The DOI matches its Crossref record; 116 of the 116 references it cites were found in a registry or an index; none of the 153 sources its claims cite is checked for support yet.
Hypoxic control of metastasis
Open accessAbstract
Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Hypoxia is a potent microenvironmental factor promoting metastatic progression. Clinically, hypoxia and the expression of the hypoxia-inducible transcription factors HIF-1 and HIF-2 are associated with increased distant metastasis and poor survival in a variety of tumor types. Moreover, HIF signaling in malignant cells influences multiple steps within the metastatic cascade. Here we review research focused on elucidating the mechanisms by which the hypoxic tumor microenvironment promotes metastatic progression. These studies have identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at preventing and treating metastatic disease.
Overview
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Written from the paper’s full text.
TL;DR
This review synthesizes mechanisms by which hypoxia and HIF-1/HIF-2 signaling promote metastatic progression, from immune evasion and EMT to premetastatic niche formation and distant-site metabolic adaptation. It highlights candidate biomarkers and therapeutic targets, including AXL, LOX, exosomes, CKB, and PDK1.
Key findings
- Metastatic disease is responsible for more than 90% of cancer-related deaths, and an estimated 50 to 60% of solid tumors contain regions of hypoxia and/or anoxia; clinically, hypoxia and HIF expression are associated with increased metastasis, therapy resistance, and poor survival.
- HIF signaling influences multiple steps of the metastatic cascade, including immune evasion, EMT/invasion/migration, premetastatic niche formation, and growth/survival at distant sites; specific mediators discussed include AXL, LOX/LOXL2/4, exosomes, CKB, and PDK1.
- In the liver, an oxygen gradient exists with periportal blood at 60 to 65 mm Hg and perivenous blood at 30 to 35 mm Hg; colon cancer cells adapt to hepatic hypoxia via CKB/phosphocreatine, and breast cancer liver metastases depend on glycolysis largely through the HIF-1 target PDK1.
- High HIF-1 expression is associated with metastasis in gynecological, pancreatic, esophageal, lung, and prostate cancers, while HIF-2 expression is associated with distant metastasis in small cell lung and breast cancers; experimentally, HIF overexpression promotes metastasis and HIF inactivation decreases metastatic potential.
Methods
- Design: narrative review of the literature on hypoxia, HIF signaling, and metastasis.
- Data or sample: no primary dataset; the paper synthesizes clinical observations and preclinical models, including human tumor immunohistochemical analyses and mouse metastasis studies.
- Main analysis: thematic synthesis of mechanisms by which hypoxia and HIF-dependent signaling regulate immune evasion, EMT, premetastatic niche formation, and distant-site colonization.
Limitations
- Stated limitations: Not stated in the paper.
- Evident limitations: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or quantitative synthesis, so selection bias is possible.
- Evident limitations: many mechanistic conclusions rely on preclinical models and association studies in human tumors, which may not establish causality in patients.
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Claims the paper makes
0 of 153 cited sources checked · 0 supported · 0 flagged
None of the sources cited for this claim have been checked yet.
In the paper
“Hypoxia and activation of HIF signaling influence multiple steps within the metastatic cascade, including invasion and migration, intravasation and extravasation, and establishment of the premetastatic niche, as well as survival and growth at the distant site”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“The hypoxia-inducible transcription factors HIF-1 and HIF-2 coordinate the adaptive cellular response to low oxygen tensions by activating gene expression programs controlling glucose uptake, metabolism, angiogenesis, erythropoiesis, cell proliferation, differentiation, and apoptosis”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [1] Semenza GL Cell 2012 148 399 408 22304911 PMC3437543 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Hypoxia is a potent microenvironmental factor promoting metastatic progression.”
§ Hypoxic control of metastasis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“HIF signaling in malignant cells influences multiple steps within the metastatic cascade.”
§ Hypoxic control of metastasis > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“This hydroxylation event allows the von Hippel–Lindau tumor suppressor protein (VHL), the substrate recognition component of an E3 ubiquitin ligase complex, to bind to HIF-α and target it for proteasomal degradation”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [10] Jaakkola P Science 2001 292 468 472 11292861 source
- Not checked yetcites [11] Ivan M Science 2001 292 464 468 11292862 source
- Not checked yetcites [12] Maynard MA J. Biol. Chem 2003 278 11032 11040 12538644 source
- Not checked yetcites [13] Maxwell PH Nature 1999 399 271 275 10353251 source
- Not checked yetcites [14] Tanimoto K Makino Y Pereira T Poellinger L EMBO J 2000 19 4298 4309 10944113 PMC302039 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Hypoxia activates HIF signaling by promoting the protein stability of HIF-α subunits.”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Under normoxic conditions, prolyl hydroxylase enzymes (EGLN 1–3, also known as PHD 1–3) use oxygen as a substrate to hydroxylate key proline residues within the HIF-1 and HIF-2 α subunits”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“In the nucleus, HIF-α subunits dimerize with aryl hydrocarbon receptor nuclear translocator (ARNT) and bind to hypoxia-responsive elements in target genes to activate gene transcription by recruiting transcriptional coactivators including p300/CBP”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [15] Schödel J Blood 2011 117 e207 e217 21447827 PMC3374576 source
- Not checked yetcites [16] Wang GL Jiang BH Rue EA Semenza GL Proc. Natl. Acad. Sci. U.S.A 1995 92 5510 5514 7539918 PMC41725 source
- Not checked yetcites [17] Wang GL Semenza GL Proc. Natl. Acad. Sci. U.S.A 1993 90 4304 4308 8387214 PMC46495 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesThe paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Hundreds of genes are activated in response to HIF-1 and HIF-2”
§ Hypoxic control of metastasis > Hypoxic signaling
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Additionally, PHD activity can be inhibited by reactive oxygen species (ROS) produced by the mitochondria”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passes
- It may state two separate claims as one. 27
- Probably not a substantial claim. 5
None of the sources cited for this claim have been checked yet.
In the paper
“Clinically, hypoxia is associated with HIF activation, metastasis, and resistance to chemotherapy and radiotherapy, as well as poor patient survival”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [4] Rankin EB Giaccia AJ Cell Death Differ 2008 15 678 685 18259193 PMC3050610 source
- Not matchedcites [5] Schindl M Clin. Cancer Res 2002 8 1831 1837 12060624
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- Not checked yetcites [6] Yamamoto Y Breast Cancer Res. Treat 2008 110 465 475 17805961 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Clinically, HIF-1 and HIF-2 are highly expressed in primary tumors and metastases.”
- Also stated in: § Hypoxic signaling · hedged
“increased HIF expression is often linked with increased patient mortality in a variety of human cancers”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [41] Semenza GL Oncogene 2010 29 625 634 19946328 PMC2969168 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Hypoxic signaling · hedged
In the paper
“It has been estimated that 50 to 60% of solid tumors contain regions of hypoxia and/or anoxia”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [2] Vaupel P Mayer A Cancer Metastasis Rev 2007 26 225 239 17440684 source
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“In tumor cells, mutations in the genes encoding succinate dehydrogenase (SDH) or fumarate hydratase (FH) cause the accumulation of cytosolic succinate or fumarate; this inhibits the activity of prolyl hydroxylases and leads to HIF stabilization under normoxic conditions”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [22] Kaelin WG Jr. Cold Spring Harb. Symp. Quant. Biol 2011 76 335 345 22089927 PMC4197849 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As a result, EGLN 1–3 activity and HIF-α stability are affected by iron availability and can be inhibited by Krebs cycle intermediates, including succinate and fumarate, which compete with 2-oxoglutarate”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [18] Pan Y Mol. Cell. Biol 2007 27 912 925 17101781 PMC1800695 source
- Not checked yetcites [19] Nandal A Cell Metab 2011 14 647 657 22055506 PMC3361910 source
- Not checked yetcites [20] Jones DT Trowbridge IS Harris AL Cancer Res 2006 66 2749 2756 16510596 source
- Not checked yetcites [21] Majmundar AJ Wong WJ Simon MC Mol. Cell 2010 40 294 309 20965423 PMC3143508 source
- Not checked yetcites [22] Kaelin WG Jr. Cold Spring Harb. Symp. Quant. Biol 2011 76 335 345 22089927 PMC4197849 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“these factors allow cells to survive and adapt to low oxygen tensions, as well as confer changes in both and host that promote metastasis”
§ Hypoxic control of metastasis > Hypoxic signaling
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Under hypoxic conditions, PHD activity is inhibited, resulting in HIF-α stabilization and translocation to the nucleus.”
§ Hypoxic control of metastasis > Hypoxic signaling
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“WSB1 expression in tumor cells leads to HIF stabilization under normoxic and hypoxic conditions and correlates with metastasis in cancer patients”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [27] Kim JJ Genes Dev 2015 29 2244 2257 26545811 PMC4647558 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Although genetic inactivation of VHL is thought to be an early event in the pathogenesis of ccRCC”
§ Hypoxic control of metastasis > Hypoxic signaling
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Genetic mutations or epigenetic inactivation of VHL causes VHL disease, which is associated with constitutive activation of HIF-1 and HIF-2 and the development of highly vascularized tumors”
§ Hypoxic control of metastasis > Hypoxic signaling
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Both HIF-α mRNA transcription and translation are regulated by TORC1 activity”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [22] Kaelin WG Jr. Cold Spring Harb. Symp. Quant. Biol 2011 76 335 345 22089927 PMC4197849 source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Renal cell carcinoma is a major cause of morbidity in VHL patients, owing to the ability of these tumors to metastasize to other tissue sites”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [24] Lonser RR Lancet 2003 361 2059 2067 12814730
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“UCHL1 is associated with HIF-1 and distant metastasis in cancer patients”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [35] Goto Y Nat. Commun 2015 6 6153 25615526 PMC4317501 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“HIF-1 mRNA translation can be enhanced under normoxic and hypoxic conditions through the binding of YB-1, an RNA and DNA binding protein; this leads to increased HIF-1 protein and prometastatic activity in sarcoma cells”
§ Hypoxic control of metastasis > Hypoxic signaling
What the sources say
- Not checked yetcites [34] El-Naggar AM Cancer Cell 2015 27 682 697 25965573
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“respiratory hyperoxia was associated with a decrease in intratumoral hypoxia and an immunopermissive tumor microenvironment characterized by abundant CD8+ T cell infiltration and decreased regulatory T cell infiltration”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > Hypoxic signaling and immune evasion
What the sources say
- Not checked yetcites [50] Hatfield SM Sci. Transl. Med 2015 7 277ra30 PMC4641038 25739764 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In preclinical models, respiratory hyperoxia (60% O2) can promote tumor regression, reduce metastatic disease, and prolong animal survival”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > Hypoxic signaling and immune evasion
What the sources say
- Not checked yetcites [50] Hatfield SM Sci. Transl. Med 2015 7 277ra30 PMC4641038 25739764 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Once in the tumor microenvironment, Tregs promote immune tolerance and angiogenesis, which supports metastatic tumor growth”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > Hypoxic signaling and immune evasion
What the sources say
- Not checked yetcites [60] Facciabene A Nature 2011 475 226 230 21753853 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Hypoxic signaling in MDSCs and macrophages directly contributes to tumor progression by promoting an immunosuppressive phenotype and stimulating angiogenesis”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > Hypoxic signaling and immune evasion
What the sources say
- Not checked yetcites [57] Palazon A Goldrath AW Nizet V Johnson RS Immunity 2014 41 518 528 25367569 PMC4346319 source
- Not checked yetcites [61] Corzo CA J. Exp. Med 2010 207 2439 2453 20876310 PMC2964584 source
- Not checked yetcites [62] Colegio OR Nature 2014 513 559 563 25043024 PMC4301845 source
- Not checked yetcites [63] Chaturvedi P Gilkes DM Takano N Semenza GL Proc. Natl. Acad. Sci. U.S.A 2014 111 E2120 E2129 24799675 PMC4034192 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Hypoxic signaling can promote resistance to T cell–mediated killing by increasing the expression of programmed death–ligand 1 (PD-L1) on tumor cells and myeloid-derived suppressor cells (MDSCs), and by enhancing CTLA-4 expression on CD8+ T cells”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > Hypoxic signaling and immune evasion
What the sources say
- Not checked yetcites [57] Palazon A Goldrath AW Nizet V Johnson RS Immunity 2014 41 518 528 25367569 PMC4346319 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Cell-cell adhesions are mediated primarily by cadherin proteins expressed at intercellular junctions”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling in EMT, invasion, and migration
What the sources say
- Not checked yetcites [65] Cavallaro U Christofori G Nat. Rev. Cancer 2004 4 118 132 14964308
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“Loss of AXL does not appear to have deleterious effects on embryonic development or normal adult tissue function in mice”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling in EMT, invasion, and migration
What the sources say
Strength:hedged· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“biological inhibitors of AXL, such as soluble AXL decoy receptors, are specific and are not associated with normal tissue or hematologic toxicities in mice”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling in EMT, invasion, and migration
What the sources say
- Not checked yetcites [82] Rankin EB Cancer Res 2010 70 7570 7579 20858715 PMC3408227
- Not checked yetcites [89] Kariolis MS Nat. Chem. Biol 2014 10 977 983 25242553 PMC4372605
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Given that LOX also promotes tumor cell proliferation, invasion, and angiogenesis, LOX is an attractive therapeutic target for cancer therapy (97).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and the premetastatic niche
What the sources say
- Not checked yetcites [97] Cox TR Gartland A Erler JT Cancer Res 2016 76 188 192 26732355
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“IL-6 secretion by the tumor activates signal transducer and activator of transcription 3 (STAT3) signaling in LECs localized within the lymph node and lung to promote (i) CCL5-mediated recruitment of CCR5-positive breast cancer cells into the lymphatic system and (ii) VEGF-mediated lung vascular permeability and lymph node angiogenesis (98).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and the premetastatic niche
What the sources say
- Not checked yetcites [98] Lee E Nat. Commun 2014 5 4715 25178650 PMC4351998 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Moreover, tumor-derived exosomes preferentially localize to sites of metastasis, including liver, lung, and bone marrow, where they promote vascular permeability and increase BMDC recruitment (101–104).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and the premetastatic niche
What the sources say
- Not checked yetcites [101] Peinado H Nat. Med 2012 18 883 891 22635005 PMC3645291 source
- Not checked yetcites [102] Costa-Silva B Nat. Cell Biol 2015 17 816 826 25985394 PMC5769922 source
- Not checked yetcites [103] Hoshino A Nature 2015 527 329 335 26524530 PMC4788391 source
- Not checked yetcites [104] Umezu T Blood 2014 124 3748 3757 25320245 PMC4263983 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Because oxygen is an essential electron acceptor for oxidative metabolism, hepatocytes that perform glucose or fatty acid oxidation are located in the aerobic periportal zone, whereas oxygen-independent metabolic functions such as glucose uptake, glycolysis, and fatty acid synthesis are predominantly performed by perivenous hepatocytes (108).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and cellular growth and survival at the distant site
What the sources say
- Not checked yetcites [108] Jungermann K Semin. Liver Dis 1988 8 329 341 3062788
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“The partial pressure of oxygen in periportal blood is 60 to 65 mm Hg and in the perivenous blood it is 30 to 35 mm Hg (107).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and cellular growth and survival at the distant site
What the sources say
- Not checked yetcites [107] Jungermann K Kietzmann T Hepatology 2000 31 255 260 10655244
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“VEGF-A is a proangiogenic factor produced by tumor cells that stimulates the recruitment and proliferation of endothelial cells, as well as promoting pericyte proliferation and migration (113).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and cellular growth and survival at the distant site
What the sources say
- Not checked yetcites [113] Joyce JA Pollard JW Nat. Rev. Cancer 2009 9 239 252 19279573 PMC3251309 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“suggesting that hepatic hypoxia is a barrier for colon cancer cells early in metastatic dissemination and that cells overcome this metabolic stress by generating ATP from phosphocreatine reserves (Fig. 3) (109).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and cellular growth and survival at the distant site
What the sources say
- Not checked yetcites [109] Loo JM Cell 2015 160 393 406 25601461 PMC4312495 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“VEGF-A is a well-established HIF target, and its expression is induced by HIF signaling in both primary tumors and metastases (114).”
§ Hypoxic control of metastasis > Mechanisms of HIF-mediated metastasis > HIF signaling and cellular growth and survival at the distant site
What the sources say
- Not checked yetcites [114] Maxwell PH Proc. Natl. Acad. Sci. U.S.A 1997 94 8104 8109 9223322 PMC21564 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Recent work has identified the receptor tyrosine kinase, AXL, as a critical mediator of HIF-dependent invasion and metastasis, as well as a potential therapeutic target for the prevention and treatment of metastatic disease.”
§ Hypoxic control of metastasis > Conclusions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In summary, recent studies have begun to highlight the diverse mechanisms by which hypoxia and HIF-dependent signaling promote metastatic tumor progression.”
§ Hypoxic control of metastasis > Conclusions
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✗ Based: failsProbably not a substantial claim. The paper may give no reason why it holds.
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?
In the citing paper
“Hypoxia plays an important role in triggering EMT by regulating HIFs.”
From Hypoxia signaling in cancer: Implications for therapeutic interventions (2023) · cites this paper as [82]
In the citing paper
“Hypoxia is a hallmark of most solid tumors and a common trait of TME that is associated with cancer progression and metastasis8–10.”
In the citing paper
“Hypoxia plays a crucial role in tumor growth, metastasis, and drug resistance in solid tumors8,9”
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.
Glycolytic liver zone identified inconsistently
MinorThe paper first places glycolysis predominantly in perivenous hepatocytes, but later attributes the liver's glycolytic phenotype to periportal regions.
“Consistent with the concept that hepatic hypoxia and the associated glycolytic phenotype in periportal regions of the liver provide a barrier for metastatic colonization”
“oxygen-independent metabolic functions such as glucose uptake, glycolysis, and fatty acid synthesis are predominantly performed by perivenous hepatocytes (108).”
Citations
Cites
3 retracted
Lysyl oxidase is essential for hypoxia-induced metastasis
Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., Chi, J.-T. A., Jeffrey, S. S., & Giaccia, A. J. (2006) · Nature · doi:10.1038/nature04695 · Cited by 1,309
Self-citationRetractedCox, T. R., Rumney, R. M. H., Schoof, E. M., Perryman, L., Høye, A. M., Agrawal, A., Bird, D., Latif, N. A., Forrest, H., Evans, H. R., et al. (2015) · Nature · doi:10.1038/nature14492 · Cited by 482
RetractedZhang, H., Wong, C. C. L., Wei, H., Gilkes, D. M., Korangath, P., Chaturvedi, P., Schito, L., Chen, J., Krishnamachary, B., Winnard, P. T., et al. (2012) · Oncogene · doi:10.1038/onc.2011.365 · Cited by 326
RetractedMolecular Mechanisms of Stress-Responsive Changes in Collagen and Elastin Networks in Skin
Aziz, J., Shezali, H., Radzi, Z., Yahya, N. A., Abu Kassim, N. H., Czernuszka, J., & Rahman, M. T. (2016) · Skin Pharmacology and Physiology · doi:10.1159/000447017 · Cited by 7,323
Wang, G. L., Jiang, B. H., Rue, E. A., & Semenza, G. L. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.12.5510 · Cited by 6,212
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The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis
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HIFα Targeted for VHL-Mediated Destruction by Proline Hydroxylation: Implications for O 2 Sensing
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Melanoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET
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Du, J., Sun, J., Liu, X., Wu, Q., Shen, W., Gao, Y., Liu, Y., & Wu, C. (2022) · European Journal of Pharmaceutical Sciences · doi:10.1016/j.ejps.2022.106338 · Cited by 36
In-Cell NAD(P)H Photocatalysis with a Metal Complex for Photocatalytic Anticancer Therapy
Li, W., Dao, A., Yuan, G., Zhang, P., & Huang, H. (2025) · Accounts of Chemical Research · doi:10.1021/acs.accounts.5c00455 · Cited by 36
Hypoxia-Induced Fibroblast Growth Factor 11 Stimulates Osteoclast-Mediated Resorption of Bone
Knowles, H. J. (2017) · Calcified Tissue International · doi:10.1007/s00223-016-0228-1 · Cited by 36
CHCHD4 Regulates Intracellular Oxygenation and Perinuclear Distribution of Mitochondria
Thomas, L. W., Staples, O. D., Turmaine, M., & Ashcroft, M. A. (2017) · Frontiers in Oncology · doi:10.3389/fonc.2017.00071 · Cited by 40
APD-Containing Cyclolipodepsipeptides Target Mitochondrial Function in Hypoxic Cancer Cells
Jacobsen, K. M., Villadsen, N. L., Tørring, T., Nielsen, C. B., Salomón, T., Nielsen, M. M., Tsakos, M., Sibbersen, C., Scavenius, C., Nielsen, R., et al. (2018) · Cell chemical biology · doi:10.1016/j.chembiol.2018.07.010 · Cited by 36
Therapeutic Options for Metastatic Breast Cancer
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Qian, X., Zhang, Q., Shao, N., Shan, Z., Cheang, T., Zhang, Z., Su, Q., Wang, S., & Lin, Y. (2019) · Europe PMC (PubMed Central) · Cited by 36
Magnetic beads-based electrochemical immunosensing of HIF-1α, a biomarker of tumoral hypoxia
Martín, C. M., Gamella, M., Pedrero, M., Montero‐Calle, A., Barderas, R., Campuzano, S., & Pingarrón, J. M. (2019) · Sensors and Actuators B Chemical · doi:10.1016/j.snb.2019.127623 · Cited by 36
Wang, M., Zhou, B., Wang, L., Zhou, F., Smith, N., Saunders, D., Towner, R. A., Song, J., Qu, J., & Chen, W. R. (2020) · Journal of Materials Chemistry B · doi:10.1039/d0tb01453b · Cited by 36
Huang, B., Zhou, Z., Liu, J., Wu, X., Li, X., He, Q., Zhang, P., & Tang, X. (2020) · International Journal of Biological Sciences · doi:10.7150/ijbs.46966 · Cited by 36
“However, under hypoxic conditions, PHD activity is inhibited, resulting in the stabilization and translocation of HIF-1α to the nucleus [34].”
BackgroundZhang, P., Zhang, L., Wang, J., Zhu, L., Li, Z., Chen, H., & Gao, Y. (2021) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2021.118655 · Cited by 36
Short Review on Advances in Hydrogel-Based Drug Delivery Strategies for Cancer Immunotherapy
Seo, H. S., Wang, C. J., Park, W., & Park, C. G. (2021) · Tissue Engineering and Regenerative Medicine · doi:10.1007/s13770-021-00369-6 · Cited by 38
Hypoxia-induced circRNF13 promotes the progression and glycolysis of pancreatic cancer
Zhao, Q., Zhu, Z., Xiao, W., Zong, G., Wang, C., Jiang, W., Li, K., Shen, J., Guo, X., Cui, J., et al. (2022) · Experimental & Molecular Medicine · doi:10.1038/s12276-022-00877-y · Cited by 37
HIF-1 inhibitor-based one-stone-two-birds strategy for enhanced cancer chemodynamic-immunotherapy
Zhang, X., He, C., He, X., Fan, S., Ding, B., Lu, Y., & Xiang, G. (2023) · Journal of Controlled Release · doi:10.1016/j.jconrel.2023.03.026 · Cited by 35
Ma, J., Fu, G., Wu, J., Han, S., Zhang, L., Yang, M., Yu, Y., Zhang, M., Lin, Y., & Wang, Y. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.281 · Cited by 36
Nanomedicine‐Enabled Modulation of Tumor Hypoxic Microenvironment for Enhanced Cancer Therapy
Wang, J., Zhang, B., Sun, J., Wang, Y., & Wang, H. (2019) · Advanced Therapeutics · doi:10.1002/adtp.201900083 · Cited by 36
Mi, Y., Mu, L., Huang, K., Hu, Y., Yan, C., Zhao, H., Ma, C., Li, X., Tao, D., & Qin, J. (2020) · Cell Death and Disease · doi:10.1038/s41419-020-02797-z · Cited by 38
Circulating tumor cell-derived preclinical models: current status and future perspectives
Kahounová, Z., Pícková, M., Drápela, S., Bouchal, J., Szczyrbová, E., Navrátil, J., & Souček, K. (2023) · Cell Death and Disease · doi:10.1038/s41419-023-06059-6 · Cited by 37
“Hypoxia and HIF signaling are important factors affecting many steps in the metastatic cascade — immune evasion, migration and invasion, establishment of premetastatic niche, or survival of cancer cells in distant sites (summarized in [93]).”
BackgroundCitrullination modulation stabilizes HIF-1α to promote tumour progression
Chen, R., Lin, Z., Shen, S., Zhu, C., Yan, K., Suo, C., Liu, R., Wei, H., Gao, L., Fan, K., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-51882-w · Cited by 40
Wakiyama, K., Kitajima, Y., Tanaka, T., Kaneki, M., Yanagihara, K., Aishima, S., Nakamura, J., & Noshirο, H. (2017) · Scientific Reports · doi:10.1038/s41598-017-12929-9 · Cited by 33
Gastric Leptin and Tumorigenesis: Beyond Obesity
Inagaki‐Ohara, K. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112622 · Cited by 34
Immune‐mediated ECM depletion improves tumour perfusion and payload delivery
Yeow, Y. L., Kotamraju, V. R., Wang, X., Chopra, M., Azme, N., Wu, J., Schoep, T. D., Delaney, D. S., Feindel, K. W., Li, J., et al. (2019) · EMBO Molecular Medicine · doi:10.15252/emmm.201910923 · Cited by 35
“Appendix Fig S4A shows that TNFa-CSG-treated 4T1 tumours were less hypoxic especially in areas containing wider blood vessels, which reduces the likelihood of hypoxia-driven metastatic dissemination (Rankin & Giaccia, 2016).”
BackgroundGan, L., Camarena, V., Mustafi, S., & Wang, G. (2019) · Nutrients · doi:10.3390/nu11122997 · Cited by 34
“Hypoxia-inducible factor 1α (HIF-1α) is the master regulator of cancer cell metastasis [1].”
BackgroundGreville, G., Llop, E., Huang, C., Creagh-Flynn, J., Pfister, S., O’Flaherty, R., Madden, S. F., Peracaula, R., Rudd, P. M., McCann, A. H., et al. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01218 · Cited by 35
“It is also accepted that activation of HIF signaling, influences numerous steps in the metastatic cascade, including invasion, migration, extravasation and intravasation (25).”
BackgroundInnovative strategies of hydrogen peroxide-involving tumor therapeutics
Zhang, Y., Zhang, J., Jia, Q., Ge, J., & Wang, P. (2021) · Materials Chemistry Frontiers · doi:10.1039/d1qm00134e · Cited by 34
Zhang, F., Wang, X., Bai, Y., Hu, H., Yang, Y., Wang, J., Tang, Y., Ma, H., Feng, D., Li, D., et al. (2021) · Frontiers in Genetics · doi:10.3389/fgene.2021.670384 · Cited by 34
“Hypoxia and hypoxiainducible factors could regulate the expression of multiple genes in tumor cells and influence functions of tumor cells, such as proliferation, angiogenesis, invasion, metastasis, and immune invasion (Gilkes et al., 2014; Rankin and Giaccia, 2016; Lin et al., 2020; Liu et al., 2020; Mo et al., 2020).”
BackgroundlncRNA DLEU2 promotes gastric cancer progression through ETS2 via targeting miR-30a-5p
Han, S., Qi, Y., Xu, Y., Wang, M., Wang, J., Wang, J., Yuan, M., Jia, Y., Ma, X., Wang, Y., et al. (2021) · Cancer Cell International · doi:10.1186/s12935-021-02074-9 · Cited by 34
“HIF1 is the core component of hypoxia signaling pathway(52).”
BackgroundAcetyl-CoA Synthetase 2 as a Therapeutic Target in Tumor Metabolism
Liu, M., Liu, N., Wang, J., Fu, S., Wang, X., & Chen, D. (2022) · Cancers · doi:10.3390/cancers14122896 · Cited by 39
Glycobiology Modifications in Intratumoral Hypoxia: The Breathless Side of Glycans Interaction
Filho, A. F. D. S., de Sena, W. L. B., de Lima, L. R. A., Carvalho, L. V. D. N., Pereira, M. C., Santos, L. G. S., Santos, R. V. C., Tavares, L. B., Pitta, M. G. D. R., & Rêgo, M. J. B. D. M. (2017) · Cellular Physiology and Biochemistry · doi:10.1159/000471912 · Cited by 35
Lyu, F., Li, Y., Yan, Z., He, Q., Cheng, L., Zhang, P., Liu, B., Liu, C., Song, Y., Xing, Y., et al. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03398-4 · Cited by 33
“This suggests that hypoxia may lead to tumor progression and treatment resistance [8, 9].”
BackgroundTanaka, A., Ogawa, M., Zhou, Y., Namba, K., Hendrickson, R. C., Miele, M. M., Li, Z., Klimstra, D. S., Buckley, P. G., Gulcher, J. R., et al. (2024) · Cell Reports · doi:10.1016/j.celrep.2024.113810 · Cited by 37
Chen, H., Yu, S., Ma, R., Deng, L., Yi, Y., Niu, M., Xu, C. S., & Xiao, Z. J. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01271-z · Cited by 35
Shaikat, A. H., Azad, S. M. A. K., Tamim, M. A. R., Ullah, M. S., Amin, M. N., Sabbir, M. K., Tarun, M. T. I., Mostaq, M. S., Sabrin, S., Mahmud, M. Z., et al. (2025) · Cancer Pathogenesis and Therapy · doi:10.1016/j.cpt.2025.07.003 · Cited by 37
P4HA1: A single-gene surrogate of hypoxia signatures in oral squamous cell carcinoma patients
Kappler, M., Kotrba, J., Kaune, T., Bache, M., Rot, S., Bethmann, D., Wichmann, H., Güttler, A., Bilkenroth, U., Horter, S., et al. (2017) · Clinical and Translational Radiation Oncology · doi:10.1016/j.ctro.2017.05.002 · Cited by 32
He, Y., Cong, C., Li, X., Zhu, R., Li, A., Zhao, S., Li, X., Cheng, X. M., Yang, M., & Gao, D. (2019) · Theranostics · doi:10.7150/thno.33534 · Cited by 33
“of synergistic therapy to eliminate the deep-seated tumor cells inevitably leads to tumor recurrence and metastasis [10].”
BackgroundZheng, X., Cui, L., Chen, M., Soto, L. A. C., Graves, E. E., & Rao, J. (2019) · Cancer Research · doi:10.1158/0008-5472.can-19-0530 · Cited by 33
“Hypoxia is a characteristic feature of most solid tumors and plays a crucial role in their resistance to cancer treatment, especially radiotherapy (RT) (1,2).”
BackgroundMutant p53 induces a hypoxia transcriptional program in gastric and esophageal adenocarcinoma
Sethi, N. S., Kikuchi, O., McFarland, J. M., Zhang, Y., Chung, M., Kafker, N., Islam, M., Lampson, B. L., Chakraborty, A. A., Kaelin, W. G., et al. (2019) · JCI Insight · doi:10.1172/jci.insight.128439 · Cited by 35
“Deregulation of the hypoxia pathway plays an important role in tumor progression (12, 13).”
BackgroundCheng, X., Qiu, J., Wang, S., Yang, Y., Guo, M., Wang, D., Luo, Q., & Xu, L. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2019.08.79 · Cited by 33
“Hypoxia in cancer is a local and tumor-specific microenvironmental change caused by imbalance between increased oxygen demand from rapidly growing tumor cells and relatively insufficient blood supply (7).”
BackgroundInfluentialLyu, C., Lu, G., Bao, W., Li, F., Wang, S., Zhang, F., Gao, X., Kamiya, H., Ma, G., & Wei, W. (2020) · Chemical Engineering Journal · doi:10.1016/j.cej.2020.125453 · Cited by 33
Bad neighbours: hypoxia and genomic instability in prostate cancer
Ashton, J., & Bristow, R. G. (2020) · British Journal of Radiology · doi:10.1259/bjr.20200087 · Cited by 32
A Cyclodextrin‐Hosted Ir(III) Complex for Ratiometric Mapping of Tumor Hypoxia In Vivo
Xiao, P., Liu, C., Ma, T., Lu, X., Jing, L., Hou, Y., Zhang, P., Huang, G., & Gao, M. (2021) · Advanced Science · doi:10.1002/advs.202004044 · Cited by 33
Effects of Hypoxia in Intestinal Tumors on Immune Cell Behavior in the Tumor Microenvironment
Zhang, L., Wang, S., Wang, Y., Zhao, W., Zhang, Y., Zhang, N., & Xu, H. W. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.645320 · Cited by 33
Drug delivery strategies in maximizing anti-angiogenesis and anti-tumor immunity
Lai, V., Neshat, S. Y., Rakoski, A. I., Pitingolo, J., & Doloff, J. C. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113920 · Cited by 33
Bone Metastatic Breast Cancer: Advances in Cell Signaling and Autophagy Related Mechanisms
Othman, A. H., Winogradzki, M., Lee, L., Tandon, M., Blank, A. T., & Pratap, J. (2021) · Cancers · doi:10.3390/cancers13174310 · Cited by 32
Vitamins as Possible Cancer Biomarkers: Significance and Limitations
Venturelli, S., Leischner, C., Helling, T., Burkard, M., & Marongiu, L. (2021) · Nutrients · doi:10.3390/nu13113914 · Cited by 33
“Vitamin C is also linked to histone demethylation [115,127] and the targeting of the hypoxia inducible factor (HIF) proteins used by cancer to thrive in the oxygen-depleted environment of tumor masses for proteasomal degradation via proline and asparaginyl hydroxylases (HIF hydroxylases, HIFH), which belong to the fam…”
BackgroundRecent Developments in Nanoparticle‐Based Photo‐Immunotherapy for Cancer Treatment
Guo, Z., Zhu, A. T., Fang, R. H., & Zhang, L. (2023) · Small Methods · doi:10.1002/smtd.202300252 · Cited by 34
Zhang, W., Chen, C. Y., Zhou, Z.-H., Gao, S., Tee, T. J., Yang, L., Xu, Y., Pang, T., Xu, X., Sun, Q., et al. (2017) · Journal of Cancer · doi:10.7150/jca.19057 · Cited by 36
VEGF-C-expressing TAMs rewire the metastatic fate of breast cancer cells
Banerjee, K., Kerzel, T., Bekkhus, T., Ferreira, S. D. S., Wallmann, T., Wallerius, M., Landwehr, L., Agardy, D. A., Schauer, N., Malmerfeldt, A., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.113507 · Cited by 33
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“[14] Concomitant metabolic reprogramming generates acidic microenvironments via lactate overproduction, paralyzing cytotoxic T lymphocytes and natural killer (NK) cells.”
Liang, H., Wu, Y., Ou, X., Li, J., & Li, J. (2017) · Nanotechnology · doi:10.1088/1361-6528/aa8d9c · Cited by 32
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HIF-1α Promotes the Metastasis of Esophageal Squamous Cell Carcinoma by Targeting SP1
Hu, X., Lin, J., Jiang, M., He, X., Wang, K., Wang, W., Hu, C., Shen, Z., He, Z., Lin, H., et al. (2019) · Journal of Cancer · doi:10.7150/jca.35537 · Cited by 32
Ge, L., Zhou, F., Nie, J., Wang, X., & Zhao, Q. (2021) · Experimental Biology and Medicine · doi:10.1177/15353702211011576 · Cited by 33
“The hypoxic TME plays master regulatory functions in each step of tumor development, from tumor initiation to the ultimate metastatic colonization, and the processes it regulates include tumor proliferation, apoptosis, migration, invasion, and metastasis.(6,10,11) On one hand, hypoxic tumor cells can educate Impact st…”
BackgroundInfluentialHypoxia in Lung Cancer Management: A Translational Approach
Ancel, J., Perotin, J., Dewolf, M., Launois, C., Mulette, P., Nawrocki‐Raby, B., Dalstein, V., Gilles, C., Deslée, G., Polette, M., et al. (2021) · Cancers · doi:10.3390/cancers13143421 · Cited by 32
Hypoxic Jumbo Spheroids On-A-Chip (HOnAChip): Insights into Treatment Efficacy
Refet-Mollof, E., Najyb, O., Chermat, R., Glory, A., Lafontaine, J., Wong, P., & Gervais, T. (2021) · Cancers · doi:10.3390/cancers13164046 · Cited by 34
Nanotechnological strategies to increase the oxygen content of the tumor
Zhang, J., Tang, K., Fang, R., Liu, J., Liu, M., Ma, J., Wang, H., Ding, M., Wang, X., Song, Y., et al. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1140362 · Cited by 33
Wang, Y., Sun, H., Zhang, D., Fan, D., Zhang, Y., Dong, X., Liu, S., Yang, Z., Ni, C., Li, Y., et al. (2018) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13625 · Cited by 32
Mierke, C. T. (2024) · Biomolecules · doi:10.3390/biom14020184 · Cited by 33
Angiogenesis and EMT regulators in the tumor microenvironment in lung cancer and immunotherapy
Yan, T., & Shi, J. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1509195 · Cited by 33
Yu, H., Du, Y., He, Y., Sun, Y., Li, J., Jia, B., Chen, J., Peng, X., An, T., Li, J., et al. (2025) · Cell Host & Microbe · doi:10.1016/j.chom.2025.06.013 · Cited by 34
Wang, T., Meng, J., Wang, C., Wen, T., Jia, M., Ge, Y., Xie, L., Hao, S., Liu, J., & Xu, H. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00333 · Cited by 32
“e-As4S4 Down-Regulated HIF-1α and CD31 in Tumor Tissue The central area of the solid tumor is generally hypoxic because of the rapid growth of tumor cells (19).”
BackgroundZhang, J. C., Xu, M., Mu, Y., Li, J., Foda, M. F., Zhang, W., Han, K., & Han, H. (2019) · Biomaterials · doi:10.1016/j.biomaterials.2019.119312 · Cited by 31
Qiu, L., Zhao, Q. L., Dai, L.-L., Zhu, A., Xu, X., Zhao, S., & Chen, J. (2020) · Artificial Cells Nanomedicine and Biotechnology · doi:10.1080/21691401.2020.1725026 · Cited by 31
“HIF-1 a , a core regulator of hypoxia response [16], was detected in our study to further examine the functional mechanism of DANCR.”
RetractedZhang, Z., Zhang, S., Chen, H., Mao, Y., Li, Z., Kong, C., Han, B., Zhang, J., Chen, Y., Xue, W., et al. (2020) · Cell Proliferation · doi:10.1111/cpr.12853 · Cited by 30
Luo, R., Zhang, Z., Han, L., Xue, Z. H., Zhang, K., Liu, F., Feng, F., Xue, J., Liu, W., & Qu, W. (2021) · Biomaterials Science · doi:10.1039/d1bm00284h · Cited by 31
Sun, X., Luo, H., Chenbo, H., Zhang, Y., & Yan, C. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.700062 · Cited by 31
Golgi Phosphoprotein 73: The Driver of Epithelial-Mesenchymal Transition in Cancer
Liu, Y., Hu, X., Liu, S., Zhou, S., Chen, Z., & Jin, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.783860 · Cited by 30
“As a result, cancer cells have to shift to places with high oxygen concentrations to promise cell metabolism and resist cell death, the process of which is named cancer metastasis (5).”
BackgroundHypoxia induces hepatocellular carcinoma metastasis via the HIF-1α/METTL16/lnc-CSMD1-7/RBFOX2 axis
Wang, Y., Yang, Y., Yang, Y., Dang, Y., Guo, Z., Zhuang, Q., Zheng, X., Wang, F., Cheng, N., Liu, X., et al. (2023) · iScience · doi:10.1016/j.isci.2023.108495 · Cited by 30
CARM1 drives triple-negative breast cancer progression by coordinating with HIF1A
Feng, D., Gao, J., Liu, R., Liu, W., Gao, T., Yang, Y., Zhang, D., Yang, T., Yin, X., Yu, H., et al. (2024) · Protein & Cell · doi:10.1093/procel/pwae010 · Cited by 31
“The hypoxia pathway is related to metastasis, metabolism, angiogenesis, and stemness in various cancer types (de Heer et al., 2020; Eales et al., 2016; Rankin and Giaccia, 2016; Vadde et al., 2017).”
BackgroundHypoxic tumor microenvironment: Destroyer of natural killer cell function
Zhang, Y., Guo, F., & Wang, Y. (2024) · Chinese Journal of Cancer Research · doi:10.21147/j.issn.1000-9604.2024.02.04 · Cited by 32
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Reversing the Tumor Target: Establishment of a Tumor Trap
Najberg, M., Mansor, M. H., Boury, F., Alvarez‐Lorenzo, C., & Garcion, E. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.00887 · Cited by 36
Zheng, H., Wu, Y., Guo, T., Liu, F., Xu, Y., & Cai, S. (2020) · BioMed Research International · doi:10.1155/2020/5958272 · Cited by 31
Deng, F., Chen, D., Wei, X., Lu, S., Luo, X., He, J., Liu, J., Meng, T., Yang, A., & Chen, H. (2020) · Aging · doi:10.18632/aging.102820 · Cited by 30
“It is well known that O2 concentration is significantly decreased in tumor tissues compared with adjacent normal tissues [10].”
BackgroundTumor Microenvironment – Selective Pressures Boosting Cancer Progression
Nunes, S. C. (2020) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-34025-4_2 · Cited by 33
Raggi, F., & Bosco, M. C. (2020) · Cancers · doi:10.3390/cancers12051337 · Cited by 30
“A hypoxia response element (HRE) [25,78,203] was identified in the human TREM-1 gene promoter [110,111], and the hypoxia-inducible transcription factor (HIF)-1, the master regulator of cell response to hypoxia and an important activator of innate immune cells [204], was shown to be involved in TREM-1 inducibility by h…”
BackgroundChen, D., Xie, S., Wu, Y., Cui, Y., Cai, Y., Lan, L., Yang, H., Chen, J., & Chen, W. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2020.572672 · Cited by 29
Cellular and Molecular Mechanisms of Pristimerin in Cancer Therapy: Recent Advances
Chen, R., Yang, F., Zhang, M., Sun, Z., & Zhang, N. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.671548 · Cited by 29
Dutta, D., Zhou, Q., Mukerabigwi, J. F., Lu, N., & Ge, Z. (2021) · Biomacromolecules · doi:10.1021/acs.biomac.1c01152 · Cited by 30
Nanotechnology and Matrix Metalloproteinases in Cancer Diagnosis and Treatment
González-Ávila, G., Sommer, B., García-Hernández, A. A., Ramos, C., & Flores‐Soto, E. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.918789 · Cited by 30
“For instance, solid tumors have zones with a low concentration of O2 due to the increase in tumor cell proliferation and the presence of infiltrated immune cells, along with difficulties in the O2 delivery caused by a disorganized tumor vasculature and slow blood flow (Rankin and Giaccia, 2016).”
BackgroundProgress and perspectives of platinum nanozyme in cancer therapy
Wang, X., He, X., Liu, C., Zhao, W., Yuan, X., & Li, R. (2022) · Frontiers in Chemistry · doi:10.3389/fchem.2022.1092747 · Cited by 30
“However, hypoxia and abnormal blood supply play a certain role in promoting tumor growth, promoting tumor invasion and metastasis (Rankin and Giaccia, 2016).”
BackgroundMolecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound
Park, K., Lee, H., Lee, S. H., Lee, D., Lee, T., & Lee, Y. M. (2016) · Oncotarget · doi:10.18632/oncotarget.13955 · Cited by 33
Travelling under pressure - hypoxia and shear stress in the metastatic journey
Ildız, E. S., Gvozdenovic, A., Kovacs, W. J., & Aceto, N. (2023) · Clinical & Experimental Metastasis · doi:10.1007/s10585-023-10224-8 · Cited by 31
Szulc, A., & Woźniak, M. (2024) · Cancers · doi:10.3390/cancers16081483 · Cited by 32
“Lysyl oxidase (LOX), matrix metalloproteinases (MMPs), and genes that promote epithelial-mesenchymal transition (EMT) are among the genes whose expression is regulated by hypoxia and HIF at every phase of the metastatic process [136].”
BackgroundHypoxia and aging: molecular mechanisms, diseases, and therapeutic targets
Nisar, A., Khan, S., Li, W., Hu, L., Samarawickrama, P. N., Gold, N. M., Zi, M., Mehmood, S. A., Miao, J., & He, Y. (2024) · MedComm · doi:10.1002/mco2.786 · Cited by 33
“257 234–236 In addition to HIF inhibitors, other strategies for targeting HIF pathways include the use of small molecules, peptides, and gene therapy approaches to modulate HIF activity.”
BackgroundManganese oxide nanomaterials: bridging synthesis and therapeutic innovations for cancer treatment
Balwe, S. G., Moon, D., Hong, M., & Song, J. M. (2024) · Nano Convergence · doi:10.1186/s40580-024-00456-z · Cited by 35
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“Cancer cells within hypoxic tumor regions often instigate EMT, invasion, and metastasis [29].”
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“5,6 However, the underlying mechanisms that reprogram tumor-intrinsic cellular metabolism leading to an increased invasive phenotype in the TME remain elusive.”
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Ferroptosis-related signaling pathways in cancer drug resistance
Yang, Y., Yu, S., Liu, W., Zhuo, Y., Qu, C., & Zeng, Y. (2025) · Cancer Drug Resistance · doi:10.20517/cdr.2024.151 · Cited by 32
The Bidirectional Regulation between MYL5 and HIF-1α Promotes Cervical Carcinoma Metastasis
Zhang, L., Huang, S.-T., Feng, Y.-L., Wan, T., Gu, H.-F., Xu, J., Yuan, L.-J., Zhou, Y., Yu, X.-J., Huang, L., et al. (2017) · Theranostics · doi:10.7150/thno.20796 · Cited by 28
Wang, W., Shen, X., Huang, D.-B., Jia, W. P., Liu, W., & He, Y. (2019) · Cellular Oncology · doi:10.1007/s13402-019-00460-0 · Cited by 28
“Metastasis is a multi-step process, which involves detachment of cancer cells from primary lesions, entry into the circulation system and formation of metastatic lesions at distal sites [1].”
Background
Metadata
- Authors
- Rankin, E. B., & Giaccia, A. J.
- Affiliations
- Stanford Medicine (US)
- Corresponding author
- Giaccia, Amato J.
- Venue
- Science
- Published
- 2016-04-08
- Volume
- 352
- Issue
- 6282
- Pages
- 175-180
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC4898055
- OpenAlex
- W2323751645
- Semantic Scholar
- 7c7208ae7f676afe4b7ee95982fba82e04f585f9
- Cited by
- 1,340
- References
- 116
- Citations by year
- 2026: 98 · 2025: 117 · 2024: 127 · 2023: 119 · 2022: 191 · 2021: 186 · 2020: 160 · 2019: 143 · 2018: 87 · 2017: 85 · 2016: 26
- FWCI
- 47.32
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH (CA-198291, CA-67166, CA-197713)
- Silicon Valley Foundation
- Sydney Frank Foundation
- Kimmelman Fund
- Department of Defense Ovarian Cancer Research Academy (OC140611)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mechanisms of cancer metastasis
- Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
- Keywords
- tumor hypoxia, metastasis, hypoxia-inducible factor, HIF-1, HIF-2, tumor microenvironment, metastatic progression, biomarkers, therapeutic target, cancer therapy
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Animals, Cell Movement, Humans, Neoplasm Invasiveness, Neoplasm Metastasis, Radiation Tolerance, Biomarkers, Tumor, Signal Transduction, Cell Hypoxia, Disease Progression, Drug Resistance, Neoplasm, Basic Helix-Loop-Helix Proteins, Hypoxia-Inducible Factor 1, alpha Subunit, Epithelial-Mesenchymal Transition, Tumor Microenvironment
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