The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment

Nejad, Asieh Emami; Najafgholian, Simin; Rostami, Alireza; Sistani, Alireza; Shojaeifar, Samaneh; Esparvarinha, Mojgan; Nedaeinia, Reza; Javanmard, Shaghayegh Haghjooy; Taherian, Marjan; Ahmadlou, Mojtaba; Salehi, Roya; Sadeghi, Bahman; Manian, Mostafa

doi:10.1186/s12935-020-01719-5

Cited by 382 publications

(280 citation statements)

References 332 publications

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“…Hypoxia has been recognized as a key factor in TME that contributes to the plasticity and heterogeneity of CSCs [ 71 ] . Cancer cells localized in hypoxic regions tend to display CSC-like phenotypes and are more invasive than cells in oxygenated regions within tumors [ 72 ] . The non-CSCs grow and proliferate rapidly, which leads to hypoxia in the nearby milieu [ 13 ] .…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

“…Inhibition of glycolysis also serves as a promising approach in combination with chemotherapy, which was shown to effectively eradicate chemoresistant glioblastoma CSCs which reside in their hypoxic niches and rely on glycolysis for ATP generation [ 87 ] . Additionally, inhibition of glycolysis by dichloroacetate may reverse the metabolic shift to OXPHOS, leading to increased ROS and promoted apoptosis in CSCs of several cancer types [ 72 ] .…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

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Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

Zhang¹,

Steed²,

Co³

et al. 2021

CDR

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The cancer stem cell (CSC) state and epithelial-mesenchymal transition (EMT) activation are tightly interconnected. Cancer cells that acquire the EMT/CSC phenotype are equipped with adaptive metabolic changes to maintain low reactive oxygen species levels and stemness, enhanced drug transporters, anti-apoptotic machinery and DNA repair system. Factors present in the tumor microenvironment such as hypoxia and the communication with non-cancer stromal cells also promote cancer cells to enter the EMT/CSC state and display related resistance. ATP, particularly the high levels of intratumoral extracellular ATP functioning through both signaling pathways and ATP internalization, induces and regulates EMT and CSC. The three of them work together to enhance drug resistance. New findings in each of these factors will help us explore deeper into mechanisms of drug resistance and suggest new resistance-associated markers and therapeutic targets.

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Section: Cancer Stem Cellsmentioning

confidence: 99%

Section: Cancer Stem Cellsmentioning

confidence: 99%

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

Zhang¹,

Steed²,

Co³

et al. 2021

CDR

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show abstract

“…Tumor hypoxia, a microenvironment usually found in the central part of tumors (139), promotes the process of cancer invasion and metastasis (140). Hypoxia-inducible factor-1 (HIF-1) is the most critical transcription factor of hypoxia (141).…”

Section: Pancreatic Cancer and Cholangiocarcinomamentioning

confidence: 99%

Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors

et al. 2021

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Epithelial-to-mesenchymal transition (EMT), a complicated program through which polarized epithelial cells acquire motile mesothelial traits, is regulated by tumor microenvironment. EMT is involved in tumor progression, invasion and metastasis via reconstructing the cytoskeleton and degrading the tumor basement membrane. Accumulating evidence shows that resveratrol, as a non-flavonoid polyphenol, can reverse EMT and inhibit invasion and migration of human tumors via diverse mechanisms and signaling pathways. In the present review, we will summarize the detailed mechanisms and pathways by which resveratrol and its analogs (e.g. Triacetyl resveratrol, 3,5,4’-Trimethoxystilbene) might regulate the EMT process in cancer cells to better understand their potential as novel anti-tumor agents. Resveratrol can also reverse chemoresistance via EMT inhibition and improvement of the antiproliferative effects of conventional treatments. Therefore, resveratrol and its analogs have the potential to become novel adjunctive agents to inhibit cancer metastasis, which might be partly related to their blocking of the EMT process.

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“…For tumor cells, hypoxia promotes angiogenesis and remodeling by inducing HIF expression enhancement, and is a marker of tumor proliferation, metastasis, and recurrence (Muz et al, 2015). Potential mechanisms include altered gene expression, oncogene activation, antioncogene inactivation, decreased genomic stability and clonal selection (Emami Nejad et al, 2021). Therefore, inhibiting the production of HIF has become an important research direction of tumor therapy.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia Constructing the Prognostic Model of Colorectal Adenocarcinoma and Related to the Immune Microenvironment

Zhang

Yang

Peng

et al. 2021

Front. Cell Dev. Biol.

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Background: Hypoxia is a common phenomenon in solid tumors, which plays an important role in tumor proliferation, apoptosis, angiogenesis, invasion and metastasis, energy metabolism and chemoradiotherapy resistance. However, comprehensive analysis of hypoxia markers in colorectal adenocarcinoma (COAD) is still lacking. And there is a need for mechanism exploration and clinical application.Methods: The gene expression, mutation and clinical data of COAD were downloaded from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases, respectively. Tumor samples from TCGA were randomly divided into the training and internal validation groups, while tumor samples from GEO were used as the external validation group. Univariate COX—LASSO—multivariate COX method was applied to construct the prognostic model. We clustered all TCGA tumor samples into high, medium and low hypoxia groups, evaluated the correlation between hypoxia degree and immunoactivity, and explored the combined effect of mutation for common target genes and model riskscore on survival in COAD patients. Finally, we developed a dynamic nomograph App online for direct clinical application and carried out multiple validations of the prognostic model.Results: Our hypoxia-related prognostic model for COAD patients is accurate and has been successfully validated internally and externally. Single Sample Gene Set Enrichment Analysis (ssGSEA) and Gene Set Enrichment Analysis (GSEA) results suggest that for COAD patients with higher hypoxia, the stronger the associated immunosuppressive activity, providing a possible mechanism for the lower survival rate. Finally, the dynamic nomograph App online enhances the clinical translational significance of the study.Conclusion: In this study, an accurate prognostic model for COAD patients was established and validated. In addition, our innovative findings include correlations between hypoxia levels and immune activity, as well as an in-depth exploration of common target gene mutations.

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The role of hypoxia in the tumor microenvironment and development of cancer stem cell: a novel approach to developing treatment

Cited by 382 publications

References 332 publications

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

Cancer stem cells, epithelial-mesenchymal transition, ATP and their roles in drug resistance in cancer

Resveratrol and Its Analogs: Potent Agents to Reverse Epithelial-to-Mesenchymal Transition in Tumors

Hypoxia Constructing the Prognostic Model of Colorectal Adenocarcinoma and Related to the Immune Microenvironment

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