factor ◽

B Cell Lymphoma ◽

Tumour Microenvironment ◽

Hypoxia Inducible Factor 1 ◽

Apoptotic Protein ◽

Donor Cells

Extracellular vesicles (EV) secreted in the tumour microenvironment (TME) are emerging as major antagonists of anticancer therapies by orchestrating the therapeutic outcome through altering the behaviour of recipient cells. Recent evidence suggested that chemotherapeutic drugs could be responsible for the EV-mediated tumour–stroma crosstalk associated with cancer cell drug resistance. Here, we investigated the capacity of tumour EV (TEV) secreted by normoxic and hypoxic (1% oxygen) C26 cancer cells after doxorubicin (DOX) treatment to alter the response of naïve C26 cells and RAW 264.7 macrophages to DOX. We observed that C26 cells were less responsive to DOX treatment under normoxia compared to hypoxia, and a minimally cytotoxic DOX concentration that mounted distinct effects on cell viability was selected for TEV harvesting. Homotypic and heterotypic pretreatment of naïve hypoxic cancer and macrophage-like cells with normoxic DOX-elicited TEV rendered these cells slightly less responsive to DOX treatment. The observed effects were associated with strong hypoxia-inducible factor 1-alpha (HIF-1α) induction and B-cell lymphoma–extra-large anti-apoptotic protein (Bcl-xL)-mediated anti-apoptotic response in normoxic DOX-treated TEV donor cells, being also tightly connected to the DOX-TEV-mediated HIF-1α induction, as well as Bcl-xL levels increasing in recipient cells. Altogether, our results could open new perspectives for investigating the role of chemotherapy-elicited TEV in the colorectal cancer TME and their modulatory actions on promoting drug resistance.

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