Hypoxia Signaling in Cancer: From Basics to Clinical Practice

In the paper

“| LUAD | — | Atezolizumab | Bevacizumab | — | + |”

In the paper

“| RCC | Pembrolizumab | — | — | Axitinib | + |”

In the paper

“| HCC | — | Atezolizumab | Bevacizumab | — | + |”

In the paper

“| RCC | Nivolumab | — | — | Axitinib | + |”

In the paper

“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

“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.”

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

In the paper

“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].”

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

“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).”

In the paper

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

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

“Therefore, mTOR hyperactivity provides stabilization of HIF1α protein and other regulatory failures contributing to the HIF1α stabilization in pseudohypoxic tumor tissues [44].”

What the sources say

• Not checked yetcites [44] Li, 2007, Hypoxia-induced Endothelial Proliferation Requires Both mTORC1 and mTORC2, Circ Res source

In the paper

“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].”

What the sources say

• Not checked yetcites [11] Morris, 2009, Mutation Analysis of Hypoxia-Inducible Factors HIF1α and HIF2α in Renal Carcinoma, Anticancer Res
• Not checked yetcites [12] Pang, 2019, Nonmosaic Somatic HIF2A Mutations Associated with Late Onset Polycythemia‐paraganglioma Syndrome: Newly Recognized Subclass of Polycythemia‐paraganglioma Syndrome, Cancer source

In the paper

“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].”

What the sources say

• Not checked yetcites [14] Dizman, 2020, Genomic Profiling in Renal Cell Carcinoma, Nat Rev Nephrol source

In the paper

“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].”

What the sources say

• Not checked yetcites [24] Dezső, 2009, Development of Arterial Blood Supply in Experimental Liver Metastases, Am J Pathol source
• Not checked yetcites [25] Szabó, 2015, Mechanism of Tumour Vascularization in Experimental Lung Metastases, J Pathol source

In the paper

“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].”

What the sources say

• Not checked yetcites [16] Szendrői, 2016, Opposite Prognostic Roles of HIF1α and HIF2α Expressions in Bone Metastatic Clear Cell Renal Cell Cancer, Oncotarget source

In the paper

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

What the sources say

• Not checked yetcites [52] Kaur, 2014, CD47 Signaling Regulates the Immunosuppressive Activity of VEGF in T Cells, J.I. source

In the paper

“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).”

In the paper

“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].”

What the sources say

• Not checked yetcites [53] Petrova, 2018, The Hypoxic Tumour Microenvironment, Oncogenesis source

In the paper

“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].”

What the sources say

• Not checked yetcites [58] Scotto, 2003, Transcriptional Regulation of ABC Drug Transporters, Oncogene source

In the paper

“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].”

What the sources say

• Not checked yetcites [10] Kaplan, 2020, Impact of Hypoxia on DNA Repair and Genome Integrity, Mutagenesis source

In the paper

“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].”

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 [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
• Not checked yetcites [9]

In the paper

“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).”

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
• Not checked yetcites [7] Pugh, 2017, New Horizons in Hypoxia Signaling Pathways, Exp Cel Res source

In the paper

“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].”

What the sources say

• Not checked yetcites [54] Reiniger, 2019, Tumor Necrosis Correlates with PD-L1 and PD-1 Expression in Lung Adenocarcinoma, Acta Oncologica source

In the paper

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

In the paper

“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.”

In the paper

“small molecule HIF2α inhibitors, PT2977/MK6482 and PT2385 have been developed recently and tested in clinical trials [89].”

What the sources say

• Not checked yetcites [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

In the paper

“The other approach is to target HIF protein synthesis using digoxin [83], 2-methoxy-estradiol [85] or topotecan [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
• Not checked yetcites [85] Mabjeesh, 2003, 2ME2 Inhibits Tumor Growth and Angiogenesis by Disrupting Microtubules and Dysregulating HIF, Cancer Cell source

In the paper

“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.”

What the sources say

• Not checked yetcites [92] Janssen, 2012, Accelerated Radiotherapy with Carbogen and Nicotinamide for Laryngeal Cancer: Results of a Phase III Randomized Trial, J Clin Oncol source

In the paper

“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.”

What the sources say

• Not checked yetcites [83] Karakhasev, 2015, Progress toward Overcoming Hypoxia-Induced Resistance to Solid Tumor Therapy, Cancer Management Res source
• Not checked yetcites [88] Yeo, 2003, YC-1: A Potential Anticancer Drug Targeting Hypoxia-Inducible Factor 1, JNCI J Natl Cancer Inst source

In the paper

“If hypoxia affects antitumoral immune responses, it is justified to propose that hypoxia may affect immunotherapy as well [74].”

What the sources say

• Not checked yetcites [74] Fukumura, 2018, Enhancing Cancer Immunotherapy Using Antiangiogenics: Opportunities and Challenges, Nat Rev Clin Oncol source

In the paper

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

In the paper

“The development of combination strategies with immunotherapy was clinically very effective [75] leading to FDA approval of several combinations with multikinase inhibitors (Table 4).”

What the sources say

• Not checked yetcites [75] Rassy, 2020, Tyrosine Kinase Inhibitors and Immunotherapy Combinations in Renal Cell Carcinoma, Ther Adv Med Oncol source

In the paper

“In human melanoma preclinical models, ZnSO4 administration was able to downregulate HIF1α expression selectively which had antitumoral and antimetastatic effects [84].”

What the sources say

• Not checked yetcites [84] Burián, 2020, Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma, Pathol Oncol Res source

In the paper

“It has become evident, that only certain patients and tumors respond well to immunotherapy.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [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

In the paper

“Immunotherapy and anti-angiogenic treatment combination also approved recently in lung adenocarcinoma [76] and hepatocellular carcinoma [77] (Table 4).”

What the sources say

• Not checked yetcites [76] Gubens, 2019, NCCN Guidelines Updates: New Immunotherapy Strategies for Improving Outcomes in Non-small Cell Lung Cancer, J Natl Compr Canc Netw source
• Not checked yetcites [77] Hilmi, 2019, Angiogenesis and Immune Checkpoint Inhibitors as Therapies for Hepatocellular Carcinoma: Current Knowledge and Future Research Directions, J Immunotherapy Cancer source

In the paper

“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].”

What the sources say

• Not checked yetcites [71] Haibe, 2020, Resistance Mechanisms to Anti-angiogenic Therapies in Cancer, Front Oncol source
• Not checked yetcites [72] Uribesalgo, 2019, Apelin Inhibition Prevents Resistance and Metastasis Associated with Anti‐angiogenic Therapy, EMBO Mol Med source

In the paper

“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].”

What the sources say

• Not checked yetcites [82] Zou, 2020, mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Progress and Challenges, Cell Biosci source

In the paper

“This cancer is multidrug resistant, it genetically depends on HIF activation and characterized by extreme VEGF production.”

What the sources say

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

In the paper

“normalization of tumoral blood vessels improving drug perfusion [80]”

What the sources say

• Not checked yetcites [80] Tóvári, 2005, Recombinant Human Erythropoietin α Targets Intratumoral Blood Vessels, Improving Chemotherapy in Human Xenograft Models, Cancer Res source

In the paper

“According to preclinical models, these agents could be effective, however, there are no available clinical data.”

In the paper

“Overall, anti-angiogenic drugs have been developed and this therapy became the fourth modality following chemo-, radiotherapy and surgery.”

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [100] Wick, 2016, Current Status and Future Directions of Anti-angiogenic Therapy for Gliomas, Neuro Oncol source
• Not checked yetcites [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 yetcites [102] Grozinsky-Glasberg, 2020, Preclinical Drug Studies in MEN1-Related Neuroendocrine Neoplasms (MEN1-NENs), Endocr Relat Cancer source

In the paper

“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].”

What the sources say

• Not checked yetcites [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 yetcites [106] Markowska, 2017, Angiogenesis and Cancer Stem Cells: New Perspectives on Therapy of Ovarian Cancer, Eur J Med Chem source
• Not checked yetcites [107] Petővári, 2020, Inhibition of Metabolic Shift Can Decrease Therapy Resistance in Human High-Grade Glioma Cells, Pathol Oncol Res source

In the paper

“Autophagy-targeted therapies and the combinatorial effect of anti-angiogenic treatments were confirmed among experimental conditions e.g. in lung carcinomas [105].”

What the sources say

• Not checked yetcites [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

In the paper

“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.”