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Cited by 535Cancer, Hypoxia, and MetabolismAngiogenesis and VEGF in CancerCancer Cells and Metastasis

The hypoxic tumor microenvironment: A driving force for breast cancer progression

Open access
Semenza, Gregg L.·2016·Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
DOI 10.1016/j.bbamcr.2015.05.036PMC PMC4678039
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Abstract

Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality. Hypoxia-inducible factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate secondary tumors. Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer.

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Written from the paper’s full text.

TL;DR

Intratumoral hypoxia stabilizes hypoxia-inducible factors (HIFs), which activate genes that drive breast cancer vascularization, invasion, metastasis, premetastatic niche formation, and the cancer stem cell phenotype. Preclinical studies suggest that combining cytotoxic chemotherapy with HIF inhibitors may improve outcomes for women with triple-negative breast cancer.

Key findings

  • Intratumoral hypoxia is common in breast cancer: median PO2 was 10 mmHg in breast cancers prior to therapy versus 65 mmHg in normal breast tissue, and intratumoral PO2 < 10 mmHg is associated with decreased disease-free survival. Increased HIF-1α protein is linked to increased risk of metastasis and mortality across lymph node-positive, lymph node-negative, HER2-positive, estrogen receptor-positive, and unselected breast cancer patients.
  • HIFs promote multiple metastatic steps in mouse models: HIF-1α promotes primary tumor growth and vascularization; HIF-dependent PDGF-B supports lymphatic vessel density and lymph node metastasis; conditional HIF-1α knockout in mammary epithelial cells decreased spontaneous lung metastases by ~50%.
  • Hypoxia-induced ECM remodeling is pro-metastatic: P4HA1/P4HA2 knockdown completely eliminated lung metastasis and impaired tissue invasion/intravasation; PLOD2 knockdown decreased fibrillar collagen content and stiffness and reduced lymph node and lung metastasis; LOX/LOXL knockdown inhibited pre-metastatic niche formation and lung metastasis.
  • HIF-1 induces TAZ expression and nuclear localization via WWTR1 and SIAH1/LATS2, increasing ALDH+ and mammosphere-forming breast cancer stem cells; after injection of 1000 cells, tumors formed in 7/7 control mice versus 3/7 TAZ-knockdown, 2/7 HIF-2α-knockdown, and 0/7 HIF-1α-knockdown groups. RAB22A-dependent microvesicles from hypoxic breast cancer cells transfer invasive/metastatic properties to non-hypoxic cells.

Methods

  • Narrative review synthesizing clinical PO2 measurements, immunohistochemical and gene-expression studies of patient biopsies, mouse models (xenograft, orthotopic, MMTV-PyMT, syngeneic 4T1), cell culture experiments, chromatin immunoprecipitation, and TCGA/patient survival analyses.
  • No primary experimental methods or systematic literature-search strategy are described; evidence is drawn from cited preclinical and clinical studies.

Limitations

  • The paper states specific model limitations: Boyden chamber assays have confounding effects of gravity and pore size and cannot perform dynamic or single-cell analysis; direct left-ventricle injection of breast cancer cells does not provide compelling evidence that HIF-1 is required for spontaneous breast-to-bone metastasis; many mechanistic experiments used human MDA-MB-231 cells in immunodeficient mice.
  • Evident from the text: as a narrative review, it lacks a systematic search or formal quality assessment, and many mechanistic conclusions are preclinical and require clinical validation.

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

Integrity signals

Registry

Crossref · 10.1016/j.bbamcr.2015.05.036

Cites

109 of 109 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 164 cited sources checked · 0 supported · 0 flagged

  • Interpretationnone given

    The combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer.

    “Recent preclinical studies suggest that the combination of cytotoxic chemotherapy with drugs that inhibit hypoxia-inducible factors may improve outcome for women with triple-negative breast cancer.”
    Quote in the paperSubstantial claim
  • Premisecitation

    In cervical and head and neck cancers, intratumoral PO2 < 10 mmHg is associated with decreased disease-free survival.

    “in these cancers, multiple studies demonstrated an association between intratumoral PO2 < 10 mmHg and decreased disease-free survival [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Vaupel P Höckel M Mayer A Detection and characterization of tumor hypoxia using pO2 histography Antioxid. Redox Signal 2007 9 1221 1235 17536958 source

      Not checked in the free run.

  • Premisecitation

    Many stromal cells recruited to the primary tumor promote primary tumor growth or metastasis.

    “Many of the stromal cells recruited to the primary tumor promote primary tumor growth or metastasis [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Hanahan D Coussens LM Accessories to the crime: functions of cells recruited to the tumor microenvironment Cancer Cell 2012 21 309 322 22439926 source

      Not checked in the free run.

  • Premisecitation

    Knockdown of HIF-1α, HIF-2α, or both in human MDA-MB-231 breast cancer cells significantly decreased the number of spontaneous lung metastases and total lung metastatic burden in immunodeficient mice after mammary fat pad injection.

    “Knockdown of HIF-1α, HIF-2α, or both in human MDA-MB-231 BCCs significantly decreased the number of spontaneous lung metastases and total lung metastatic burden in immunodeficient mice after mammary fat pad injection [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Zhang H Wong CC Wei H Gilkes DM Korangath P Chaturvedi P Schito L Chen J Krishnamachary B Winnard Jr PT Raman V Zhen L Mitzner WA Sukumar S Semenza GL HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene 2012 31 1757 1770 21860410 PMC3223555 source

      Not checked in the free run.

  • Premisecitation

    Increased expression in primary breast cancers of a panel of 99 or 16 mRNAs encoded by HIF target genes is associated with increased patient mortality.

    “Increased expression in primary breast cancers of a panel of 99 [20] or 16 [21] mRNAs encoded by HIF target genes is also associated with increased patient mortality.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [20] Winter SC Buffa FM Silva P Miller C Valentine HR Turley H Shah KA Cox GJ Corbridge RJ Homer JJ Musgrove B Slevin N Sloan P Price P West CM Harris AL Relation of a hypoxia metagene derived from head and neck cancer to prognosis of multiple cancers Cancer Res 2007 67 3441 3449 17409455 source

      Not checked in the free run.

    • cites [21] Samanta D Gilkes DM Chaturvedi P Xiang L Semenza GL Hypoxia-inducible factors are required for chemotherapy resistance of breast cancer stem cells Proc. Natl. Acad. Sci. U. S. A 2014 111 E5429 E5438 25453096 PMC4273385 source

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  • May combine two claims. 65
  • Classified as probably not a substantial claim. 4

  • May combine two claims.

    Premisecitation

    Intratumoral hypoxia is common in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality.

    “Intratumoral hypoxia is a common finding in breast cancer and is associated with a significantly increased risk of metastasis and patient mortality.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [7] Vaupel P Höckel M Mayer A Detection and characterization of tumor hypoxia using pO2 histography Antioxid. Redox Signal 2007 9 1221 1235 17536958

      Not checked in the free run.

    • cites [14] Dales JP Garcia S Meunier-Carpentier S Andrac-Meyer L Haddad O Lavaut MN Allasia C Bonnier P Charpin C Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: retrospective study in a series of 745 patients Int. J. Cancer 2005 116 734 739 15849727

      Not checked in the free run.

    • cites [15] Schindl M Schoppmann SF Samonigg H Hausmaninger H Kwasny W Gnant M R. associated with an unfavorable prognosis in lymph node-positive breast cancer Clin. Cancer Res 2002 8 1831 1837 12060624

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Hypoxia-inducible factors activate transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype required to generate secondary Tum

    “Hypoxia-inducible factors activate the transcription of a large battery of genes encoding proteins that promote primary tumor vascularization and growth, stromal cell recruitment, extracellular matrix remodeling, premetastatic niche formation, cell motility, local tissue invasion, extravasation at sites of metastasis, and maintenance of the cancer stem cell phenotype that is required to generate”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The median PO2 in normal breast tissue is 65 mmHg, whereas the median PO2 in breast cancers prior to therapy is 10 mmHg.

    “Groundbreaking clinical studies, in which PO2 measurements of breast cancers were obtained in situ by use of Eppendorf microelectrodes, revealed a median of 65 mmHg (with all measurements > 10 mmHg) in normal breast tissue; in contrast, a meta-analysis of 10 studies involving over 200 patients revealed that the median PO2 in breast cancers prior to therapy was 10 mmHg [7].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [7] Vaupel P Höckel M Mayer A Detection and characterization of tumor hypoxia using pO2 histography Antioxid. Redox Signal 2007 9 1221 1235 17536958

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Production of CSF-1 by breast cancer cells stimulates recruitment of macrophages to primary breast tumors, leading to TAM secretion of epidermal growth factor, which stimulates invasion and metastasis.

    “The production of colony stimulating factor 1 (CSF-1; also known as macrophage colony stimulating factor) by BCCs, has been reported to stimulate the recruitment of macrophages to primary breast tumors, leading to the secretion by tumor-associated macrophages (TAMs) of epidermal growth factor, which binds to its cognate receptor on BCCs to stimulate invasion and metastasis [36–38].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [36] Wyckoff J Wang W Lin EY Wang Y Pixley F Stanley ER Graf T Pollard JW Segall J Condeelis J A paracrine loop between tumor cells and macrophages is required for tumor cell migration in mammary tumors Cancer Res 2004 64 7022 7029 15466195

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    • cites [37] Goswami S Sahai E Wyckoff JB Cammer M Cox D Pixley FJ Stanley ER Segall JE Condeelis JS Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop Cancer Res 2005 65 5278 5283 15958574

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    • cites [38] Noy R Pollard JW Tumor-associated macrophages: from mechanisms to therapy Immunity 2014 41 49 61 25035953 PMC4137410 source

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    Premisecitation

    There is no association between HIF-1α and PDGF-B levels in grade 1 breast cancers but an association is observed in grade 2 and grade 3 cancers, suggesting HIF-1α is necessary but not sufficient for PDGFB gene expression during breast cancer progression.

    “Remarkably, immunohistochemistry revealed that there was no association between HIF-1α and PDGF-B levels in biopsies from grade 1 breast cancers but an association was observed in grade 2 and grade 3 cancers, suggesting that HIF-1α was necessary but not sufficient for PDGFB gene expression during breast cancer progression [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Schito L Rey S Tafani M Zhang H Wong CC Russo A Russo MA Semenza GL Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2012 109 E2707 E2716 23012449 PMC3479586 source

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    Premisecitation

    Conditioned medium from breast cancer cells cultured under hypoxia increased migration and proliferation of lymphatic endothelial cells, and these effects were lost when HIF-1α and HIF-2α shRNA was expressed.

    “Conditioned medium, which was collected from BCCs cultured under hypoxic conditions, increased the migration and proliferation of lymphatic ECs, whereas the effects of hypoxia were lost when HIF-1α and HIF-2α shRNA was expressed [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Schito L Rey S Tafani M Zhang H Wong CC Russo A Russo MA Semenza GL Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2012 109 E2707 E2716 23012449 PMC3479586 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In breast cancer, the degree of axillary lymph node involvement predicts distant metastasis, and most women with distant metastases have lymph node involvement.

    “In breast cancer, the most important clinical finding that predicts distant metastasis is the degree of axillary lymph node involvement; conversely, most women with distant metastases have lymph node involvement and it is likely that, at least in some cases, breast cancers access the peripheral circulation via the lymphatic system [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Ran S Volk L Hall K Flister MJ Lymphangiogenesis and lymphatic metastasis in breast cancer Pathophysiology 2010 17 229 251 20036110 PMC2891887

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  • May combine two claims.

    Premisecitation

    Increased HIF-1α protein levels in tumor biopsies are linked with increased risk of metastasis and mortality in lymph node-positive, lymph node-negative, HER2-positive, estrogen receptor-positive, and unselected breast cancer patients.

    “Immunohistochemical studies of tumor biopsies have linked increased HIF-1α protein levels with increased risk of metastasis [14] and mortality in lymph node-positive [15], lymph node-negative [16], HER2-positive [17], estrogen receptor-positive [18], and unselected [14, 19] breast cancer patients.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [14] Dales JP Garcia S Meunier-Carpentier S Andrac-Meyer L Haddad O Lavaut MN Allasia C Bonnier P Charpin C Overexpression of hypoxia-inducible factor HIF-1α predicts early relapse in breast cancer: retrospective study in a series of 745 patients Int. J. Cancer 2005 116 734 739 15849727

      Not checked in the free run.

    • cites [15] Schindl M Schoppmann SF Samonigg H Hausmaninger H Kwasny W Gnant M R. associated with an unfavorable prognosis in lymph node-positive breast cancer Clin. Cancer Res 2002 8 1831 1837 12060624

      Not checked in the free run.

    • cites [16] Bos R van der Groep P Greijer AE Shvarts A Meijer S Pinedo HM Semenza GL van Diest PJ van der Wall E Levels of hypoxia-inducible factor-1α independently predict prognosis in patients with lymph node negative breast carcinoma Cancer 2003 97 1573 1581 12627523 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In an orthotopic mouse model, shRNA inhibition of HIF-1α, HIF-2α, or both decreased lymphatic vessel density in the primary tumor and decreased metastasis to the ipsilateral axillary lymph node.

    “expression of short hairpin RNA (shRNA) to inhibit HIF-1α, HIF-2α, or both led to decreased lymphatic vessel density in the primary tumor and decreased metastasis to the ipsilateral axillary lymph node [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Schito L Rey S Tafani M Zhang H Wong CC Russo A Russo MA Semenza GL Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2012 109 E2707 E2716 23012449 PMC3479586 source

      Not checked in the free run.

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    Premisecitation

    MSCs express CXCL10, which binds CXCR3 on breast cancer cells, and breast cancer cells produce CXCL16, which binds CXCR6 on MSCs and promotes their recruitment to the primary tumor.

    “MSCs express the chemokine CXCL10, which binds to its cognate receptor CXCR3 on BCCs, and BCCs produce the chemokine CXCL16, which binds to its cognate receptor CXCR6 on MSCs and promotes their recruitment to the primary tumor [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chaturvedi P Gilkes DM Takano N Semenza GL Hypoxia-inducible factor- dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment Proc. Natl. Acad. Sci. U. S. A 2014 111 E2120 E2129 24799675 PMC4034192 source

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  • May combine two claims.

    Premisecitation

    Hypoxia induces HIF-dependent expression of placental growth factor by breast cancer cells, which binds VEGF receptor 1 on MSCs and promotes their recruitment to primary breast tumors.

    “Hypoxia induces the HIF-dependent expression of placental growth factor (PGF) by BCCs, which binds to VEGF receptor 1 on MSCs and promotes their recruitment to primary breast tumors [40].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [40] Chaturvedi P Gilkes DM Wong CC Kshitiz Luo W Zhang H Wei H Takano N Schito L Levchenko A Semenza GL Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis J. Clin. Invest 2013 123 189 205 23318994 PMC3533298

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    Premisecitation

    Three general processes have major effects on cancer initiation and progression: somatic mutations, epigenetic alterations, and alterations in the tumor microenvironment.

    “Three general processes have major effects on cancer initiation and progression. First, discrete somatic mutations lead to tumor suppressor loss-of-function and oncoprotein gain-of-function [1]; second, epigenetic alterations change patterns of gene expression [2]; and third, alterations in the tumor microenvironment also lead to broad changes in gene expression [3].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Vogelstein B Papadopoulos N Velculescu VE Zhou S Diaz LA Jr Kinzler KW Cancer genome landscapes Science 2013 339 1546 1558 23539594 PMC3749880 source

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    • cites [2] Baylin SB Jones PA A decade of exploring the cancer epigenome - biological and translational implications Nat. Rev. Cancer 2011 11 726 734 21941284 PMC3307543 source

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    • cites [3] Bissell MJ Hines WC Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression Nat. Med 2011 17 320 329 21383745 PMC3569482

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

    Premisecitation

    Over 1500 HIF target genes have been identified, and in any given cell several hundred of these increase transcription significantly in response to hypoxia.

    “Over 1500 HIF target genes have been identified thus far, although in any given cell, transcription of several hundred of these will increase significantly in response to hypoxia [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Semenza GL Hypoxia-inducible factor 1 and cardiovascular disease Annu. Rev. Physiol 2014 76 39 56 23988176 PMC4696033

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  • May combine two claims.

    Premisecitation

    Changes in the tumor microenvironment are less easily assayed but have profound effects on cancer progression.

    “In contrast, changes in the tumor microenvironment are less easily assayed but have profound effects on cancer progression.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Bissell MJ Hines WC Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression Nat. Med 2011 17 320 329 21383745 PMC3569482

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  • May combine two claims.

    Premisecitation

    Bone metastases formed after injection of MDA-MB-231 cells contained hypoxic regions, and exposure of spleen cells to hypoxia in vitro inhibited osteoblast differentiation and stimulated osteoclast differentiation.

    “The bone metastases that formed after injection of MDA-MB-231 cells contained hypoxic regions and exposure of spleen cells to hypoxia in vitro inhibited osteoblast differentiation and stimulated osteoclast differentiation [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Hiraga T Kizaka-Kondoh S Hirota K Hiraoka M Yoneda T Hypoxia and hypoxia-inducible factor 1 expression enhance osteolytic bone metastases of breast cancer Cancer Res 2007 67 4157 4163 17483326 source

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    Premisecitation

    HIF-1α knockdown by shRNA reduced the radiographic area of osteolytic lesions, decreased vessel density in bone metastases, and increased survival time after injection of breast cancer cells.

    “HIF-1α knockdown by shRNA also reduced the radiographic area of osteolytic lesions, decreased vessel density in bone metastases, and increased survival time after injection of BCCs [33].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [33] Dunn LK Mohammed KS Fournier PG McKenna CR Davis HW Niewolna M Peng XH Chirgwin JM Guise TA Hypoxia and TGF-β drive breast cancer metastases through parallel signaling pathways in tumor cells and the bone microenvironment PLoS One 2009 4 e6896 19727403 PMC2731927

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  • May combine two claims.

    Premisecitation

    HIF-1 activates transcription of the VEGF gene, and HIF-1α levels in breast cancers are associated with VEGF expression and microvessel density even in ductal carcinoma in situ.

    “HIF-1 activates transcription of the VEGF gene encoding vascular endothelial growth factor [26] and HIF-1α levels in breast cancers are associated with VEGF expression and with microvessel density, even in ductal carcinoma in situ, the pre-invasive stage of breast cancer pathogenesis [27].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [26] Forsythe JA Jiang BH Iyer NV Agani F Leung SW Koos RD Semenza GL Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1 Mol. Cell. Biol 1996 16 4604 4613 8756616 PMC231459 source

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    • cites [27] Bos R Zhong H Hanrahan CF Mommers EC Semenza GL Pinedo HM Abeloff MD Simons JW van Diest PJ van der Wall E Levels of hypoxia-inducible factor-1α during breast carcinogenesis J. Natl. Cancer Inst 2001 93 309 314 11181778

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    Premisecitation

    Conditional knockout of HIF-1α in mammary epithelial cells increased survival of MMTV-PyMT mice and decreased the number of spontaneous lung metastases by approximately 50%.

    “Conditional knockout of HIF-1α in mammary epithelial cells increased survival of MMTV-PyMT mice and decreased the number of spontaneous lung metastases by ~50% [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Liao D Corle C Seagroves TN Johnson RS Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression Cancer Res 2007 67 563 572 17234764

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  • May combine two claims.

    Premisecitation

    HIF-1α promotes tumor xenograft growth and vascularization, and this was also observed in an autochthonous MMTV-PyMT mouse model of breast cancer.

    “Studies in many cancer cell types have established that HIF-1α promotes tumor xenograft growth and vascularization [22–24], which was also observed in an autochthonous model of breast cancer driven by expression of polyoma middle T antigen (PyMT) from the mouse mammary tumor virus (MMTV) promoter [25].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [22] Semenza GL Targeting HIF-1 for cancer therapy Nat. Rev. Cancer 2003 3 721 732 13130303 source

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    • cites [23] Liao D Johnson RS Hypoxia: a key regulator of angiogenesis in cancer Cancer Metastasis Rev 2007 26 281 290 17603752

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    • cites [24] Semenza GL Defining the role of hypoxia-inducible factor 1 in cancer biology Oncogene 2010 29 625 634 19946328 PMC2969168 source

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    • cites [25] Liao D Corle C Seagroves TN Johnson RS Hypoxia-inducible factor-1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression Cancer Res 2007 67 563 572 17234764

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  • May combine two claims.

    Premisecitation

    HIF-dependent expression of PDGF-B is required for the effects of hypoxia on lymphatic endothelial cell migration and proliferation in vitro, and PDGF-B knockdown decreases lymphatic vessel density and lymph node metastasis in vivo.

    “HIF-dependent expression of platelet-derived growth factor B (PDGF-B) was required for, and PDGF-B knockdown eliminated, the effects of hypoxia on lymphatic EC migration and proliferation in vitro; PDGF-B knockdown also decreased lymphatic vessel density and lymph node metastasis in vivo [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Schito L Rey S Tafani M Zhang H Wong CC Russo A Russo MA Semenza GL Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2012 109 E2707 E2716 23012449 PMC3479586 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In mice implanted with MDA-MB-435 breast cancer cells in the mammary fat pad, increased collagen cross-linking was observed in the lungs on day 8, increased CD11b+ bone marrow-derived cells were first detected on day 16, and breast cancer cells were first detected on day 24, demonstrating sequential pre-metastatic niche formation.

    “In mice implanted with MDA-MB-435 BCCs in the mammary fat pad, increased collagen cross-linking was observed in the lungs on day 8, whereas increased CD11b+ bone marrow-derived cells were first detected in the lungs on day 16, and BCCs were first detected in the lungs on day 24, demonstrating the sequential process of pre-metastatic niche formation [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Wong CC Gilkes DM Zhang H Chen J Wei H Chaturvedi P Fraley SJ Wong CM Khoo US Ng IO Wirtz D Semenza GL Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation Proc. Natl. Acad. Sci. U. S. A 2011 108 16369 16374 21911388 PMC3182724

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  • May combine two claims.

    Premisecitation

    Protein tyrosine kinase 6 is a downstream effector of MET that is also encoded by a HIF target gene and promotes breast cancer metastasis.

    “Protein tyrosine kinase 6 (PTK6) is a downstream effector of MET that is also encoded by a HIF target gene and promotes breast cancer metastasis [75].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [75] Regan Anderson TM Peacock DL Daniel AR Hubbard GK Lofgren KA Girard BJ Schörg A Hoogewijs D Wenger RH Seagroves TN Lange CA Breast tumor kinase (Brk/PTK6) is a mediator of hypoxia-associated breast cancer progression Cancer Res 2013 73 5810 5820 23928995 PMC3820501

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    Premisecitation

    Active GTP-bound Rho interacts with and activates Rho-associated coiled-coil-forming kinase, which mediates phosphorylation of myosin light chain, leading to actin-myosin contraction.

    “Active (GTP-bound) Rho interacts with, and activates, Rho-associated coiled-coil-forming kinase (ROCK), which mediates the phosphorylation of myosin light chain (MLC), either directly or indirectly by inactivating myosin phosphatase, leading to actin-myosin contraction [63, 64].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [63] Narumiya S Tanji M Ishizaki T Rho signaling, ROCK, and mDia1, in transformation, metastasis and invasion Cancer Metastasis Rev 2009 28 65 76 19160018

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    • cites [64] Olson MF Sahai E The actin cytoskeleton in cancer cell motility Clin. Exp. Metastasis 2009 26 273 287 18498004

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  • May combine two claims.

    Interpretationcitation

    Hypoxia is sufficient to activate RhoA → ROCK1 → MLC → FAK signaling, which is the basis for breast cancer cell motility.

    “Thus, hypoxia is sufficient to activate RhoA → ROCK1 → MLC → FAK signaling, which is the basis for BCC motility.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hypoxia induced stress fiber formation in control MDA-MB-231 cells, which was markedly impaired in HIF-1α/HIF-2α knockdown cells.

    “Hypoxia induced stress fiber formation in shEV cells, which was markedly impaired in sh1/2α cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Gilkes DM Xiang L Lee SJ Chaturvedi P Hubbi ME Wirtz D Semenza GL Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2014 111 E384 E393 24324133 PMC3903228

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    Interpretationcitation

    The effect of LOX or LOXL knockdown on metastasis is due in part to ECM remodeling of the primary tumor and also to remote ECM remodeling in the lungs.

    “While the effect of LOX or LOXL knockdown on metastasis is due in part to ECM remodeling of the primary tumor, it is also due to remote ECM remodeling in the lungs, as described below.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Hepatocyte growth factor stimulates cell migration by binding to its cognate receptor MET, which is encoded by a HIF target gene.

    “Hepatocyte growth factor (HGF) stimulates cell migration by binding to its cognate receptor MET, which is encoded by a HIF target gene [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Pennacchietti S Michieli P Galluzzo M Mazzone M Giordano S Comoglio PM Hypoxia promotes invasive growth by transcriptional activation of the met protooncogene Cancer Cell 2003 3 347 361 12726861

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    Interpretationcitation

    Recruitment of MSCs facilitates subsequent recruitment of MDSCs and TAMs, with hypoxia stimulating homing of MSCs as well as MDSCs and TAMs to the primary tumor, leading to increased metastasis.

    “Thus, the recruitment of MSCs facilitates the subsequent recruitment of MDSCs and TAMs, with hypoxia stimulating homing of MSCs as well as MDSCs and TAMs to the primary tumor, leading to increased metastasis (Fig. 1).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Collagen deposition and fiber formation, hydroxyproline content, and stiffness were decreased in primary tumors derived from mammary fat pad implantation of P4HA1- or P4HA2-knockdown cells.

    “Collagen deposition and fiber formation, hydroxyproline content, and stiffness were decreased in primary tumors derived from mammary fat pad implantation of P4HA1- or P4HA2-knockdown cells.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Gilkes DM Chaturvedi P Bajpai S Wong CC Wei H Pitcairn S Hubbi ME Wirtz D Semenza GL Collagen prolyl hydroxylases are essential for breast cancer metastasis Cancer Res 2013 73 3285 3296 23539444 PMC3674184

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    LOX produced in the primary tumor modifies collagen in the lungs, which facilitates recruitment of bone marrow-derived cells and in turn facilitates recruitment of metastatic breast cancer cells.

    “In addition to modifying collagen in the primary tumor, LOX produced in the primary tumor modifies collagen in the lungs, which facilitates the recruitment of bone marrow-derived cells, which in turn facilitates the recruitment of metastatic BCCs [59].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Erler JT Bennewith KL Cox TR Lang G Bird D Koong A Le QT Giaccia AJ Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche Cancer Cell 2009 15 35 44 19111879 PMC3050620

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  • May combine two claims.

    Premisecitation

    HIF-1α/HIF-2α double knockdown in 4T1 mouse mammary carcinoma cells inhibited recruitment of TAMs and MDSCs to primary tumors and metastasis of breast cancer cells to lymph nodes and lungs after mammary fat pad injection.

    “HIF-1α/HIF-2α double knockdown in 4T1 cells inhibited the recruitment of TAMs and MDSCs to primary tumors and the metastasis of BCCs to lymph nodes and lungs after mammary fat pad injection [41].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chaturvedi P Gilkes DM Takano N Semenza GL Hypoxia-inducible factor- dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment Proc. Natl. Acad. Sci. U. S. A 2014 111 E2120 E2129 24799675 PMC4034192 source

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  • May combine two claims.

    Premisecitation

    The HIF inhibitors digoxin and acriflavine blocked hypoxia-induced expression of all LOX and LOXL proteins, inhibited pre-metastatic niche formation, and significantly reduced lung metastasis.

    “the HIF inhibitors digoxin and acriflavine blocked hypoxia-induced expression of all LOX and LOXL proteins, inhibited pre-metastatic niche formation, and significantly reduced lung metastasis [60].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [60] Wong CC Zhang H Gilkes DM Chen J Wei H Chaturvedi P Hubbi ME Semenza GL Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis J. Mol. Med 2012 90 803 815 22231744 PMC3437551

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  • May combine two claims.

    Premisecitation

    Hypoxia induced phosphorylation of MLC and FAK in metastatic breast cancer cell lines, which was blocked by treatment with the ROCK inhibitor Y-27632.

    “Hypoxia also induced phosphorylation of MLC and FAK in the metastatic cell lines, which was blocked by treatment with the ROCK inhibitor Y-27632 [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Gilkes DM Xiang L Lee SJ Chaturvedi P Hubbi ME Wirtz D Semenza GL Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2014 111 E384 E393 24324133 PMC3903228

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  • May combine two claims.

    Premisecitation

    Expression of PLOD1 and PLOD2 mRNA and protein were induced by hypoxia in MDA-MB-231 cells, and induction was lost in cells with HIF-1α knockdown, whereas HIF-2α knockdown had no significant effect.

    “Expression of PLOD1 and PLOD2 mRNA and protein were induced by hypoxia in MDA-MB-231 cells and induction was lost in cells with HIF-1α knockdown, whereas HIF-2α knockdown had no significant effect [55].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Gilkes DM Bajpai S Wong CC Chaturvedi P Hubbi ME Wirtz D Semenza GL Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis Mol. Cancer Res 2013 11 456 466 23378577 PMC3656974

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  • May combine two claims.

    Premisecitation

    Treatment of tumor-bearing mice with ethyl-3,4-dihydroxybenzoate, a P4H inhibitor, modestly decreased primary tumor growth but dramatically reduced collagen content in the primary tumor and metastatic burden in the lungs.

    “Treatment of tumor-bearing mice with ethyl-3,4-dihydroxybenzoate, a P4H inhibitor, modestly decreased primary tumor growth but dramatically reduced collagen content in the primary tumor and metastatic burden in the lungs.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Gilkes DM Chaturvedi P Bajpai S Wong CC Wei H Pitcairn S Hubbi ME Wirtz D Semenza GL Collagen prolyl hydroxylases are essential for breast cancer metastasis Cancer Res 2013 73 3285 3296 23539444 PMC3674184

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The effect of hypoxia on motility was lost when cells were plated on a soft substratum, providing a direct connection to ECM remodeling.

    “Remarkably, the effect of hypoxia on motility was lost when cells were plated on a soft substratum [73], thereby providing a direct connection to the ECM remodeling (described in sections 3.2 and 3.3 above), which is also induced by hypoxia (Fig. 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Gilkes DM Xiang L Lee SJ Chaturvedi P Hubbi ME Wirtz D Semenza GL Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2014 111 E384 E393 24324133 PMC3903228

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  • May combine two claims.

    Premisecitation

    Knockdown of P4HA1 or P4HA2 expression significantly impaired primary tumor growth and lymph node metastasis and completely eliminated lung metastasis.

    “Knockdown of P4HA1 or P4HA2 expression significantly impaired primary tumor growth and lymph node metastasis as well as completely eliminating lung metastasis.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Gilkes DM Chaturvedi P Bajpai S Wong CC Wei H Pitcairn S Hubbi ME Wirtz D Semenza GL Collagen prolyl hydroxylases are essential for breast cancer metastasis Cancer Res 2013 73 3285 3296 23539444 PMC3674184

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PLOD2 knockdown had no effect on growth or total collagen content of primary tumors, but decreased fibrillar collagen content and stiffness and dramatically reduced local tissue invasion and metastasis to lymph nodes and lungs.

    “PLOD2 knockdown had no effect on the growth or total collagen content of primary tumors, but decreased fibrillar (crosslinked) collagen content and stiffness of primary tumors, and dramatically reduced local tissue invasion as well as metastasis to lymph nodes and lungs [55].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Gilkes DM Bajpai S Wong CC Chaturvedi P Hubbi ME Wirtz D Semenza GL Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis Mol. Cancer Res 2013 11 456 466 23378577 PMC3656974

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia induced LOX and LOXL4 expression in MDA-MB-231 cells, whereas LOXL2 was induced in MDA-MB-435 breast cancer cells, and LOX/LOXL proteins were not detected in non-metastatic MCF-7 breast cancer cells.

    “Analysis of LOX and LOXL1-4 expression in breast cancer cell lines revealed that hypoxia induced LOX and LOXL4 expression in MDA-MB-231 cells, whereas LOXL2 was induced in MDAMB-435 BCCs [56], and expression of LOX/LOXL proteins was not detected in non-metastatic MCF-7 BCCs [53].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Chambers AF MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res 2009 69 5292 5293 19549886 source

      Not checked in the free run.

    • cites [53] Wong CC Gilkes DM Zhang H Chen J Wei H Chaturvedi P Fraley SJ Wong CM Khoo US Ng IO Wirtz D Semenza GL Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation Proc. Natl. Acad. Sci. U. S. A 2011 108 16369 16374 21911388 PMC3182724

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  • May combine two claims.

    Premisecitation

    CXCL10MSC→CXCR3BCC signaling stimulates CXCL16BCC→CXCR6MSC signaling and vice versa.

    “In addition, CXCL10MSC → CXCR3BCC signaling stimulates CXCL16BCC → CXCR6MSC signaling and vice versa [41], providing a molecular basis for the stimulatory effect of co-culture.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Chaturvedi P Gilkes DM Takano N Semenza GL Hypoxia-inducible factor- dependent signaling between triple-negative breast cancer cells and mesenchymal stem cells promotes macrophage recruitment Proc. Natl. Acad. Sci. U. S. A 2014 111 E2120 E2129 24799675 PMC4034192 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increased expression of P4HA1 and P4HA2 mRNA and protein was induced by exposure of MDA-MB-231 cells to 1% O2, and knockdown of HIF-1α, HIF-2α, or both significantly impaired the induction.

    “Increased expression of P4HA1 and P4HA2 mRNA and protein was induced by exposure of MDA-MB-231 cells to 1% O2 and knockdown of HIF-1α, HIF-2α, or both significantly impaired the induction [54].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Gilkes DM Chaturvedi P Bajpai S Wong CC Wei H Pitcairn S Hubbi ME Wirtz D Semenza GL Collagen prolyl hydroxylases are essential for breast cancer metastasis Cancer Res 2013 73 3285 3296 23539444 PMC3674184

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The clinical results are consistent with a role for HIF-1 in amplifying TAZ target gene expression and other TAZ-independent mechanisms by which HIF-1 promotes breast cancer metastasis.

    “These clinical results are consistent with a role for HIF-1 in amplifying TAZ target gene expression as well as the other (TAZ-independent) molecular mechanisms described in previous sections by which HIF-1 promotes breast cancer metastasis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hypoxia increased the expression of connective tissue growth factor mRNA and increased the binding of TAZ to a region of the CTGF gene promoter containing multiple TAZ/TEAD-binding sites in a HIF-1α-dependent and HIF-2α-independent manner.

    “Hypoxia increased the expression of connective tissue growth factor (CTGF) mRNA and increased the binding of TAZ to a region of the CTGF gene promoter containing multiple TAZ/TEAD-binding sites (but no HIF-1 sites) in a HIF-1α-dependent (and HIF-2α-independent) manner”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Xiang L Gilkes DM Hu H Takano N Luo W Lu H Bullen JW Samanta D Liang H Semenza GL Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype Oncotarget 2014 5 12509 12527 25587023 PMC4350363

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In non-hypoxic breast cancer cells, LATS1 is constitutively expressed at low levels, whereas LATS2 is abundantly expressed.

    “Immunoblot assays revealed constitutive, low-level expression of LATS1, whereas LATS2 was abundantly expressed in non-hypoxic BCCs [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Xiang L Gilkes DM Hu H Takano N Luo W Lu H Bullen JW Samanta D Liang H Semenza GL Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype Oncotarget 2014 5 12509 12527 25587023 PMC4350363

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  • May combine two claims.

    Premisecitation

    TAZ expression is increased in 80% of high-grade breast cancers, which is associated with amplification of the WWTR1 locus encoding TAZ in approximately 10% of breast cancers.

    “TAZ expression is increased in 80% of high-grade breast cancers, which is associated with amplification of the WWTR1 locus encoding TAZ in approximately 10% of breast cancers [80]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Cordenonsi M Zanconato F Azzolin L Forcato M Rosato A Frasson C Inui M Montagner M Parenti AR Poletti A Daidone MG Dupont S Basso G Bicciato S Piccolo S The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells Cell 2011 147 759 772 22078877 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Breast cancer cells secrete angiopoietin-like 4, which binds to receptors on endothelial cells and inhibits endothelial cell-endothelial cell interactions, enabling extravasation.

    “In order for BCCs to migrate between adjacent ECs, they secrete angiopoietin-like 4 (ANGPTL4), which binds to receptors on ECs and inhibits EC-EC interactions [35, 76].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Zhang H Wong CC Wei H Gilkes DM Korangath P Chaturvedi P Schito L Chen J Krishnamachary B Winnard Jr PT Raman V Zhen L Mitzner WA Sukumar S Semenza GL HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene 2012 31 1757 1770 21860410 PMC3223555 source

      Not checked in the free run.

    • cites [76] Padua D Zhang XH Wang Q Nadal C Gerald WL Gomis RR Massagué J TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4 Cell 2008 133 66 77 18394990 PMC2390892

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    HIF-2 may play either a role in CSCs not reflected in ALDH and mammosphere assays or a non-CSC-related role required for early tumor formation, such as promoting vascularization.

    “These results are consistent with the role of TAZ and HIF-1 in promoting the breast CSC phenotype, whereas HIF-2 may play either a role in CSCs that is not reflected in the ALDH and mammosphere assays or a non-CSC-related role that is required for early tumor formation, such as promoting vascularization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hypoxia induces nuclear localization of TAZ in MDA-MB-231 cells, dependent on HIF-1α but not HIF-2α.

    “Analysis of TAZ by immunofluorescence or subcellular fractionation revealed that hypoxia induced the nuclear localization of TAZ in MDA-MB-231 subclones expressing a control shRNA or an shRNA targeting HIF-2α, but not in cells expressing an shRNA targeting HIF-1α [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Xiang L Gilkes DM Hu H Takano N Luo W Lu H Bullen JW Samanta D Liang H Semenza GL Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype Oncotarget 2014 5 12509 12527 25587023 PMC4350363

      Not checked in the free run.

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

    Premisecitation

    In different cancers, extracellular vesicles promote angiogenesis, cancer stem cells, epithelial-mesenchymal transition, or metastasis by effects on a variety of cell types in the tumor microenvironment.

    “In different cancers, extracellular vesicles have been reported to promote angiogenesis, cancer stem cells, epithelial-mesenchymal transition, or metastasis by effects on a variety of cell types in the tumor microenvironment [90].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [90] Azmi AS Bao B Sarkar FH Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review Cancer Metastasis Rev 2013 32 623 642 23709120 PMC3843988

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of ANGPTL4 expression in MDA-MB-231 cells had no effect on primary tumor growth but dramatically impaired hypoxia-induced extravasation after intravenous injection and lung metastasis after mammary fat pad implantation.

    “Knockdown of ANGPTL4 expression in MDA-MB-231 cells had no effect on primary tumor growth but dramatically impaired hypoxia-induced extravasation after intravenous injection and lung metastasis after mammary fat pad implantation [35, 76].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [35] Zhang H Wong CC Wei H Gilkes DM Korangath P Chaturvedi P Schito L Chen J Krishnamachary B Winnard Jr PT Raman V Zhen L Mitzner WA Sukumar S Semenza GL HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene 2012 31 1757 1770 21860410 PMC3223555 source

      Not checked in the free run.

    • cites [76] Padua D Zhang XH Wang Q Nadal C Gerald WL Gomis RR Massagué J TGFβ primes breast tumors for lung metastasis seeding through angiopoietin-like 4 Cell 2008 133 66 77 18394990 PMC2390892

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TAZ interacts with HIF-1α and serves as a co-activator for HIF-1-dependent gene transcription in hypoxic breast cancer cells.

    “Finally, in addition to the role of HIF-1 in mediating increased TAZ activity, TAZ interacts with HIF-1α and serves as a co-activator for HIF-1-dependent gene transcription in hypoxic BCCs [86], indicating that TAZ and HIF amplify the activity of each other.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Bendinelli P Maroni P Matteucci E Luzatti A Perrucchini G Desiderio MA Hypoxia inducible factor-1 is activated by transcriptional co-activator with PDZ-binding motif (TAZ) versus WW domain-containing oxidoreductase (WWOX) in hypoxic microenvironment of bone metastasis from breast cancer Eur. J. Cancer 2013 49 2608 2618 23566416

      Not checked in the free run.

  • May combine two claims.

    Premiseown data

    In mice injected with MDA-MB-231 subclones, tumor formation occurred in 7/7 control, 3/7 TAZ knockdown, 2/7 HIF-2α knockdown, and 0/7 HIF-1α knockdown.

    “Whereas 7 out of 7 mice injected with BCCs expressing the non-targeting control shRNA developed tumors, tumors formed in only 3/7, 2/7, and 0/7 mice injected with cells expressing shRNA targeting TAZ, HIF-2α, or HIF-1α, respectively.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Xiang L Gilkes DM Hu H Takano N Luo W Lu H Bullen JW Samanta D Liang H Semenza GL Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype Oncotarget 2014 5 12509 12527 25587023 PMC4350363

      Not checked in the free run.

    • Rests on an assumption: Tumor formation in immunodeficient mice after injection of breast cancer cells reflects tumor-initiating cell activity.

  • May combine two claims.

    Premisecitation

    The hypoxia-induced increase in ALDH+ and mammosphere-forming CSCs is inhibited by shRNA knockdown of HIF-1α or SIAH1, but not HIF-2α.

    “Hypoxia increased the number of ALDH+ and mammosphere-forming CSCs, which was inhibited by shRNA knockdown of HIF-1α or SIAH1, but not HIF-2α, whereas TAZ knockdown reduced breast CSCs under both hypoxic and non-hypoxic conditions [82].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [82] Xiang L Gilkes DM Hu H Takano N Luo W Lu H Bullen JW Samanta D Liang H Semenza GL Hypoxia-inducible factor 1 mediates TAZ expression and nuclear localization to induce the breast cancer stem cell phenotype Oncotarget 2014 5 12509 12527 25587023 PMC4350363

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In breast cancer stem cells, the co-activator TAZ promotes breast cancer stem cell self-renewal and tumor-initiation capacity.

    “In the case of breast CSCs, the co-activator TAZ (transcriptional activator with PDZ-binding motif) has been shown to promote breast CSC self-renewal and tumor-initiation capacity [80].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [80] Cordenonsi M Zanconato F Azzolin L Forcato M Rosato A Frasson C Inui M Montagner M Parenti AR Poletti A Daidone MG Dupont S Basso G Bicciato S Piccolo S The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells Cell 2011 147 759 772 22078877 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypoxia was first shown to induce the cancer stem cell phenotype in glioma and subsequently in breast cancer, in a HIF-dependent manner.

    “Hypoxia was first shown to induce the CSC phenotype in glioma [77] and, subsequently, in breast cancer [78, 79], in a HIF-dependent manner.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [77] Li Z Bao S Wu Q Wang H Eyler C Sathornsumetee S Shi Q Cao Y Lathia J McLendon RE Hjelmeland AB Rich JN Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells Cancer Cell 2009 15 759 772 PMC2693960 19477429 source

      Not checked in the free run.

    • cites [78] Conley SJ Gheordunescu E Kakarala P Newman B Korkaya H Heath AN Clouthier SG Wicha MS Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia Proc. Natl. Acad. Sci. U. S. A 2012 109 2784 2789 22308314 PMC3286974 source

      Not checked in the free run.

    • cites [79] Schwab LP Peacock DL Majumdar D Ingels JF Jensen LC Smith KD Cushing RC Seagroves TN Hypoxia-inducible factor 1α promotes primary tumor growth and tumorinitiating cell activity in breast cancer Breast Cancer Res 2012 14 R6 22225988 PMC3496121

      Not checked in the free run.

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

    Premisecitation

    RAB27A and RAB27B are implicated in exosome biogenesis in melanoma and HeLa cells.

    “The small GTPases RAB27A and RAB27B have been implicated in exosome biogenesis in melanoma and HeLa cells [91, 92], but the molecular mechanisms regulating extracellular vesicle formation have not been delineated.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [91] Ostrowski M Carmo NB Krumeich S Fanget I Raposo G Savina A Moita CF Schauer K Hume AN Freitas RP Gould B Benaroch P Hacohen N Fukuda M Desnos C Seabra MC Darchen F Amigorena S Moita LF Thery C Rab27a and Rab27b control different steps of the exosome secretion pathway Nat. Cell Biol 2010 12 19 30 19966785

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    • cites [92] Peinado H Alečković M Lavotshkin S Matei I Costa-Silva B Moreno-Bueno G Hergueta-Redondo M Williams C García-Santos G Ghajar C Nitadori-Hoshino A Hoffman C Badal K Garcia BA Callahan MK Yuan J Martins VR Skog J Kaplan RN Brady MS Wolchok JD Chapman PB Kang Y Bromberg J Lyden D Melanaoma exosomes educate bone marrow progenitor cells toward a pro-metastatic phenotype through MET Nat. Med 2012 18 883 891 22635005 PMC3645291

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  • May combine two claims.

    Premisecitation

    Knockdown of L1CAM markedly impaired adherence of breast cancer cells to vascular endothelial cells ex vivo, reduced lung colonization after intravenous injection, and decreased the number of spontaneous lung metastases after mammary fat pad implantation.

    “Knockdown of L1CAM markedly impaired adherence of BCCs to vascular ECs ex vivo, reduced lung colonization after intravenous injection, and decreased the number of spontaneous lung metastases after mammary fat pad implantation [35].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] Zhang H Wong CC Wei H Gilkes DM Korangath P Chaturvedi P Schito L Chen J Krishnamachary B Winnard Jr PT Raman V Zhen L Mitzner WA Sukumar S Semenza GL HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene 2012 31 1757 1770 21860410 PMC3223555 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Breast cancer stem cells are enriched among breast cancer cells that express ALDH and among those that form mammospheres.

    “Breast CSCs are enriched among BCCs that express aldehyde dehydrogenase (ALDH+) and among BCCs that form mammospheres when cultured on ultra-low adherence plates [84, 85].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Ginestier C Hur MH Charafe-Jauffret E Monville F Dutcher J Brown M Jacquemier J Viens P Kleer CG Liu S Schott A Hayes D Birnbaum B Wicha MS Dontu G ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome Cell Stem Cell 2007 1 555 567 18371393 PMC2423808

      Not checked in the free run.

    • cites [85] Ponti D Costa A Zaffaroni N Pratesi G Petrangolini G Coradini D Pilotti S Pierotti MA Daidone MG Isolation and in vitro propagation of tumorigenic breast cancer cells with stem/progenitor cell properties Cancer Res 2005 65 5506 5511 15994920

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    shRNA targeting RAB22A eliminates hypoxia-induced microvesicle formation and hypoxia-induced invasion of breast cancer cells through Matrigel.

    “Immunocytochemistry suggested that RAB22A was a component of the microvesicles that formed in hypoxic cells and expression of shRNA targeting RAB22A eliminated hypoxia-induced microvesicle formation as well as hypoxia-induced invasion of BCCs through Matrigel [100].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Wang T Gilkes DM Takano N Xiang L Luo W Bishop CJ Chaturvedi P Green JJ Semenza GL Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis Proc. Natl. Acad. Sci. U. S. A 2014 111 E3234 E3242 24938788 PMC4128139

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microvesicles collected from hypoxic breast cancer cells and incubated with non-hypoxic cells induce focal adhesion formation and invasion in vitro, as well as lung colonization after intravenous injection.

    “Microvesicles collected from hypoxic BCCs and incubated with non-hypoxic cells induced focal adhesion formation and invasion in vitro, as well as lung colonization after intravenous injection, and this effect was lost in cells expressing shRNA that targeted RAB22A.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Wang T Gilkes DM Takano N Xiang L Luo W Bishop CJ Chaturvedi P Green JJ Semenza GL Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis Proc. Natl. Acad. Sci. U. S. A 2014 111 E3234 E3242 24938788 PMC4128139

      Not checked in the free run.

    • Rests on an assumption: Microvesicle-induced focal adhesion formation and invasion in vitro and lung colonization in mice reflect metastatic potential in human breast cancer.

  • May combine two claims.

    Premisecitation

    RAB22A expression greater than the median is associated with increased overall survival and distant metastasis-free survival in primary breast cancers.

    “Expression of RAB22A was correlated with the expression of HIF target genes in primary breast cancers and RAB22A expression greater than the median was associated with increased overall survival and distant metastasis-free survival.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Wang T Gilkes DM Takano N Xiang L Luo W Bishop CJ Chaturvedi P Green JJ Semenza GL Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis Proc. Natl. Acad. Sci. U. S. A 2014 111 E3234 E3242 24938788 PMC4128139

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    JMJD2C encodes a histone demethylase that is recruited by HIF-1 to target genes to further amplify their expression.

    “In addition to HIF target genes encoding proteins that directly participate in metastasis, HIF-1 encodes transcriptional regulatory proteins such as JMJD2C, which is required for breast cancer metastasis and encodes a histone demethylase that is recruited by HIF-1 to target genes to further amplify their expression [102].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [102] Luo W Chang R Zhong J Pandey A Semenza GL Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression Proc. Natl. Acad. Sci. U. S. A 2012 109 E3367 E3376 23129632 PMC3523832

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acriflavine, digoxin, and ganetespib inhibit HIF-1.

    “There are now several drugs (acriflavine, digoxin, and ganetespib) that have been shown to inhibit HIF-1 and shown to block breast cancer primary tumor growth, angiogenesis, pre-metastatic niche formation, and local invasion as well as metastasis to lymph nodes and lungs in orthotopic mouse models [31, 35, 60, 104].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [31] Schito L Rey S Tafani M Zhang H Wong CC Russo A Russo MA Semenza GL Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2012 109 E2707 E2716 23012449 PMC3479586 source

      Not checked in the free run.

    • cites [35] Zhang H Wong CC Wei H Gilkes DM Korangath P Chaturvedi P Schito L Chen J Krishnamachary B Winnard Jr PT Raman V Zhen L Mitzner WA Sukumar S Semenza GL HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene 2012 31 1757 1770 21860410 PMC3223555 source

      Not checked in the free run.

    • cites [60] Wong CC Zhang H Gilkes DM Chen J Wei H Chaturvedi P Hubbi ME Semenza GL Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis J. Mol. Med 2012 90 803 815 22231744 PMC3437551

      Not checked in the free run.

    • cites [104] Xiang L Gilkes DM Chaturvedi P Luo W Hu H Takano N Liang H Semenza GL Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer J. Mol. Med 2014 92 151 164 24248265 PMC3946681

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acriflavine, digoxin, and ganetespib block breast cancer primary tumor growth, angiogenesis, pre-metastatic niche formation, local invasion, and metastasis to lymph nodes and lungs in orthotopic mouse models.

    “There are now several drugs (acriflavine, digoxin, and ganetespib) that have been shown to inhibit HIF-1 and shown to block breast cancer primary tumor growth, angiogenesis, pre-metastatic niche formation, and local invasion as well as metastasis to lymph nodes and lungs in orthotopic mouse models [31, 35, 60, 104].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [31] Schito L Rey S Tafani M Zhang H Wong CC Russo A Russo MA Semenza GL Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells Proc. Natl. Acad. Sci. U. S. A 2012 109 E2707 E2716 23012449 PMC3479586 source

      Not checked in the free run.

    • cites [35] Zhang H Wong CC Wei H Gilkes DM Korangath P Chaturvedi P Schito L Chen J Krishnamachary B Winnard Jr PT Raman V Zhen L Mitzner WA Sukumar S Semenza GL HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs Oncogene 2012 31 1757 1770 21860410 PMC3223555 source

      Not checked in the free run.

    • cites [60] Wong CC Zhang H Gilkes DM Chen J Wei H Chaturvedi P Hubbi ME Semenza GL Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis J. Mol. Med 2012 90 803 815 22231744 PMC3437551

      Not checked in the free run.

    • cites [104] Xiang L Gilkes DM Chaturvedi P Luo W Hu H Takano N Liang H Semenza GL Ganetespib blocks HIF-1 activity and inhibits tumor growth, vascularization, stem cell maintenance, invasion, and metastasis in orthotopic mouse models of triple-negative breast cancer J. Mol. Med 2014 92 151 164 24248265 PMC3946681

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Triple-negative breast cancers have a wide diversity of somatic mutations, none of which are found at high frequency.

    “Analysis of hundreds of triple-negative breast cancers revealed a wide diversity of somatic mutations none of which were found at high frequency [4].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] The Cancer Genome Atlas Network Comprehensive molecular portrait of human breast tumors Nature 2012 490 61 70 23000897 PMC3465532 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Triple-negative breast cancers have greatly increased rates of relapse, metastasis, and death compared to other breast cancer types.

    “Cancers that lack expression of ER, PR, or HER2, which constitute approximately 15% of all breast cancers (30% among African-American women), are designated “triple negative” and, in the absence of any targeted therapy, are treated with cytotoxic chemotherapy, with greatly increased rates of relapse, metastasis, and death compared to the other breast cancer types [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] O'Toole SA Beith JM Millar EK West R McLean A Cazet A Swarbrick A Oakes SR Therapeutic targets in triple negative breast cancer J. Clin. Pathol 2013 66 530 542 23436929

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockdown of RAB22A expression in MDA-MB-231 cells has no effect on primary tumor growth after mammary fat pad injection but significantly reduces the number of metastases from breast to lungs.

    “Knockdown of RAB22A expression in MDA-MB-231 cells had no effect on primary tumor growth after mammary fat pad injection but significantly reduced the number of metastases from breast to lungs [100].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [100] Wang T Gilkes DM Takano N Xiang L Luo W Bishop CJ Chaturvedi P Green JJ Semenza GL Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis Proc. Natl. Acad. Sci. U. S. A 2014 111 E3234 E3242 24938788 PMC4128139

      Not checked in the free run.

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

    Premisecitation

    The MDA-MB-231 cell line was derived from a metastatic triple-negative breast cancer.

    “Many of the studies described in this review were performed with the MDA-MB-231 cell line, which was derived from a metastatic triple-negative breast cancer [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Cailleau R Young R Olivé M Reeves WJ Jr Breast tumor cell lines from pleural effusions J. Natl. Cancer Inst 1978 53 661 674 4412247 PMC7364228

      Not checked in the free run.

68 of 68

  • The paper relies on this without support.

    Somatic mutations are not the cause of RhoA or ROCK1 expression in most breast cancers.

    “Somatic mutations are not the cause of RhoA or ROCK1 expression in most breast cancers, leaving the underlying molecular mechanism undefined.”

  • The paper relies on this without support.

    Only a small percentage of cancer cells within a primary tumor have the capacity to initiate a secondary tumor.

    “Only a small percentage of cancer cells within a primary tumor, designated tumor-initiating cells or cancer stem cells (CSCs), have the capacity to undergo asymmetric divisions in which a CSC divides, yielding one CSC and one cell that has the ability to undergo a limited number of cell divisions that will contribute to the exponential growth of the bulk tumor.”

  • The paper relies on this without support.

    The mechanisms of breast cancer progression observed in MDA-MB-231 cells and mouse models are representative of human breast cancer.

    “Many of the studies described in this review were performed with the MDA-MB-231 cell line, which was derived from a metastatic triple-negative breast cancer [30].”

  • The paper relies on this without support.

    Tumor formation in immunodeficient mice after injection of breast cancer cells reflects tumor-initiating cell activity.

    “To analyze the effect of HIF or TAZ loss-of-function on tumor-initiating cells, 1000 cells of each MDA-MB-231 subclone were injected into the mammary fat pad of immunodeficient female mice, which were scored for the presence of mammary tumors 6 weeks later.”

  • The paper relies on this without support.

    Microvesicle-induced focal adhesion formation and invasion in vitro and lung colonization in mice reflect metastatic potential in human breast cancer.

    “Microvesicles collected from hypoxic BCCs and incubated with non-hypoxic cells induced focal adhesion formation and invasion in vitro, as well as lung colonization after intravenous injection, and this effect was lost in cells expressing shRNA that targeted RAB22A.”

  • The paper relies on this without support.

    MDA-MB-435 is a breast cancer cell line.

    “Microvesicle formation was increased in metastatic MDA-MB-231 and MDA-MB-435 cells as compared to non-metastatic MCF-7 BCCs, whereas hypoxia induced microvesicle formation by two-fold in all three BCC lines, but this effect was lost in subclones expressing shRNAs targeting HIF-1α and HIF-2α [100].”

  • The paper relies on this without support.

    A median expression threshold is a clinically meaningful cutoff for patient survival analyses.

    “Analysis of gene expression and survival data from over 1,000 breast cancer patients revealed that patients with expression of both HIF and TAZ target genes in their primary tumor that was greater than the median had significantly reduced survival compared to patients with low expression of HIF and/or TAZ target genes [82].”
7 of 7

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?

  • Hypoxia and activation of HIF signaling influence multiple steps within the metastatic cascade, including invasion and migration, intravasation and extravasation, establishment of the premetastatic niche, and survival and growth at the distant site.

    “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”

    From Hypoxic control of metastasis (2016) · cites this paper as [49]

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

    “However, constitutive activation of oncogene-driven signaling pathways may also activate hypoxia signaling independently of oxygen supply.”

    From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [18]

  • HIFα stabilization can be a consequence of increased activity of the RAS-MEK-ERK signaling pathway.

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

    From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [18]

  • In hypoxic tumor cells, HIF activates HRE genes essential for migration, invasion, and metastasis (AMF/AMFR, MET, CXCR4, MMP2/9, LOX, P4HA).

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

    From Hypoxia Signaling in Cancer: From Basics to Clinical Practice (2021) · cites this paper as [18]

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.

  • HIF knockdown is reported to both increase and abolish hypoxia-induced motility

    Minor

    The first statement says hypoxia significantly increased motility in HIF-1α/HIF-2α-knockdown cells but not in control cells. The later statement says the hypoxia-induced motility increase was lost with the same knockdown.

1 of 1

Cites

7 retracted

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Related

Authors
Semenza, G. L.
Affiliations
Johns Hopkins University (US)
Corresponding author
Semenza, Gregg L.
ORCID
Semenza, Gregg L.
Venue
Biochimica et Biophysica Acta (BBA) - Molecular Cell Research
Publisher
Elsevier BV
Published
2016-03
Volume
1863
Issue
3
Pages
382-391
ISSN
0167-4889 (ISSN-L)
DOI
10.1016/j.bbamcr.2015.05.036
PMC
PMC4678039
OpenAlex
W576850159
Semantic Scholar
be57ab7027935f476d39130da061a6a5632dc606
Cited by
535
References
109
Citations by year
2026: 21 · 2025: 39 · 2024: 23 · 2023: 51 · 2022: 49 · 2021: 64 · 2020: 73 · 2019: 55 · 2018: 62 · 2017: 47 · 2016: 38 · 2015: 13
FWCI
5.18
Type
journal article
Language
en
Open access
Licence
Locations
  • Biochimica et Biophysica Acta (BBA) - Molecular Cell Research (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • American Cancer Society (122437-RP-12-090-01-COUN)
  • Department of Defense Breast Cancer Research Program (W81XWH-12-1-0464)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
intratumoral hypoxia, tumor microenvironment, breast cancer progression, hypoxia-inducible factor, metastasis, pre-metastatic niche, cancer stem cells, tumor vascularization, extracellular matrix remodeling, triple-negative breast cancer, HIF inhibitors, combination chemotherapy
MeSH terms
Breast Neoplasms, Cell Movement, Female, Humans, Models, Biological, Cell Hypoxia, Disease Progression, Hypoxia-Inducible Factor 1, Tumor Microenvironment

About these checks

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

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

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

Statistics and arithmetic are recomputed, not judged.

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