Hypoxia-Inducible Factors and Cancer

Jun, Jonathan C.; Rathore, Aman; Younas, Haris; Gilkes, Daniele M.; Polotsky, Vsevolod Y.

doi:10.1007/s40675-017-0062-7

Cited by 186 publications

(140 citation statements)

References 133 publications

(125 reference statements)

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“…Our studies demonstrated that the 3D-O model while supporting BCa cell growth, simulated physiological oxygen levels and generated intratumoral hypoxic hallmarks such as increased HIF expression (Figure 3). Upregulated HIF expression is a well-known parameter associated with hypoxia and is known to affect several downstream biochemical processes (89). Our results confirm that oxygen deprivation within 3D-O can efficiently reiterate HIF-driven regulation in the resident BCa cells.…”

Section: Immune Cell Infiltration Into 3d Matrices Has Been Observedsupporting

confidence: 79%

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bhattacharya

Calar

Evans

et al. 2019

Preprint

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Oxygen deprivation within tumors is one of the most prevalent causes of resilient cancer cell survival and increased immune evasion in breast cancer (BCa). Current in vitro models do not adequately mimic physiological oxygen levels relevant to breast tissue and its tumor-immune interactions. Here, we propose an approach to engineer a three-dimensional (3D) model (named 3D engineered oxygen, 3D-O) that supports growth of BCa cells and generates physio-and pathophysiological oxygen levels. Low oxygen-induced changes within the 3D-O model supported known tumor hypoxia characteristics such as reduced BCa cell proliferation, increased extracellular matrix protein expression, increased extracellular vesicle secretion and enhanced immune surface marker expression on BCa cells. We further demonstrated that low oxygeninduced changes mimicked tumor-immune interactions leading to immune evasion mechanisms. CD8+ T cell infiltration was significantly impaired under pathophysiological oxygen levels andwe were able to establish that hypoxia inhibition re-sensitize BCa cells to cytotoxic CD8+ T cells.Therefore, our novel 3D-O model could serve as a promising platform for the evaluation of immunological events and as a drug-screening platform tool to overcome hypoxia-driven immune evasion.

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Section: Immune Cell Infiltration Into 3d Matrices Has Been Observedsupporting

confidence: 79%

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bhattacharya

Calar

Evans

et al. 2019

Preprint

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“…Targeting the HIF pathway in cancer is quite challenging due to the heterogeneity of the target genes and also their different regulation dependent on the cancer types [135]. Currently, there are several therapeutics in preclinical testing able to block HIF activity with the intention of limiting the tumor development, angiogenesis, and metastasis.…”

Section: Resultsmentioning

confidence: 99%

“…However, none of these small molecules were designed for specific targeting of HIF-1α, fact that hampers the translational switch toward the patients due to difficulties in controlling the level of action and selection of the targeted cohort [137]. There are also clinical approved drugs that were shown to interfere with HIF-1α activity (non-specific HIF-1α inhibitors): Angiotensin-2 receptor blocker, digoxin or metformin [135,138,139]. Prostate cancer patients prescribed with one of these three therapies have been associated with decreased risk of cancer progression [140].…”

Section: Resultsmentioning

confidence: 99%

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

Tirpe

Gulei

Ciortea

et al. 2019

IJMS

274

183

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Hypoxia represents a frequent player in a number of malignancies, contributing to the development of the neoplastic disease. This review will discuss the means by which hypoxia powers the mechanisms behind cancer progression, with a majority of examples from lung cancer, the leading malignancy in terms of incidence and mortality rates (the frequent reference toward lung cancer is also for simplification purposes and follow up of the global mechanism in the context of a disease). The effects induced by low oxygen levels are orchestrated by hypoxia-inducible factors (HIFs) which regulate the expression of numerous genes involved in cancer progression. Hypoxia induces epithelial-to-mesenchymal transition (EMT) and metastasis through a complex machinery, by mediating various pathways such as TGF-β, PI3k/Akt, Wnt, and Jagged/Notch. Concomitantly, hypoxic environment has a vast implication in angiogenesis by stimulating vessel growth through the HIF-1α/VEGF axis. Low levels of oxygen can also promote the process through several other secondary factors, including ANGPT2, FGF, and HGF. Metabolic adaptations caused by hypoxia include the Warburg effect—a metabolic switch to glycolysis—and GLUT1 overexpression. The switch is achieved by directly increasing the expression of numerous glycolytic enzymes that are isoforms of those found in non-malignant cells.

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“…HIF1 is a key sensor of oxygen availability. In normoxia, HIF1 is hydroxylated and rapidly degraded, whereas under hypoxic conditions, HIF1 hydroxylation is reduced, leading to stabilization of HIF1 expression levels . The two subunits of HIF1, α and β, function as transcription factors, resulting in enhanced expression of specific genes that promote survival during hypoxia .…”

Section: Regulation Of Endocytic Traffic By Hypoxiamentioning

confidence: 99%

Energetic adaptations: Metabolic control of endocytic membrane traffic

Rahmani

Defferrari

Wakarchuk

et al. 2019

Traffic

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Endocytic membrane traffic controls the access of myriad cell surface proteins to the extracellular milieu, and thus gates nutrient uptake, ion homeostasis, signaling, adhesion and migration. Coordination of the regulation of endocytic membrane traffic with a cell's metabolic needs represents an important facet of maintenance of homeostasis under variable conditions of nutrient availability and metabolic demand. Many studies have revealed intimate regulation of endocytic membrane traffic by metabolic cues, from the specific control of certain receptors or transporters, to broader adaptation or remodeling of the endocytic membrane network. We examine how metabolic sensors such as AMP‐activated protein kinase, mechanistic target of rapamycin complex 1 and hypoxia inducible factor 1 determine sufficiency of various metabolites, and in turn modulate cellular functions that includes control of endocytic membrane traffic. We also examine how certain metabolites can directly control endocytic traffic proteins, such as the regulation of specific protein glycosylation by limiting levels of uridine diphosphate N‐acetylglucosamine (UDP‐GlcNAc) produced by the hexosamine biosynthetic pathway. From these ideas emerge a growing appreciation that endocytic membrane traffic is orchestrated by many intrinsic signals derived from cell metabolism, allowing alignment of the functions of cell surface proteins with cellular metabolic requirements. Endocytic membrane traffic determines how cells interact with their environment, thus defining many aspects of nutrient uptake and energy consumption. We examine how intrinsic signals that reflect metabolic status of a cell regulate endocytic traffic of specific proteins, and, in some cases, exert broad control of endocytic membrane traffic phenomena. Hence, endocytic traffic is versatile and adaptable and can be modulated to meet the changing metabolic requirements of a cell.

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Hypoxia-Inducible Factors and Cancer

Cited by 186 publications

References 133 publications

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Hypoxia: Overview on Hypoxia-Mediated Mechanisms with a Focus on the Role of HIF Genes

Energetic adaptations: Metabolic control of endocytic membrane traffic

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