Hypoxia Signaling in Cancer: From Basics to Clinical Practice

In the paper

“| RCC | — | Avelumab | — | Cabozantinib | + |”

In the paper

“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].”

What the sources say

• Not checked yetcites [3] Heldin, 2004, High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy, Nat Rev Cancer source
• Not checked yetcites [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 yetcites [5] Lee, 2020, Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond, Nat Rev Mol Cel Biol source
• Not checked yetcites [6] Semenza, 2002, HIF-1 and Tumor Progression: Pathophysiology and Therapeutics, Trends Mol Med source

In the paper

“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].”

What the sources say

• Not checked yetcites [1] Muz, 2015, The Role of Hypoxia in Cancer Progression, Angiogenesis, Metastasis, and Resistance to Therapy, Hp source
• Not checked yetcites [2] Folkman, 1971, Tumor Angiogenesis: Therapeutic Implications, N Engl J Med source
• Not checked yetcites [3] Heldin, 2004, High Interstitial Fluid Pressure - an Obstacle in Cancer Therapy, Nat Rev Cancer source

In the paper

“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].”

What the sources say

• Not checked yetcites [17] Aoki, 2017, Oncogenic Roles of the PI3K/AKT/mTOR axis, Curr Top Microbiol Immunol source
• Not checked yetcites [18] Semenza, 2016, The Hypoxic Tumor Microenvironment: A Driving Force for Breast Cancer Progression, Biochim Biophys Acta (Bba) - Mol Cel Res source

In the paper

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

In the paper

“However, the contribution of vasculogenesis to the vascularization of tumor tissue is minimal in humans [21].”

What the sources say

• Not checked yetcites [21] Döme, 2006, Identification and Clinical Significance of Circulating Endothelial Progenitor Cells in Human Non-small Cell Lung Cancer, Cancer Res source

In the paper

“On the other hand, in hypoxia oxygenic stress response is activated by NRF2, which activates HIF1α, but more importantly an array of multidrug resistance genes such as MDR1/ABCB1, MRP1/ABCC1 and BCRP/ABCG2 resulting in resistance to a variety of other chemotherapeutics [59, 60].”

What the sources say

• Not checked yetcites [59] Jin, 2020, Enhancer-bound Nrf2 Licenses HIF-1α Transcription under Hypoxia to Promote Cisplatin Resistance in Hepatocellular Carcinoma Cells, Aging source
• Not checked yetcites [60] Belisario, 2020, Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance, Cells source

In the paper

“On the other hand, NK cells remain active against tumor cells in hypoxia [51].”

What the sources say

• Not checked yetcites [51] Taylor, 2017, Regulation of Immunity and Inflammation by Hypoxia in Immunological Niches, Nat Rev source

In the paper

“The gold standard technology to measure tumor tissue pO2 levels is PET using 15O2.”

In the paper

“On the other hand, HIFα stabilization can also be the consequence of the increased activity of the RAS-MEK-ERK signaling pathway [18].”

What the sources say

• Not checked yetcites [18] Semenza, 2016, The Hypoxic Tumor Microenvironment: A Driving Force for Breast Cancer Progression, Biochim Biophys Acta (Bba) - Mol Cel Res source

In the paper

“Mutations of HIF regulators–such as VHL, even in the form of germline ones (von-Hippel Lindau syndrome)–are much more frequent in cancers [13].”

What the sources say

• Not checked yetcites [13] Gläsker, 2020, Von Hippel-Lindau Disease: Current Challenges and Future Prospects, Ott source

In the paper

“It was shown in skin melanoma that increased tumoral vascular density is associated with increased macrophage and T-cell density [55].”

What the sources say

• Not checked yetcites [55] Kiss, 2007, Association of Microvessel Density with Infiltrating Cells in Human Cutaneous Malignant Melanoma, Pathol Oncol Res source

In the paper

“Moreover, mTORC1 influences the protein expression level of several onco-proteins such as HIF1α at post-transcriptional, translational level.”

What the sources say

• Not checked yetcites [43] He, 2018, mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-dependent Foxk1 Phosphorylation, Mol Cel source

In the paper

“Antitumoral immune responses are affected by (tumor) tissue hypoxia [40].”

What the sources say

• Not checked yetcites [40] Sarkadi, 2020, Glutaminases as a Novel Target for SDHB-Associated Pheochromocytomas/Paragangliomas, Cancers source

In the paper

“In hypoxic tumor cells, HIF activates several HRE genes that are essential for migration, invasion and metastasis: for example, autocrine motility factor and its receptor (AMF and AMFR); MET oncoprotein, receptor for scatter factor (paracrine regulators); CXCR4 chemokine receptor, matrix metalloproteinases such as MMP2/9 and collagen network remodeling lysil- and prolyl-hydroxylases (LOX and P4HA”

What the sources say

• Not checked yetcites [6] Semenza, 2002, HIF-1 and Tumor Progression: Pathophysiology and Therapeutics, Trends Mol Med source
• Not checked yetcites [18] Semenza, 2016, The Hypoxic Tumor Microenvironment: A Driving Force for Breast Cancer Progression, Biochim Biophys Acta (Bba) - Mol Cel Res source
• Not checked yetcites [19] Tátrai, 2017, Cell Type-dependent HIF1 α-mediated Effects of Hypoxia on Proliferation, Migration and Metastatic Potential of Human Tumor Cells, Oncotarget source

In the paper

“It has been well-known since the early 2000s, that the HIF1α stabilization and the elevated HIF1α protein levels are characteristic for ∼50% of tumor cells under normoxia [35].”

What the sources say

• Not checked yetcites [35] Robey, 2005, Hypoxia-Inducible Factor-1α and the Glycolytic Phenotype in Tumors, Neoplasia source

In the paper

“In hypoxic microenvironment, HIF activation results in the accumulation of lactic acid (as a consequence of anaerobic glycolysis) which is a characteristic metabolic feature of the majority of tumors.”

In the paper

“Mutations of growth factor receptors or members of their respective signaling pathways are characteristics for many different cancer types: EGFR mutations in lung adenocarcinoma, HER2 amplifications in breast and gastric cancers, RAS mutations in lung and colorectal cancers, BRAF mutations in melanoma, thyroid or GI-tract cancers or mutations of the lipid kinase signaling pathway members (PI3KCA,”

What the sources say

• Not checked yetcites [17] Aoki, 2017, Oncogenic Roles of the PI3K/AKT/mTOR axis, Curr Top Microbiol Immunol source

In the paper

“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.”

In the paper

“Experimental and clinicopathological data demonstrated that the vessel-cooption (incorporation of preexisting vessels) is the most conventional form of vascularization of primary and metastatic tumor tissues.”

What the sources say

• Not checked yetcites [2] Folkman, 1971, Tumor Angiogenesis: Therapeutic Implications, N Engl J Med source
• Not checked yetcites [20] Döme, 2007, Alternative Vascularization Mechanisms in Cancer, Am J Pathol source
• Not checked yetcites [23] Bridgeman, 2017, Vessel Co-option Is Common in Human Lung Metastases and Mediates Resistance to Anti-angiogenic Therapy in Preclinical Lung Metastasis Models, J Pathol source

In the paper

“Furthermore, HIF activation in hypoxia enhances immune suppressive effects of myeloid-derived suppressor cells [50].”

What the sources say

• Not checked yetcites [50] Vetsika, 2019, Myeloid-Derived Suppressor Cells: Major Figures that Shape the Immunosuppressive and Angiogenic Network in Cancer, Cells source

In the paper

“It is important that macrophages are sensitive to hypoxia and instead of the M1/antitumoral polarization in normoxia, under such circumstances they obtain M2/immunosuppressive phenotype [49].”

What the sources say

• Not checked yetcites [49] Díaz-Bulnes, 2020, Crosstalk between Hypoxia and ER Stress Response: a Key Regulator of Macrophage Polarization, Front Immunol source

In the paper

“Chemotherapy resistance depends on genetic and epigenetic factors among which tissue hypoxia is a significant factor.”

In the paper

“The parallel use of the two technologies give the best assessment of tumor tissue hypoxia in clinical situations [56, 57].”

What the sources say

• Not checked yetcites [56] Serganova, 2006, Tumor Hypoxia Imaging: Fig. 1, Clin Cancer Res source
• Not checked yetcites [57] Krohn, 2008, Molecular Imaging of Hypoxia, J Nucl Med source

In the paper

“However, chronic hypoxia is the most typical form of hypoxia in tumor tissues [5].”

What the sources say

• Not checked yetcites [5] Lee, 2020, Cellular Adaptation to Hypoxia through Hypoxia Inducible Factors and beyond, Nat Rev Mol Cel Biol source

In the paper

“In non-transformed cells of well-oxygenated tissues and even in tumor cells which are located near to blood vessels, an oxidative phenotype, the reverse utilization of lactic acid (reverse Warburg effect) can be observed [36].”

What the sources say

• Not checked yetcites [36] Faubert, 2020, Metabolic Reprogramming and Cancer Progression, Science source

In the paper

“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.”

What the sources say

• Not checked yetcites [32] Lőrincz, 2004, Alterations of Microvascular Density in Bone Metastases of Adenocarcinomas, Pathol Oncol Res source

In the paper

“It is of note, chemotherapy resistance can be predicted by the expression of HIF1α in some types of squamous cancers [1].”

What the sources say

• Not checked yetcites [1] Muz, 2015, The Role of Hypoxia in Cancer Progression, Angiogenesis, Metastasis, and Resistance to Therapy, Hp source

In the paper

“Even if tumor tissue would be optimally vascularized, systemic hypoxia could also lead to tumor tissue hypoxia in cancer patients.”

What the sources say

• Not checked yetcites [33] Gilreath, 2014, Diagnosis and Treatment of Cancer-Related Anemia, Am J Hematol source

In the paper

“Anti-hypoxia therapies have already been introduced in case of radiotherapy using hyperbaric O2 (HBO), which could have some activity in squamous cancers of the head and neck [91].”

What the sources say

• Not checked yetcites [91] Overgaard, 2011, Hypoxic Modification of Radiotherapy in Squamous Cell Carcinoma of the Head and Neck - A Systematic Review and Meta-Analysis, Radiother Oncol source

In the paper

“Later on, it was turned out that all these agents are able to normalize the malfunctioning tumoral blood vessels [67] by improving tumor tissue perfusion and decreasing hypoxia.”

What the sources say

• Not checked yetcites [67] Martin, 2019, Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges, Annu Rev Physiol source

In the paper

“However, similar to almost all cancer treatment forms, anti-angiogenic therapy also leads to emergence of resistance.”

In the paper

“Similar to other therapeutic modalities, efficacy of anti-angiogenic agents is also dependent on the optimal perfusion of the tumor tissue [73].”

What the sources say

• Not checked yetcites [73] Török, 2017, Limited Tumor Tissue Drug Penetration Contributes to Primary Resistance against Angiogenesis Inhibitors, Theranostics source

In the paper

“On the other hand, these agents are not effective in monotherapy except for renal cell cancer.”

In the paper

“In case of colorectal cancers, chemotherapy in combination with anti-VEGF antibody is similarly effective in KRAS-mutant and wild-type tumors [69].”

What the sources say

• Not checked yetcites [69] Sun, 2017, KRAS Mutation and Primary Tumor Location Do Not Affect Efficacy of Bevacizumab-Containing Chemotherapy in Stagae IV Colorectal Cancer Patients, Sci Rep source

In the paper

“In case of renal cell cancer, anti-angiogenic monotherapy is the basis of tumor management.”

In the paper

“Metabolic adaptation can be observed in case tumor cells survive the consequences of anti-angiogenetic or anti-HIF1α treatments.”

What the sources say

• Not checked yetcites [95] Jiménez-Valerio, 2017, Angiogenesis and Metabolism: Entwined for Therapy Resistance, Trends Cancer source

In the paper

“MK6482 was used clinically in VHL syndrome related renal cell cancer with promising activity [90].”

What the sources say

• Not checked yetcites [90] Jonasch, 2020, Phase II Study of the Oral HIF-2α Inhibitor MK-6482 for Von Hippel-Lindau Disease-Associated Renal Cell Carcinoma, Jco source

In the paper

“On the contrary, in case of lung adenocarcinoma, chemotherapy combination with anti-VEGF antibody is effective in KRAS wild-type tumors exclusively [70].”

What the sources say

• Not checked yetcites [70] Ghimessy, 2019, KRAS Mutations Predict Response and Outcome in Advanced Lung Adenocarcinoma Patients Receiving First-Line Bevacizumab and Platinum-Based Chemotherapy, Cancers source

In the paper

“the HIF complex-induced binding to HRE regions in promoters of various genes can be achieved by echinomycin [87].”

What the sources say

• Not checked yetcites [87] Kong, 2005, Echinomycin, a Small-Molecule Inhibitor of Hypoxia-Inducible Factor-1 DNA-Binding Activity, Cancer Res source

In the paper

“Accordingly, the alteration of tumoral microvessel density upon irradiation is a sensitive prognostic factor for radiotherapy efficacy [64].”

What the sources say

• Not checked yetcites [64] Lövey, 2006, Antiangiogenic Effects of Radiotherapy but Not Initial Microvessel Density Predict Survival in Inoperable Oropharyngeal Squamous Cell Carcinoma, Strahlenther Onkol source

In the paper

“It is also an important consideration that a fraction of anti-angiogenic agents are “dirty” (not highly specific) VEGFR inhibitors which affect other receptors, crucially important in the normal function of anti-tumoral T-cells.”

In the paper

“Based on these results, MK6482 became the first FDA-approved HIF2α inhibitor.”

In the paper

“In oxygenated environment, tumorous or even normal cells can consume the excreted metabolites of other cells located in the stroma.”

What the sources say

• Not checked yetcites [37] Yoshida, 2015, Metabolic Reprogramming: the Emerging Concept and Associated Therapeutic Strategies, J Exp Clin Cancer Res source

In the paper

“promoting efficacy of radiotherapy [81], asx observed in preclinical models.”

What the sources say

• Not checked yetcites [81] Lövey, 2008, Recombinant Human Erythropoietin Alpha Improves the Efficacy of Radiotherapy of a Human Tumor Xenograft, Affecting Tumor Cells and Microvessels, Strahlenther Onkol source

In the paper

“HIF1α overexpression in oral cancer is a negative predictive factor for radiotherapy [63].”

What the sources say

• Not checked yetcites [63] Aebersold, 2001, Expression of Hypoxia Inducible Factor-Alpha: a Novel Predictive, Prognostic Parameter in the Radiotherapy of Oropharyngeal Cancer, Cancer Res

In the paper

“Stabilization of HIFα can be suspended by HSP-90 inhibitor in vivo [86].”

What the sources say

• Not checked yetcites [86] Modi, 2011, HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab, Clin Cancer Res source

In the paper

“In experimental models, it was possible to downregulate HIF1/2α by antisense oligos or sh-RNA [83].”

What the sources say

• Not checked yetcites [83] Karakhasev, 2015, Progress toward Overcoming Hypoxia-Induced Resistance to Solid Tumor Therapy, Cancer Management Res source

In the paper

“the effector of the O2-independent oncogenic driver-driven pathway is mTOR (Table 5; Figure 3).”

In the paper

“Other major therapeutic modality of cancers is radiotherapy, however, it requires optimal normoxic conditions [62].”

What the sources say

• Not checked yetcites [62] Koshinani, 2016, Hypoxia: a Double-Edged Sword in Cancer Therapy, Cancer Invest source

In the paper

“Generation of intratumoral O2 is also feasible to improve the efficacy of radiotherapy by using bioactive albumin-MnO2 nanoparticles [94].”

What the sources say

• Not checked yetcites [94] Barker, 2015, The Tumour Microenvironment after Radiotherapy: Mechanisms of Resistance and Recurrence, Nat Rev Cancer source

In the paper

“lactate produced during “lactic glycolysis” of hypoxic or pseudo-hypoxic cells can be utilized in this manner [37] (Figure 6).”

What the sources say

• Not checked yetcites [37] Yoshida, 2015, Metabolic Reprogramming: the Emerging Concept and Associated Therapeutic Strategies, J Exp Clin Cancer Res source

In the paper

“It was observed that the activity pattern of mTOR shows intratumoral heterogeneity as a consequence of anti-angiogenic therapies.”

What the sources say

• Not checked yetcites [98] AllenMiéville, 2016, Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling, Cel Rep source

In the paper

“mTOR inhibitors could inhibit tumor progression as having a complex modifying role on metabolism [108–113].”

What the sources say

• Not checked yetcites [108] Felkai, 2020, Characterization of mTOR Activity and Metabolic Profile in Pediatric Rhabdomyosarcoma, Cancers source
• Not checked yetcites [109] Petővári, 2020, In situ metabolic Characterisation of Breast Cancer and its Potential Impact on Therapy, Cancers source
• Not checked yetcites [110] Rotundo, 2016, mTOR Inhibitors, a New Era for Metastatic Luminal HER2-Negative Breast Cancer? A Systematic Review and a Meta-Analysis of Randomized Trials, Oncotarget source
• Not checked yetcites [111] Wu, 2019, Metronomic Combination Chemotherapy Using Everolimus and Etoposide for the Treatment of non‐Hodgkin Lymphoma, Cancer Med source
• Not checked yetcites [112] Hue-Fontaine, 2020, Metformin and Everolimus in Neuroendocrine Tumours: A Synergic Effect?, Clin Res Hepatol Gastroenterol source
• Not checked yetcites [113] Ariaans, 2017, Anti-tumor Effects of Everolimus and Metformin Are Complementary and Glucose-dependent in Breast Cancer Cells, BMC Cancer source

In the paper

“Autophagy can be induced by certain treatments or microevironmental effects in relation to metabolic adaptation and resistance [45].”

What the sources say

• Not checked yetcites [45] Daskalaki, 2018, Hypoxia and Selective Autophagy in Cancer Development and Therapy, Front Cel Dev. Biol. source

In the paper

“This finding calls the attention to the master regulatory role of mTOR kinase in developing therapy resistance [98].”

What the sources say

• Not checked yetcites [98] AllenMiéville, 2016, Metabolic Symbiosis Enables Adaptive Resistance to Anti-angiogenic Therapy that Is Dependent on mTOR Signaling, Cel Rep source

In the paper

“Metabolic adaptation also has a remarkable role in maintaining/supporting the survival of the so-called cancer stem- or dormant cells [96, 97].”

What the sources say

• Not checked yetcites [96] Peiris-Pagès, 2016, Cancer Stem Cell Metabolism, Breast Cancer Res source
• Not checked yetcites [97] Liang, 2019, Autophagy Inhibition Potentiates the Anti-angiogenic Property of Multikinase Inhibitor Anlotinib through JAK2/STAT3/VEGFA Signaling in Non-small Cell Lung Cancer Cells, J Exp Clin Cancer Res source