Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications

Shi, Rachel; Liao, Chengheng; Zhang, Qing

doi:10.3390/cells10030678

Cited by 79 publications

(52 citation statements)

References 240 publications

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“…In xenograft mouse models, tumour growth and angiogenesis are associated with HIF-1α expression. In addition, HIF-1α protein synthesis is controlled by promoting the PI3K/Akt and extracellular signal-regulated kinase (ERK)/MAPK-signalling pathways and is involved in tumour growth ( Majmundar et al ., 2010 ; Shi et al ., 2021 ). Similar findings have been reported in studies on ovarian and brain cancers and indicated a regulatory role of HIF-1α in initiating angiogenesis via interactions with pro-angiogenic factors such as VEGF ( Zagzag et al ., 2000 ; Birner et al ., 2001 ).…”

Section: Discussionmentioning

confidence: 99%

Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer

Rho

Lee

et al. 2021

Biomolecules & Therapeutics

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The imprinted tumour suppressor NOEY2 is downregulated in various cancer types, including ovarian cancers. Recent data suggest that NOEY2 plays an essential role in regulating the cell cycle, angiogenesis and autophagy in tumorigenesis. However, its detailed molecular function and mechanisms in ovarian tumours remain unclear. In this report, we initially demonstrated the inhibitory effect of NOEY2 on tumour growth by utilising a xenograft tumour model. NOEY2 attenuated the cell growth approximately fourfold and significantly reduced tumour vascularity. NOEY2 inhibited the phosphorylation of the signalling components downstream of phosphatidylinositol-3’-kinase (PI3K), including phosphoinositide-dependent protein kinase 1 (PDK-1), tuberous sclerosis complex 2 (TSC-2) and p70 ribosomal protein S6 kinase (p70S6K), during ovarian tumour progression via direct binding to vascular endothelial growth factor receptor-2 (VEGFR-2). Particularly, the N-terminal domain of NOEY2 (NOEY2-N) had a potent anti-angiogenic activity and dramatically downregulated VEGF and hypoxia-inducible factor-1α (HIF-1α), key regulators of angiogenesis. Since no X-ray or nuclear magnetic resonance structures is available for NOEY2, we constructed the three-dimensional structure of this protein via molecular modelling methods, such as homology modelling and molecular dynamic simulations. Thereby, Lys15 and Arg16 appeared as key residues in the N-terminal domain. We also found that NOEY2-N acts as a potent inhibitor of tumorigenesis and angiogenesis. These findings provide convincing evidence that NOEY2-N regulates endothelial cell function and angiogenesis by interrupting the VEGFR-2/PDK-1/GSK-3β signal transduction and thus strongly suggest that NOEY2-N might serve as a novel anti-tumour and anti-angiogenic agent against many diseases, including ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer

Rho

Lee

et al. 2021

Biomolecules & Therapeutics

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“…However, relevant classifiers are still in great demand for guiding clinical treatment or predicting prognosis. Hypoxia, a kind of tumor microenvironmental stress related to poor prognosis of patients, is a hallmark of solid tumors, 39 and immune cell infiltration characterizations are also a research hotspot in many solid tumors. 40 Most classifications focus on a single biological and molecular feature and in this study, a new classifier was developed by combining the hypoxic state and immune cell infiltration of gastric cancer.…”

Section: Discussionmentioning

confidence: 99%

Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Wang¹,

Sun²,

Yang³

et al. 2021

IJGM

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Hypoxia and immune cell infiltration play an important role in the progression and metastasis of gastric cancer. However, the molecular classification of gastric cancer combined with hypoxia and immune cell infiltration remains unknown. Materials and Methods: ssGSEA was used to evaluate the hypoxic state and immune cell infiltration of 1059 gastric cancer samples collected from the GEO and TCGA database. Based on the results, unsupervised clustering was performed to obtain different gastric cancer subtypes. The differentially expressed genes related to OS between these subtypes were utilized for LASSO analysis to construct a prognostic signature (HIscore). Subsequently, small-molecule drugs were predicted using the Connectivity Map (CMAP) database. Results: We obtained three hypoxic-immune infiltration patterns (HIcluster A-C) with different prognoses and classified them as low hypoxic/low immune, high hypoxic/high immune, and low hypoxic/high immune subtypes. Based on the differential genes between HIclusters, we have also obtained other three gastric cancer subtypes (genecluster A-C) and a 13-gene signature (HIscore). At the same time, we extensively explored the clinical and transcriptome traits in different clusters and groups with high or low HIscore. We proved that HIscore is an independent prognostic biomarker and an indicator of genome stability and EMT. Using the CMAP database, we found 96 small-molecule drugs that could reverse the poor prognosis and could serve as therapeutic drugs, especially for gastric cancer patients with high HIscore. Conclusion: Our study evaluated the hypoxic state and immune cell infiltration in gastric tumors, and identified different gastric cancer subtypes. In addition, we established a hypoxia-immune signature to predict prognosis which is tightly linked to tumor EMT and genomic stability. Based on HIscore, we used the CMAP database to explore smallmolecule drugs that may have the potential in serving as therapeutic drugs.

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“…Hypoxia-inducible factor 1α (HIF-1α) is the pivotal transcription factor of response to hypoxia and a key regulator of many genes that drive both types of hypoxia-triggered cellular mechanisms, such as cancer development and invasion and immunosuppression [ 87 ]. To fix insufficient oxygen supply, HIF-1α regulates the signaling of angiogenesis pathways and promotes vascularization of tumors, increasing the expression of proangiogenic factors such as vascular endothelial growth factor A, platelet-derived growth factor subunit A, transforming growth factor-β and angiopoietin-like 4 [ 88 , 89 ].…”

Section: Hypoxia and Metabolismmentioning

confidence: 99%

“…Thus, hypoxia represents a negative prognostic factor and correlates to aggressiveness, metastatic progression and therapeutic resistance of tumors, as described in several reviews [ 91 , 92 , 93 ]. Indeed, HIF-1α regulates the expression of specific genes involved in the invasion, as fibronectin 1, lysyl oxidase-like 2, urokinase plasminogen activator receptor, epithelial–mesenchymal transition-associated transcription factors ZEB, SNAIL and TWIST [ 87 ].…”

Section: Hypoxia and Metabolismmentioning

confidence: 99%

Metabolic Changes in Tumor Microenvironment: How Could They Affect γδ T Cells Functions?

Corsale

Simone

Presti

et al. 2021

Cells

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The metabolic changes that occur in tumor microenvironment (TME) can influence not only the biological activity of tumor cells, which become more aggressive and auto sustained, but also the immune response against tumor cells, either producing ineffective responses or polarizing the response toward protumor activity. γδ T cells are a subset of T cells characterized by a plasticity that confers them the ability to differentiate towards different cell subsets according to the microenvironment conditions. On this basis, we here review the more recent studies focused on altered tumor metabolism and γδ T cells, considering their already known antitumor role and the possibility of manipulating their effector functions by in vitro and in vivo approaches. γδ T cells, thanks to their unique features, are themselves a valid alternative to overcome the limits associated with the use of conventional T cells, such as major histocompatibility complex (MHC) restriction, costimulatory signal and specific tumor-associated antigen recognition. Lipids, amino acids, hypoxia, prostaglandins and other metabolic changes inside the tumor microenvironment could reduce the efficacy of this important immune population and polarize γδ T cells toward IL17 producing cells that play a pro tumoral role. A deeper knowledge of this phenomenon could be helpful to formulate new immunotherapeutic approaches that target tumor metabolisms.

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Hypoxia-Driven Effects in Cancer: Characterization, Mechanisms, and Therapeutic Implications

Cited by 79 publications

References 240 publications

Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer

Novel Anti-Angiogenic and Anti-Tumour Activities of the N-Terminal Domain of NOEY2 via Binding to VEGFR-2 in Ovarian Cancer

Identification and Development of Subtypes with Poor Prognosis in Gastric Cancer Based on Both Hypoxia and Immune Cell Infiltration

Metabolic Changes in Tumor Microenvironment: How Could They Affect γδ T Cells Functions?

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