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Cited by 110Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerErythropoietin and Anemia Treatment

Hypoxia Signaling in Cancer: From Basics to Clinical Practice

Open access
Sebestyén, Anna, Kopper, László, Dankó, Titanilla, Tímár, József·2021·Pathology and Oncology Research
DOI 10.3389/pore.2021.1609802PMC PMC8262153
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Abstract

Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes. Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF). However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply. The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment. Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance. Accordingly, it seems inevitable to combine various therapeutic modalities of cancer patients by existing anti-hypoxic agents such as anti-angiogenics, anti-anemia therapies or specific signaling pathway inhibitors. It is evident that there is an unmet need in cancer patients to develop targeted therapies of hypoxia to improve efficacies of various anti-cancer therapeutic modalities. The case has been opened recently due to the approval of the first-in-class HIF2α inhibitor.

Verified 2026-10-10 · 1 reference not checked yet

AI snapshot

Written from the paper’s full text.

TL;DR

This review summarizes how cancer hypoxia and oxygen-independent HIF activation drive angiogenesis, metabolic reprogramming, immunosuppression, and therapy resistance. It then surveys clinical strategies to target hypoxia, including anti-angiogenics, immunotherapy combinations, anti-anemia treatment, and the first FDA-approved HIF2α inhibitor.

Key findings

  • Tumor oxygenation is much lower than in host tissues: pancreatic adenocarcinoma is 0.3% O2, hepatocellular cancer 0.8%, cervical squamous cell cancer 1.2%, renal cell cancer 1.3%, breast adenocarcinoma 1.5%, glial tumors 1.7%, rectal adenocarcinoma 1.8%, and lung cancer 2.2%, compared with host renal cortex 9.5%, breast tissue 8.5%, pancreatic tissue 7.5%, liver 7.3%, lung 5.6%, uterine cervix 5.5%, brain 4.6%, and rectal tissue 3.9%.
  • HIF activation occurs through oxygen-dependent PHD/FIH hydroxylation and VHL-mediated degradation, but oncogenic pathways such as mTORC1 and RAS-MEK-ERK can stabilize HIFα independently of oxygen (“pseudohypoxia”); 216 human genes contain HIF-responsive elements, with about 40 classical HIF-regulated genes.
  • Hypoxia/HIF activation promotes angiogenic factors (VEGF, FGF, PDGF, ANGP1/2, SDF1), metabolic shifts (lactate production, GLUT1-3, PDK1, PKM2, Warburg effect), immunosuppression (M2 macrophages, myeloid-derived suppressor cells, VEGF-driven T-regulatory cells, PDL1/CTLA-4), and therapy resistance (MDR1/ABCB1, NRF2, reduced radiotherapy efficacy).
  • Clinically, anti-angiogenic agents are generally ineffective as monotherapy except in renal cell cancer; combinations with immune checkpoint inhibitors are approved in lung adenocarcinoma, hepatocellular carcinoma, and renal cell cancer, and MK6482 became the first FDA-approved HIF2α inhibitor.

Methods

  • Narrative review; no systematic search strategy, inclusion criteria, or primary data collection are stated.
  • Synthesizes published literature and includes tables comparing cancer/host oxygenation, classical HIF1A-regulated genes, clinical anti-angiogenic drugs, approved anti-angiogenic plus immune checkpoint inhibitor combinations, and targeted HIF therapies.
  • Main analysis is qualitative synthesis of mechanisms, preclinical/clinical evidence, and therapeutic implications.

Limitations

  • The paper states that experimental data on hypoxia and immunotherapy are scanty, that biomarkers are needed for metabolic inhibitors, and that tumor heterogeneity and differences between in vitro, in vivo, and clinical specimens must be considered.
  • Evident from the text: as a narrative review, it lacks a systematic search protocol, formal quality assessment, and meta-analytic synthesis; several therapeutic statements rely on preclinical models or older references.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3389/pore.2021.1609802

Cites

116 of 117 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 114 cited sources checked · 0 supported · 0 flagged

  • Findingnone given

    Avelumab plus cabozantinib is approved for renal cell carcinoma (RCC).

    “| RCC | — | Avelumab | — | Cabozantinib | + |”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Cancer hypoxia and the induced adaptation mechanisms are major causes of therapy resistance.

    “Cancer hypoxia and the induced adaptation mechanisms are two of the major causes of therapy resistance.”
    • Also stated in: § Introduction · boosted
      “Collectively, cancer hypoxia usually is a combination of acute, chronic and systemic forms of hypoxia, which not only drives tumor progression, but also a leading cause of resistance to various therapeutic modalities [3–6].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Heldin, 2004, High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy, Nat Rev Cancer source

      Not checked in the free run.

    • cites [4] Siemann, 2011, The Unique Characteristics of Tumor Vasculature and Preclinical Evidence for its Selective Disruption by Tumor-Vascular Disrupting Agents, Cancer Treat Rev source

      Not checked in the free run.

    • cites [5] Lee, 2020, Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond, Nat Rev Mol Cel Biol source

      Not checked in the free run.

    • cites [6] Semenza, 2002, HIF-1 and Tumor Progression: Pathophysiology and Therapeutics, Trends Mol Med source

      Not checked in the free run.

  • Premisecitation

    Hypoxic tumor tissue and hypoxic tumor cells are major drivers of tumor progression.

    “Necrotic tumor tissue does not present much harm to the host organism, but the hypoxic part of the tumor tissue and the hypoxic tumor cells are usually the major drivers of tumor progression [1–3].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [1] Muz, 2015, The Role of Hypoxia in Cancer Progression, Angiogenesis, Metastasis, and Resistance to Therapy, Hp source

      Not checked in the free run.

    • cites [2] Folkman, 1971, Tumor Angiogenesis: Therapeutic Implications, N Engl J Med source

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    • cites [3] Heldin, 2004, High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy, Nat Rev Cancer source

      Not checked in the free run.

  • Premisecitation

    Constitutive activation of oncogene-driven signaling pathways may activate hypoxia signaling independently of oxygen supply.

    “However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply.”
    • Also stated in: § Oxygen-Independent HIF Activation: “Pseudohypoxia” · plain
      “One of the common functional consequence of these activating mutations is the extreme activity of mTORC1, resulting in constitutive protein synthesis and/or stabilization/functional activation of HIFα. On the other hand, HIFα stabilization can also be the consequence of the increased activity of the RAS-MEK-ERK signaling pathway [18].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Aoki, 2017, Oncogenic Roles of the PI3K/AKT/mTOR axis, Curr Top Microbiol Immunol source

      Not checked in the free run.

    • cites [18] Semenza, 2016, The Hypoxic Tumor Microenvironment: A Driving Force for Breast Cancer Progression, Biochim Biophys Acta (Bba) - Mol Cel Res source

      Not checked in the free run.

  • Premisenone given

    Cancer hypoxia affects gene expression, metabolism, and tumor biology-related processes.

    “Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Cancer hypoxia is one of the most important hallmarks of cancer.
  • Classified as probably not a substantial claim. 11
  • May combine two claims. 40

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Atezolizumab plus bevacizumab is approved for lung adenocarcinoma (LUAD).

    “| LUAD | — | Atezolizumab | Bevacizumab | — | + |”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Pembrolizumab plus axitinib is approved for renal cell carcinoma (RCC).

    “| RCC | Pembrolizumab | — | — | Axitinib | + |”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Atezolizumab plus bevacizumab is approved for hepatocellular carcinoma (HCC).

    “| HCC | — | Atezolizumab | Bevacizumab | — | + |”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingnone given

    Nivolumab plus axitinib is approved for renal cell carcinoma (RCC).

    “| RCC | Nivolumab | — | — | Axitinib | + |”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cancer hypoxia usually is a combination of acute, chronic, and systemic forms, which drives tumor progression and is a leading cause of resistance to various therapeutic modalities.

    “Collectively, cancer hypoxia usually is a combination of acute, chronic and systemic forms of hypoxia, which not only drives tumor progression, but also a leading cause of resistance to various therapeutic modalities [3–6].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [3] Heldin, 2004, High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy, Nat Rev Cancer source

      Not checked in the free run.

    • cites [4] Siemann, 2011, The Unique Characteristics of Tumor Vasculature and Preclinical Evidence for its Selective Disruption by Tumor-Vascular Disrupting Agents, Cancer Treat Rev source

      Not checked in the free run.

    • cites [5] Lee, 2020, Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond, Nat Rev Mol Cel Biol source

      Not checked in the free run.

    • cites [6] Semenza, 2002, HIF-1 and Tumor Progression: Pathophysiology and Therapeutics, Trends Mol Med source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cancers, hypoxia is almost inevitable and can be due to compressed intratumoral vessels, abnormal newly developed intratumoral capillaries, or systemic hypoxia in the host.

    “In cancers, it is almost inevitable that hypoxia would develop which can be due to: 1) compressed intratumoral vessels [3], 2) abnormal newly developed intratumoral capillaries [4], or 3) the systemic hypoxia in the host.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [3] Heldin, 2004, High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy, Nat Rev Cancer source

      Not checked in the free run.

    • cites [4] Siemann, 2011, The Unique Characteristics of Tumor Vasculature and Preclinical Evidence for its Selective Disruption by Tumor-Vascular Disrupting Agents, Cancer Treat Rev source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Oxygenation levels are much lower in cancers than in normal tissues; even the most vascularized tumors have an O2 rate of only 2% (lung cancer), and pancreatic cancers have the lowest rate (0.3%).

    “As compared to normal tissues, oxygenation levels are much lower in cancers, even in the most vascularized tumors the O2 rate is only 2% (lung cancer), but in most cases it is much lower, especially, for pancreatic cancers, where this rate is the lowest (0.3%) [1].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Muz, 2015, The Role of Hypoxia in Cancer Progression, Angiogenesis, Metastasis, and Resistance to Therapy, Hp source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient, frequently induced by anemia.

    “Major causes of cancer hypoxia are deficient or inappropriate vascularization and systemic hypoxia of the patient (frequently induced by anemia), leading to a unique form of genetic reprogramming by hypoxia induced transcription factors (HIF).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    Consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile, and the immunosuppressive microenvironment.

    “The consequences of HIF activation in tumors are the angiogenic phenotype, a novel metabolic profile and the immunosuppressive microenvironment.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Kidney cancer is characterized by the highest microvessel density followed by lung or breast cancers.

    “However, kidney cancer is characterized by the highest microvessel density followed by lung or breast cancers [32], suggesting that there is no direct connection between vascularization and oxygenation of cancer tissues.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Lőrincz, 2004, Alterations of Microvascular Density in Bone Metastases of Adenocarcinomas, Pathol Oncol Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTOR hyperactivity provides stabilization of HIF1α protein and other regulatory failures contributing to HIF1α stabilization in pseudohypoxic tumor tissues.

    “Therefore, mTOR hyperactivity provides stabilization of HIF1α protein and other regulatory failures contributing to the HIF1α stabilization in pseudohypoxic tumor tissues [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Li, 2007, Hypoxia-induced Endothelial Proliferation Requires Both mTORC1 and mTORC2, Circ Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF mutations are very rare in cancers; low-frequency HIF1α mutation can be detected in renal cell cancer, and HIF2α mutation results in paraganglioma.

    “The vital role of HIF transcription factors is reflected by the fact that their mutations are very rare in cancers: at low frequency, HIF1α mutation can be detected in renal cell cancer [11], while HIF2α mutation results in the development of a rare tumor, paraganglioma [12].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] Morris, 2009, Mutation Analysis of Hypoxia-Inducible Factors HIF1α and HIF2α in Renal Carcinoma, Anticancer Res

      Not checked in the free run.

    • cites [12] Pang, 2019, Nonmosaic Somatic HIF2A Mutations Associated with Late Onset Polycythemia‐paraganglioma Syndrome: Newly Recognized Subclass of Polycythemia‐paraganglioma Syndrome, Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The genetic prototype of HIF-deregulated cancer is sporadic renal cell carcinoma, where the incidence of loss-of-function VHL mutation is 50%, resulting in an angiogenesis-dependent tumor.

    “Accordingly, the genetic prototype of HIF-deregulated cancer is the sporadic renal cell carcinoma, where the incidence of the loss of function mutation of VHL is 50%, resulting in an angiogenesis-dependent tumor [14].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Dizman, 2020, Genomic Profiling in Renal Cell Carcinoma, Nat Rev Nephrol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Vascularization of tumor tissue is cancer-type specific and greatly depends on the host tissue, and can differ in metastases compared to primary tumors.

    “It is of note, that vascularization of tumor tissue is cancer-type specific and greatly depends on the host tissue. Accordingly, it can be different in metastases as compared to primary tumors [24, 25].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Dezső, 2009, Development of Arterial Blood Supply in Experimental Liver Metastases, Am J Pathol source

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    • cites [25] Szabó, 2015, Mechanism of Tumour Vascularization in Experimental Lung Metastases, J Pathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using combined mRNA and protein detection of HIF1/2α and their targets in metastatic renal cell cancer, high HIF1α and low HIF2α expressions or a "HIF-index" are poor prognostic factors, when CAIX, GLUT1 and GAPDH overexpressions follow this prognostic trend.

    “Using such a combined approach in metastatic renal cell cancer, it was possible to demonstrate that high HIF1α and low HIF2α expressions or a “HIF-index” are poor prognostic factors, when CAIX, GLUT1 and GAPDH overexpressions follow this prognostic trend [16].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Szendrői, 2016, Opposite Prognostic Roles of HIF1α and HIF2α Expressions in Bone Metastatic Clear Cell Renal Cell Cancer, Oncotarget source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hypoxia, VEGF promotes CD4+ T-cell differentiation into T-regulatory cells, suppressing emerging immunoreactions.

    “In hypoxia, VEGF promotes CD4+ T-cell differentiation into T-regulatory cells, suppressing the emerging immunoreactions.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Kaur, 2014, CD47 Signaling Regulates the Immunosuppressive Activity of VEGF in T Cells, J.I. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    At high O2 levels, hydroxylases label HIFα proteins for VHL, which recognizes these forms and sends them for proteasomal degradation by recruiting ubiquitin ligases.

    “At high O2 levels, hydroxylases label HIFα proteins for VHL, which recognizes these forms and send them for proteasomal degradation by recruiting ubiquitin ligases (Figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Hypoxia modulates immune checkpoint inhibitory molecules on infiltrating cells and tumor cells by inducing PDL1 expression, and in CD8+ cytotoxic T-cells induces CTLA-4.

    “Hypoxia modulates immune checkpoint inhibitory molecules on infiltrating cells and tumor cells by inducing PDL1 expression. In CD8+ cytotoxic T-cells, hypoxia also induces CTLA-4 receptor, another checkpoint regulator [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Petrova, 2018, The Hypoxic Tumour Microenvironment, Oncogenesis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In hypoxia, HIF1α induces MDR1/ABCB1 efflux transporter resulting in resistance to chemotherapeutics which are its substrates (like doxorubicin), and this mechanism is quite universal among various cancer types.

    “At first, in hypoxia HIF1α induces MDR1/ABCB1 efflux transporter resulting in resistance to chemotherapeutics which are its substrates (like doxorubicin)–this mechanism is quite universal among various cancer types [58].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Scotto, 2003, Transcriptional Regulation of ABC Drug Transporters, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia-induced metabolic changes produce ROS that can induce DNA damage, and DNA repair enzymes can be downregulated under hypoxia, risking accumulation of DNA mutations.

    “It is a unique consequence of cellular hypoxia that the induced metabolic changes result in production of reactive oxygen species (ROS) which can induce DNA damages, similar to other mutagens. Since under hypoxia the function of DNA repair enzymes can be downregulated, there is a risk of further accumulation of DNA mutations in oxygen-deprived conditions [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Kaplan, 2020, Impact of Hypoxia on DNA Repair and Genome Integrity, Mutagenesis source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    There are 216 genes in the human genome with HIF-responsive elements in their promoters, but the list of classical HIF regulated genes is much shorter (~40).

    “There are 216 genes in the human genome which contain HIF-responsive elements (HRE) in their promoters [6, 8, 9] However, the list of classical HIF regulated genes is much shorter (∼40) [9].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [6] Semenza, 2002, HIF-1 and Tumor Progression: Pathophysiology and Therapeutics, Trends Mol Med source

      Not checked in the free run.

    • cites [8] Ortiz-Barahona, 2010, Genome-wide Identification of Hypoxia-Inducible Factor Binding Sites and Target Genes by a Probabilistic Model Integrating Transcription-Profiling Data and In Silico Binding Site Prediction, Nucl Acid Res source

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    • cites [9]

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Low O2 levels stabilize HIFα proteins, which accumulate and translocate to the nucleus and activate expression of genes involved in adaptation to hypoxic conditions.

    “Low O2 levels stabilize HIFα proteins which accumulate and translocate to the nucleus. In parallel, it also activates the expression of certain genes which are involved in adaptation to hypoxic conditions [5, 7] (Figure 3).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [5] Lee, 2020, Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond, Nat Rev Mol Cel Biol source

      Not checked in the free run.

    • cites [7] Pugh, 2017, New Horizons in Hypoxia Signaling Pathways, Exp Cel Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In lung cancer, cancer cells overexpress PDL1 at the border of necrotic tumor while infiltrating cells express PD1 and activate immunosuppressive mechanisms.

    “In lung cancer, it was demonstrated that cancer cells overexpress PDL1 at the border of necrotic tumor while the infiltrating cells express PD1 and activate immunosuppressive mechanisms [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Reiniger, 2019, Tumor Necrosis Correlates with PD-L1 and PD-1 Expression in Lung Adenocarcinoma, Acta Oncologica source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    Hypoxia signaling in cancer is a key regulatory pathway affecting several aspects of cancer biology and offers an obvious target for intervention.

    “hypoxia signaling in cancer is a key regulatory pathway affecting several aspects of cancer biology offering an obvious target for intervention.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    In any other cancer types, anti-angiogenic drugs are effective only in combination with chemo- and/or radiotherapy, increasing the efficacy of cytotoxic therapies by decreasing tissue hypoxia.

    “In any other cancer types, anti-angiogenic dugs are effective only in combination with chemo- and/or radiotherapy i.e. increasing the efficacy of cytotoxic therapies by decreasing tissue hypoxia.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Small molecule HIF2α inhibitors PT2977/MK6482 and PT2385 have been developed recently and tested in clinical trials.

    “small molecule HIF2α inhibitors, PT2977/MK6482 and PT2385 have been developed recently and tested in clinical trials [89].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Courtney, 2018, Phase I Dose-Escalation Trial of PT2385, a First-In-Class Hypoxia-Inducible Factor-2α Antagonist in Patients with Previously Treated Advanced Clear Cell Renal Cell Carcinoma Antagonist in Patients with Previously Treated Advanced Clear Cell Renal Cell Carcinoma, Jco source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    HIF protein synthesis can be targeted using digoxin, 2-methoxy-estradiol, or topotecan.

    “The other approach is to target HIF protein synthesis using digoxin [83], 2-methoxy-estradiol [85] or topotecan [83].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Karakhasev, 2015, Progress toward Overcoming Hypoxia-Induced Resistance to Solid Tumor Therapy, Cancer Management Res source

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    • cites [85] Mabjeesh, 2003, 2ME2 Inhibits Tumor Growth and Angiogenesis by Disrupting Microtubules and Dysregulating HIF, Cancer Cell source

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  • May combine two claims.

    Premisecitation

    ARCON (accelerated radiotherapy with nicotinamide and carbogen) reached phase III but did not result in clinical acceptance.

    “It is another clinical approach to combine accelerated radiotherapy with nicotinamide and carbogen (ARCON) of which research reached phase-III [92] but did not resulted in clinical acceptance.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Janssen, 2012, Accelerated Radiotherapy with Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial, J Clin Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vitro, acriflavin and YC-1 can directly bind to HIF1α; they have shown some preclinical activity, but clinical development was discontinued.

    “In vitro, acriflavin [83] or YC-1 [88] can directly bind to HIF1α; although they have shown some preclinical activity, the clinical development was discontinued.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [83] Karakhasev, 2015, Progress toward Overcoming Hypoxia-Induced Resistance to Solid Tumor Therapy, Cancer Management Res source

      Not checked in the free run.

    • cites [88] Yeo, 2003, YC-1: A Potential Anticancer Drug Targeting Hypoxia-Inducible Factor 1, JNCI J Natl Cancer Inst source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Hypoxia may affect immunotherapy.

    “If hypoxia affects antitumoral immune responses, it is justified to propose that hypoxia may affect immunotherapy as well [74].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Fukumura, 2018, Enhancing Cancer Immunotherapy Using Antiangiogenics: Opportunities and Challenges, Nat Rev Clin Oncol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Premisenone given

    In preclinical models anti-angiogenic drugs decrease tumoral microvessel densities, but this has never been demonstrated at clinical circumstances.

    “Although in preclinical models these drugs were able to decrease tumoral microvessel densities – this has never been demonstrated at clinical circumstances.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Development of combination strategies with immunotherapy was clinically very effective in renal cell cancer, leading to FDA approval of several combinations with multikinase inhibitors.

    “The development of combination strategies with immunotherapy was clinically very effective [75] leading to FDA approval of several combinations with multikinase inhibitors (Table 4).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Rassy, 2020, Tyrosine Kinase Inhibitors and Immunotherapy Combinations in Renal Cell Carcinoma, Ther Adv Med Oncol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human melanoma preclinical models, ZnSO4 administration selectively downregulates HIF1α expression and has antitumoral and antimetastatic effects.

    “In human melanoma preclinical models, ZnSO4 administration was able to downregulate HIF1α expression selectively which had antitumoral and antimetastatic effects [84].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Burián, 2020, Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma, Pathol Oncol Res source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Only certain patients and tumors respond well to immunotherapy.

    “It has become evident, that only certain patients and tumors respond well to immunotherapy.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Anti-angiogenic drugs are not effective in combinations with other targeted therapies, with the exception of EGFR-mutant lung adenocarcinoma where EGFR inhibitors can be effectively combined with anti-VEGF antibody.

    “It is another fact that anti-angiogenic drugs are not effective in combinations with other targeted therapies, with the exception of EGFR-mutant lung adenocarcinoma where EGFR inhibitors can be effectively combined with anti-VEGF antibody [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Chen, 2020, Efficacy of EGFR-TKIs with or without Angiogenesis Inhibitors in Advanced Non-small-cell Lung Cancer: A Systematic Review and Meta-Analysis, J Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Doranidazole or nimorazole are clinically active in lung cancer radiotherapy and are used more widely nowadays due to the success of the DAHANCA 5-85 trial.

    “Another clinically active therapeutic option is “chemical anti-hypoxia” by the use of doranidazole or nimorazol in lung cancer radiotherapy [93] which are used more widely nowadays due to the success of the DAHANCA 5–85 trial.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [93] Thompson, 2014, NIMRAD - a Phase III Trial to Investigate the Use of Nimorazole Hypoxia Modification with Intensity-Modulated Radiotherapy in Head and Neck Cancer, Clin Oncol (R Coll Radiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Immunotherapy and anti-angiogenic treatment combination was approved recently in lung adenocarcinoma and hepatocellular carcinoma.

    “Immunotherapy and anti-angiogenic treatment combination also approved recently in lung adenocarcinoma [76] and hepatocellular carcinoma [77] (Table 4).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [76] Gubens, 2019, NCCN Guidelines Updates: New Immunotherapy Strategies for Improving Outcomes in Non-small Cell Lung Cancer, J Natl Compr Canc Netw source

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    • cites [77] Hilmi, 2019, Angiogenesis and Immune Checkpoint Inhibitors as Therapies for Hepatocellular Carcinoma: Current Knowledge and Future Research Directions, J Immunotherapy Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    One possible cause of anti-angiogenic therapy resistance is the switch of the angiogenic phenotype: VEGF to PDGF in renal cell cancer, VEGF to FGF in squamous cancers, VEGF to Bv8 peptide in glioblastoma, VEGF to TGFβ in hepatocellular cancer, and VEGF to apelin in lung or breast cancers.

    “One possible cause of anti-angiogenic therapy resistance is the switch of the angiogenic phenotype: VEGF to PDGF in renal cell cancer, VEGF to FGF in squamous cancers, VEGF to Bv8 peptide in glioblastoma, VEGF to TGFβ in hepatocellular cancer [71], and VEGF to apelin in lung or breast cancers [72].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [71] Haibe, 2020, Resistance Mechanisms to Anti-angiogenic Therapies in Cancer, Front Oncol source

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    • cites [72] Uribesalgo, 2019, Apelin Inhibition Prevents Resistance and Metastasis Associated with Anti‐angiogenic Therapy, EMBO Mol Med source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The first mTOR inhibitor therapies (everolimus and temsirolimus) were introduced into the clinic long ago for VHL-mutation dependent renal cell cancer, and more recently for breast cancer.

    “the first mTOR inhibitor therapies were introduced into the clinic long time ago in case of VHL-mutation dependent renal cell cancer (everolimus and tensirolimus), and more recently in case of breast cancer recently [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Zou, 2020, mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Progress and Challenges, Cell Biosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Renal cell cancer is multidrug resistant, genetically depends on HIF activation, and is characterized by extreme VEGF production.

    “This cancer is multidrug resistant, it genetically depends on HIF activation and characterized by extreme VEGF production.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] Gläsker, 2020, Von Hippel-Lindau Disease: Current Challenges and Future Prospects, Ott source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Erythropoiesis stimulating agent (ESA) treatment may normalize tumoral blood vessels and improve drug perfusion, as observed in preclinical models.

    “normalization of tumoral blood vessels improving drug perfusion [80]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Tóvári, 2005, Recombinant Human Erythropoietin α Targets Intratumoral Blood Vessels, Improving Chemotherapy in Human Xenograft Models, Cancer Res source

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    According to preclinical models, digoxin, 2-methoxy-estradiol, and topotecan could be effective, but no clinical data are available.

    “According to preclinical models, these agents could be effective, however, there are no available clinical data.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    Anti-angiogenic drugs have been developed and this therapy became the fourth modality following chemo-, radiotherapy and surgery.

    “Overall, anti-angiogenic drugs have been developed and this therapy became the fourth modality following chemo-, radiotherapy and surgery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Several clinical trials of renal carcinoma, glioma, neuroendocrine and gastrointestinal cancers are ongoing, involving mTOR inhibitors in combination with anti-angiogenic treatments, and results may vary between tumor types.

    “Several clinical trials of renal carcinoma, glioma, neuroendocrine and gastrointestinal cancers are ongoing, involving mTOR inhibitors in combination with anti-angiogenic treatments, however, the results may vary between tumor types [99–102].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [99] Vallet, 2015, Efficacy of Targeted Treatment beyond Third-Line Therapy in Metastatic Kidney Cancer: Retrospective Analysis from a Large-Volume Cancer Center, Clin Genitourinary Cancer source

      Not checked in the free run.

    • cites [100] Wick, 2016, Current Status and Future Directions of Anti-angiogenic Therapy for Gliomas, Neuro Oncol source

      Not checked in the free run.

    • cites [101] Galdy, 2016, Systemic Therapy beyond First-Line in Advanced Gastric Cancer: An Overview of the Main Randomized Clinical Trials, Crit Rev Oncology/Hematology source

      Not checked in the free run.

    • cites [102] Grozinsky-Glasberg, 2020, Preclinical Drug Studies in MEN1-Related Neuroendocrine Neoplasms (MEN1-NENs), Endocr Relat Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Combination of metformin or phenformin with chemotherapy could be effective, and it could significantly enhance the effect of anti-angiogenic therapy (bevacizumab) without increasing the severity of side effects, e.g. in metastatic NSCLC.

    “Based on certain studies, their combination with chemotherapy could be effective, but it could significantly enhance the effect of anti-angiogenic therapy (bevacizumab) without increasing the severity of side effects (e.g. in metastatic NSCLC) [105–107].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [105] Marrone, 2018, A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy‐Naïve Advanced or Metastatic Nonsquamous Non‐Small Cell Lung Cancer, Oncol source

      Not checked in the free run.

    • cites [106] Markowska, 2017, Angiogenesis and Cancer Stem Cells: New Perspectives on Therapy of Ovarian Cancer, Eur J Med Chem source

      Not checked in the free run.

    • cites [107] Petővári, 2020, Inhibition of Metabolic Shift Can Decrease Therapy Resistance in Human High-Grade Glioma Cells, Pathol Oncol Res source

      Not checked in the free run.

    • Rests on an assumption: Metformin and phenformin can inhibit mitochondrial electron transport chain.

  • May combine two claims.

    Premisecitation

    Autophagy-targeted therapies and the combinatorial effect of anti-angiogenic treatments were confirmed among experimental conditions, e.g. in lung carcinomas.

    “Autophagy-targeted therapies and the combinatorial effect of anti-angiogenic treatments were confirmed among experimental conditions e.g. in lung carcinomas [105].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [105] Marrone, 2018, A Randomized Phase II Study of Metformin Plus Paclitaxel/Carboplatin/Bevacizumab in Patients with Chemotherapy‐Naïve Advanced or Metastatic Nonsquamous Non‐Small Cell Lung Cancer, Oncol source

      Not checked in the free run.

    • Rests on an assumption: Autophagy activation can be observed in case of anti-angiogenic therapies.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Treatments targeting metabolic adaptation mechanisms and influencing metabolic symbiosis, including anti-angiogenic ones, administered in combination could cause metabolic catastrophe in cancer tissue adaptation machinery.

    “Treatments (including anti-angiogenic ones) targeting metabolic adaptation mechanisms and influencing metabolic symbiosis administered in combination could cause metabolic catastrophe in cancer tissue adaptation machinery.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Tumor cells in the tissue context optimize and balance the utilization of the available energy resources to maintain their continuous proliferation even in stress conditions.
    • Rests on an assumption: Metabolic plasticity and tissue co-operation are important factors of the tumor resistance to various therapies.
47 of 47

  • The paper relies on this without support.

    Cancer hypoxia is one of the most important hallmarks of cancer.

    “Cancer hypoxia, recognized as one of the most important hallmarks of cancer, affects gene expression, metabolism and ultimately tumor biology-related processes.”

  • The paper relies on this without support.

    The primary cause of systemic hypoxia in cancer patients is anemia (low Hgb levels).

    “The primary cause of systemic hypoxia in cancer patients is anemia (low Hgb levels)”

  • The paper relies on this without support.

    Transfusion and ESA administration have a severe adverse effect which is thromboembolism.

    “transfusion and ESA administration have a severe adverse effect which is thromboembolism.”

  • The paper relies on this without support.

    Iron deficient anemia is a frequent cause for cancer patient’s anemia.

    “Iron deficient anemia is a frequent cause for cancer patient’s anemia”

  • The authors state this as an assumption.

    Correction of systemic hypoxia may not be equally effective in tumors where the O2-independent HIF activation takes place.

    “it is assumed that correction of systemic hypoxia may not be equally effective in tumors where the O2-independent HIF activation takes place.”

  • The paper relies on this without support.

    Tumor cells in the tissue context optimize and balance the utilization of the available energy resources to maintain their continuous proliferation even in stress conditions.

    “Tumor cells in the tissue context, optimize and balance the utilization of the available energy resources to maintain their continuous proliferation even in stress conditions.”

  • The paper relies on this without support.

    Metabolic plasticity and tissue co-operation are important factors of the tumor resistance to various therapies.

    “Metabolic plasticity and tissue co-operation are important factors of the tumor resistance to various therapies.”

  • The paper relies on this without support.

    Autophagy can either result in apoptosis of cancer cells or provide appropriate bioenergetic background for cellular survival.

    “It can either result in apoptosis of cancer cells or provide appropriate bioenergetic background for cellular survival.”

  • The paper relies on this without support.

    Autophagy activation can be observed in case of anti-angiogenic therapies.

    “Autophagy activation can be observed in case of anti-angiogenic therapies.”

  • The paper relies on this without support.

    Metformin and phenformin can inhibit mitochondrial electron transport chain.

    “metformin and phenformin (AMPK activator) can inhibit mitochondrial electron transport chain.”

  • The paper relies on this without support.

    Significant differences could be obtained by studying in vitro and in vivo models or clinical tumor specimens.

    “Significant differences could be obtained by studying in vitro and in vivo models or clinical tumor specimens.”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Tumor oxygenation ranking conflicts with Table 1

    Minor

    The text ranks breast cancer ahead of rectal cancer, but Table 1 reports 1.5% O2 for breast cancer and 1.8% for rectal cancer. It also places glial tumors, at 1.7%, between them.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Morris, 2009, Mutation Analysis of Hypoxia-Inducible Factors HIF1α and HIF2α in Renal Carcinoma, Anticancer Res, 29, 4337

Cited by

Sorted by citations

Related

Authors
Sebestyén, A., Kopper, L., Dankó, T., & Tímár, J.
Affiliations
Semmelweis University (HU)
ORCID
Venue
Pathology and Oncology Research
Publisher
Frontiers Media SA
Published
2021-05-03
Volume
27
Pages
1609802-1609802
ISSN
  • 1219-4956 (ISSN-L)
  • 1532-2807
DOI
10.3389/pore.2021.1609802
PMC
PMC8262153
OpenAlex
W3158017061
Cited by
110
References
116
Citations by year
2026: 14 · 2025: 22 · 2024: 30 · 2023: 25 · 2022: 17 · 2021: 2
FWCI
2.23
Type
journal article
Language
en
Open access
Licence
Locations
  • Pathology & Oncology Research (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
Nemzeti Kutatási Fejlesztési és Innovációs Hivatal
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Hematology › Erythropoietin and Anemia Treatment
Keywords
tumor hypoxia, hypoxia signaling, hypoxia-inducible factor, tumor angiogenesis, cancer metabolism, immunosuppressive tumor microenvironment, treatment resistance, anemia, anti-angiogenic therapy, combination cancer therapy
MeSH terms
Animals, Hypoxia, Humans, Neoplasms, Neovascularization, Pathologic, Signal Transduction, Tumor Microenvironment

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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