Hypoxic tumor microenvironment: Implications for cancer therapy

Experimental Biology and Medicine, Journal Year: 2020, Volume and Issue: 245(13), P. 1073 - 1086

Published: June 27, 2020

Hypoxia or low oxygen concentration in tumor microenvironment has widespread effects ranging from altered angiogenesis and lymphangiogenesis, metabolism, growth, therapeutic resistance different cancer types. A large number of these are mediated by the transcription factor hypoxia inducible 1⍺ (HIF-1⍺) which is activated hypoxia. HIF1⍺ induces glycolytic genes reduces mitochondrial respiration rate hypoxic tumoral regions through modulation various cells like cancer-associated fibroblasts. Immune evasion driven HIF-1⍺ further contributes to enhanced survival cells. By altering drug target expression, metabolic regulation, consumption, leads growth Tumor conditions thus attain aggressive phenotypes become resistant chemo- radio- therapies resulting higher mortality. While a new strategies have succeeded targeting hypoxia, significant improvement needs more detailed understanding molecular mechanisms regulated its on vasculature. This review focuses chief hypoxia-driven their impact tumors that drive an phenotype. Impact statement aggressiveness promotes many solid often conventional therapies. In order achieve successful types, it necessary understand signaling pathways induced Aberrant vasculature alterations cellular metabolism due confound this problem. implications inflammatory TME regulating progression cancer, along with changes lymphangiogenic angiogenic mechanisms. Finally, overarching role mediating cancers discussed.

Language: Английский

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The Role of Hypoxia in Glioblastoma Radiotherapy Resistance

Cancers, Journal Year: 2021, Volume and Issue: 13(3), P. 542 - 542

Published: Feb. 1, 2021

Glioblastoma (GB) (grade IV astrocytoma) is the most malignant type of primary brain tumor with a 16 months median survival time following diagnosis. Despite increasing attention regarding development targeted therapies for GB that resulted in around 450 clinical trials currently undergoing, radiotherapy still remains clinically effective treatment these patients. Nevertheless, resistance (radioresistance) commonly observed patients leading to recurrence and eventually patient death. It therefore essential unravel molecular mechanisms underpinning cell radioresistance order develop novel strategies combinational focused on enhancing sensitivity radiotherapy. In this review, we present comprehensive examination current literature role hypoxia (O2 partial pressure less than 10 mmHg), main microenvironmental factor, ultimate goal identifying potential markers therapeutic targets overcome issue future.

Language: Английский

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Hypoxia/HIF Modulates Immune Responses

Biomedicines, Journal Year: 2021, Volume and Issue: 9(3), P. 260 - 260

Published: March 5, 2021

Oxygen availability varies throughout the human body in health and disease. Under physiological conditions, oxygen drops from lungs over blood stream towards different tissues into cells mitochondrial cavities leading to low conditions or hypoxia all organs including primary lymphoid organs. Moreover, immune travel searching for damaged foreign antigens facing a variety of levels. Consequently, impacts cell function finally controlling innate adaptive response mainly by transcriptional regulation via hypoxia-inducible factors (HIFs). pathophysiological such as found inflammation, injury, infection, ischemia cancer, severe can alter dysfunctional tissue damage, cancer progression autoimmunity. Here we summarize effects on activity, provide an overview control cellular hypoxia-induced pathways with focus role HIFs discuss opportunity target hypoxia-sensitive treatment

Language: Английский

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SGLT2 Inhibitors as Calorie Restriction Mimetics: Insights on Longevity Pathways and Age-Related Diseases

Endocrinology, Journal Year: 2021, Volume and Issue: 162(8)

Published: April 15, 2021

Sodium-glucose cotransporter-2 (SGLT2) inhibitors induce glycosuria, reduce insulin levels, and promote fatty acid oxidation ketogenesis. By promoting a nutrient deprivation state, SGLT2 upregulate the energy sensors AMPK SIRT1, inhibit mTOR insulin/IGF1, modulate closely linked hypoxia-inducible factor (HIF)-2α/HIF-1α pathways. Phosphorylation of upregulation adiponectin PPAR-α favor reversal metabolic syndrome which have been to suppression chronic inflammation. Downregulation insulin/IGF1 pathways signaling from reduction in glucose circulating amino acids cellular repair mechanisms, including autophagy proteostasis confer stress resistance attenuate senescence. another sensor activated by NAD+ nutrient-deficient states, is reciprocally AMPK, can deacetylate activate transcription factors, such as PCG-1α, mitochondrial A (TFAM), nuclear E2-related (NRF)-2, that regulate biogenesis. FOXO3 target genes resistance, also SIRT1. Modulation these shown alleviate diseases, vascular inflammation arterial stiffness, improve function oxidative stress-induced tissue damage. Compared with other calorie restriction mimetics metformin, rapamycin, resveratrol, precursors, appear be most promising treatment aging-related due their regulation multiple longevity resembles achieved established efficacy reducing cardiovascular events all-cause mortality. Evidence compelling for role mimetic anti-aging therapeutics.

Language: Английский

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Modulating tumor-associated macrophages to enhance the efficacy of immune checkpoint inhibitors: A TAM-pting approach

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 231, P. 107986 - 107986

Published: Sept. 2, 2021

Language: Английский

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Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms

Metabolic Brain Disease, Journal Year: 2021, Volume and Issue: 37(1), P. 51 - 66

Published: Oct. 7, 2021

Language: Английский

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Targeting HIF-2α in the Tumor Microenvironment: Redefining the Role of HIF-2α for Solid Cancer Therapy

Cancers, Journal Year: 2022, Volume and Issue: 14(5), P. 1259 - 1259

Published: Feb. 28, 2022

Inadequate oxygen supply, or hypoxia, is characteristic of the tumor microenvironment and correlates with poor prognosis therapeutic resistance. Hypoxia leads to activation hypoxia-inducible factor (HIF) signaling pathway stabilization HIF-α subunit, driving progression. The homologous alpha subunits, HIF-1α HIF-2α, are responsible for mediating transcription a multitude critical proteins that control proliferation, angiogenic signaling, metastasis, other oncogenic factors, both differentially sequentially regulating hypoxic response. Post-translational modifications HIF play central role in its behavior as mediator transcription, well temporal transition from HIF-2α occurs response chronic hypoxia. While it evident highly dynamic, remains vastly under-considered. can intensify behaviors most aggressive tumors by adapting cell oxidative stress, thereby promoting tissue remodeling, angiogenesis, upregulating cancer stem factors. structure, function, response, spatiotemporal dynamics, roles progression persistence this molecule

Language: Английский

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Mast Cell–Tumor Interactions: Molecular Mechanisms of Recruitment, Intratumoral Communication and Potential Therapeutic Targets for Tumor Growth

Cells, Journal Year: 2022, Volume and Issue: 11(3), P. 349 - 349

Published: Jan. 20, 2022

Mast cells (MCs) are tissue-resident immune that important players in diseases associated with chronic inflammation such as cancer. Since MCs can infiltrate solid tumors and promote or limit tumor growth, a possible polarization of to pro-tumoral anti-tumoral phenotypes has been proposed remains challenging research field. Here, we review the recent evidence regarding complex relationship between cells. In particular, consider: (1) multifaceted role on growth suggested by histological analysis biopsies studies performed MC-deficient animal models; (2) signaling pathways triggered tumor-derived chemotactic mediators bioactive lipids MC migration modulate their function inside tumors; (3) phenotypic changes prevalent conditions microenvironment (TME) hypoxia; (4) specifically lead production angiogenic factors, mainly VEGF; (5) fibrosis metastasis. Finally, discuss novel literature molecular mechanisms potentially related undergo into TME some therapeutic strategies targeting activation growth.

Language: Английский

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Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(699)

Published: June 7, 2023

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to disease, including cystic fibrosis (CF). Consistent requirements for luminal O 2 , surrounding in chronic obstructive disease (COPD) lungs hypoxic. Despite these observations, effects of hypoxia (CH) on epithelial host defense functions relevant have not been investigated. Molecular characterization resected individuals a spectrum muco-obstructive lung (MOLDs) COVID-19 identified molecular features hypoxia, increased EGLN3 expression, lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic revealed conversion glycolytic metabolic state maintenance cellular architecture. Chronically unexpectedly exhibited MUC5B mucin production and transepithelial Na + fluid absorption mediated HIF1α/HIF2α-dependent up-regulation β γENaC (epithelial channel) subunit expression. The combination generated hyperconcentrated predicted perpetuate obstruction. Single-cell bulk RNA sequencing analyses transcriptional changes involved wall remodeling, destruction, angiogenesis. These results were confirmed RNA–in situ hybridization studies MOLD. Our data suggest that may be central pathogenesis persistent accumulation MOLDs damage.

Language: Английский

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Targeting oral tumor microenvironment for effective therapy

Cancer Cell International, Journal Year: 2023, Volume and Issue: 23(1)

Published: May 23, 2023

Oral cancers are among the common head and neck malignancies. Different anticancer therapy modalities such as chemotherapy, immunotherapy, radiation therapy, also targeted molecular may be prescribed for targeting oral Traditionally, it has been assumed that malignant cells alone by chemotherapy radiotherapy suppresses tumor growth. In last decade, a large number of experiments have confirmed pivotal role other secreted molecules in microenvironment (TME) on progression. Extracellular matrix immunosuppressive tumor-associated macrophages, myeloid-derived suppressor (MDSCs), cancer-associated fibroblasts (CAFs), regulatory T (Tregs) play key roles progression tumors like resistance to therapy. On hand, infiltrated CD4 + CD8 lymphocytes, natural killer (NK) anti-tumor suppress proliferation cells. Modulation extracellular cells, stimulation immunity suggested treat malignancies more effectively. Furthermore, administration some adjuvants or combination this review, we discuss various interactions between cancer TME. review basic mechanisms within TME cause Potential targets approaches overcoming will reviewed. The findings potential therapeutic clinical studies

Language: Английский

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