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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BackgroundMultifunctional MnO 2 nanoparticles for tumor microenvironment modulation and cancer therapy
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“DISCUSSION As a typical hallmark of most tumors, especially solid tumors, the hypoxic microenvironment induces adaptive modulation of cancer and stromal cells that promotes cancer development and aggressiveness.(7) A large number of studies have shown that tumor cells release more exosomes in the hypoxic microenvironm…”
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“HIF1α is a key regulator of cancer metastasis.(18) To explore whether HIF1α contributed to SLC7A11mediated HCC metastasis, lentivirus was used to knock down HIF1α expression in Hep3B and Hep3BSLC7A11 cells (Fig.”
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“Previous studies have reported that hypoxia can induce tumor metastasis [13, 14].”
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“Indeed, hypoxia and the expression of HIFs are closely associated with increased drug resistance and distant metastasis, resulting in poor survival of CRC patients [1].”
BackgroundInhibition of intracellular lipolysis promotes human cancer cell adaptation to hypoxia
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Starvation and Pseudo-Starvation as Drivers of Cancer Metastasis through Translation Reprogramming
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“in metastasis including intra- and extravasation (Rankin and Giaccia, 2016; Semenza, 2016), triggers”
BackgroundNanomedicines for Cancer Therapy: Current status, Challenges and Future Prospects
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Hyperthermia can alter tumor physiology and improve chemo- and radio-therapy efficacy
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Hypoxia in solid tumors: a key promoter of cancer stem cell (CSC) resistance
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A Versatile Pt‐Based Core–Shell Nanoplatform as a Nanofactory for Enhanced Tumor Therapy
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Cell softness regulates tumorigenicity and stemness of cancer cells
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“It is known that hypoxia in primary tumors is associated with an increased metastasis and a worse prognosis in patients with cancer (Erler et al , 2006; Gilkes et al , 2014; Rankin & Giaccia, 2016).”
Tumor microenvironment-mediated chemoresistance in breast cancer
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Molecular oxygen as a signaling component in plant development
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“Moreover, several studies pointed at a correlation between metastatic progression and hypoxia (Rankin & Giaccia, 2016).”
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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