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PMID: 24827502 Published · ppublish English Review

Hypoxia and the extracellular matrix: drivers of tumour metastasis.

Nature reviews. Cancer ·Vol. 14 ·No. 6 ·2014-00-00 ·Pages 430-9

Gilkes DM, Semenza GL, Wirtz D

Abstract

Of the deaths attributed to cancer, 90% are due to metastasis, and treatments that prevent or cure metastasis remain elusive. Emerging data indicate that hypoxia and the extracellular matrix (ECM) might have crucial roles in metastasis. During tumour evolution, changes in the composition and the overall content of the ECM reflect both its biophysical and biological properties and these strongly influence tumour and stromal cell properties, such as proliferation and motility. Originally thought of as independent contributors to metastatic spread, recent studies have established a direct link between hypoxia and the composition and the organization of the ECM, which suggests a new model in which multiple microenvironmental signals might converge to synergistically influence metastatic outcome.

MeSH Terms
Extracellular Matrix/metabolism,pathology Humans Hypoxia/complications,metabolism Neoplasm Metastasis Neoplasms/etiology,metabolism,pathology
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Gilkes Daniele M
1] Vascular Program, Institute for Cell Engineering, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA.
Semenza Gregg L
1] Vascular Program, Institute for Cell Engineering, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. [2] Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA. [3] Departments of Pediatrics, Oncology, Medicine, Radiation Oncology and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Wirtz Denis
1] Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, Maryland 21218, USA. [2] Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, Maryland 21218, USA. [3] Departments of Oncology and Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
References (199)
199 references, click to expand
  1. Matrix crosslinking forces tumor progression by enhancing integrin signaling.
    Cell. 2009 Nov 25;139(5):891-906 PMID: 19931152
  2. Regulation of PDGF and its receptors in fibrotic diseases.
    Cytokine Growth Factor Rev. 2004 Aug;15(4):255-73 PMID: 15207816
  3. Overexpression of MMP-9 and HIF-1α in Breast Cancer Cells under Hypoxic Conditions.
    J Breast Cancer. 2011 Jun;14(2):88-95 PMID: 21847402
  4. Collagen polymorphism in extracellular matrix of human osteosarcoma.
    J Natl Cancer Inst. 1982 Nov;69(5):1009-16 PMID: 6957647
  5. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.
    Nat Med. 2010 Sep;16(9):1009-17 PMID: 20818376
  6. Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix.
    Mol Cancer Res. 2005 Jan;3(1):1-13 PMID: 15671244
  7. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1.
    Nat Med. 2004 Aug;10(8):858-64 PMID: 15235597
  8. A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodeling.
    J Cell Biol. 1995 Jul;130(1):227-37 PMID: 7790374
  9. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy.
    Trends Pharmacol Sci. 2012 Apr;33(4):207-14 PMID: 22398146
  10. Targeting HIF-1 for cancer therapy.
    Nat Rev Cancer. 2003 Oct;3(10):721-32 PMID: 13130303
  11. Hypoxic induction of Ctgf is directly mediated by Hif-1.
    Am J Physiol Renal Physiol. 2004 Dec;287(6):F1223-32 PMID: 15315937
  12. Modulation of hypoxia-inducible factor 1alpha expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumor angiogenesis and therapeutics.
    Cancer Res. 2000 Mar 15;60(6):1541-5 PMID: 10749120
  13. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1.
    Mol Cell Biol. 1996 Sep;16(9):4604-13 PMID: 8756616
  14. Single cell behavior in metastatic primary mammary tumors correlated with gene expression patterns revealed by molecular profiling.
    Cancer Res. 2002 Nov 1;62(21):6278-88 PMID: 12414658
  15. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis.
    Nature. 1999 May 20;399(6733):271-5 PMID: 10353251
  16. Collagen hydroxylases and the protein disulfide isomerase subunit of prolyl 4-hydroxylases.
    Adv Enzymol Relat Areas Mol Biol. 1998;72:325-98 PMID: 9559057
  17. Global expression profiling identifies signatures of tumor virulence in MMTV-PyMT-transgenic mice: correlation to human disease.
    Cancer Res. 2004 Sep 1;64(17):5973-81 PMID: 15342376
  18. Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-to-mesenchymal transition.
    J Clin Invest. 2007 Dec;117(12):3810-20 PMID: 18037992
  19. Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression.
    Int J Cancer. 1999 Feb 9;80(4):617-23 PMID: 9935166
  20. Loss of PTEN facilitates HIF-1-mediated gene expression.
    Genes Dev. 2000 Feb 15;14(4):391-6 PMID: 10691731
  21. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF-1alpha, HIF-2alpha, and other pathways.
    J Biol Chem. 2006 Jun 2;281(22):15215-26 PMID: 16565084
  22. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-beta expression in rat glomerular mesangial cells.
    J Clin Invest. 1994 Jun;93(6):2431-7 PMID: 8200978
  23. Focal adhesion size uniquely predicts cell migration.
    FASEB J. 2013 Apr;27(4):1351-61 PMID: 23254340
  24. ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix.
    J Cell Biol. 2003 Nov 10;163(3):583-95 PMID: 14610060
  25. The presence of a fibrotic focus in invasive breast carcinoma correlates with the expression of carbonic anhydrase IX and is a marker of hypoxia and poor prognosis.
    Breast Cancer Res Treat. 2003 Sep;81(2):137-47 PMID: 14572156
  26. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices.
    Mol Cell Proteomics. 2012 Apr;11(4):M111.014647 PMID: 22159717
  27. Detection and characterization of tumor hypoxia using pO2 histography.
    Antioxid Redox Signal. 2007 Aug;9(8):1221-35 PMID: 17536958
  28. Dimensional and temporal controls of three-dimensional cell migration by zyxin and binding partners.
    Nat Commun. 2012 Mar 06;3:719 PMID: 22395610
  29. VEGF and bFGF are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia.
    J Pathol. 2002 Feb;196(2):220-7 PMID: 11793374
  30. Alveolar hypoxia increases gene expression of extracellular matrix proteins and platelet-derived growth factor-B in lung parenchyma.
    Am J Respir Crit Care Med. 1998 Dec;158(6):1920-8 PMID: 9847287
  31. In situ force mapping of mammary gland transformation.
    Integr Biol (Camb). 2011 Sep;3(9):910-21 PMID: 21842067
  32. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis.
    J Clin Invest. 2004 Aug;114(3):438-46 PMID: 15286810
  33. Reduced liver fibrosis in hypoxia-inducible factor-1alpha-deficient mice.
    Am J Physiol Gastrointest Liver Physiol. 2009 Mar;296(3):G582-92 PMID: 19136383
  34. HIF-2alpha deletion promotes Kras-driven lung tumor development.
    Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14182-7 PMID: 20660313
  35. The wound healing process: an overview of the cellular and molecular mechanisms.
    J Int Med Res. 2009 Sep-Oct;37(5):1528-42 PMID: 19930861
  36. Breast cancer cell-derived matrix supports vascular morphogenesis.
    Am J Physiol Cell Physiol. 2012 Apr 15;302(8):C1243-56 PMID: 22277754
  37. Tumor hypoxia and malignant progression.
    Methods Enzymol. 2004;381:335-54 PMID: 15063685
  38. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival.
    Proc Natl Acad Sci U S A. 2005 Mar 8;102(10):3738-43 PMID: 15701700
  39. Collagens.
    Cell Tissue Res. 2010 Jan;339(1):247-57 PMID: 19693541
  40. Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumors.
    J Biomed Opt. 2008 Jan-Feb;13(1):014026 PMID: 18315384
  41. Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis.
    Matrix Biol. 2003 Mar;22(1):15-24 PMID: 12714038
  42. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis.
    Cell. 2011 Jul 8;146(1):148-63 PMID: 21729786
  43. Hypoxia-inducible factor 1 is a basic-helix-loop-helix-PAS heterodimer regulated by cellular O2 tension.
    Proc Natl Acad Sci U S A. 1995 Jun 6;92(12):5510-4 PMID: 7539918
  44. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast.
    Clin Cancer Res. 1999 May;5(5):1041-56 PMID: 10353737
  45. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha.
    Blood. 1998 Oct 1;92(7):2260-8 PMID: 9746763
  46. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis.
    Cancer Res. 2013 Mar 15;73(6):1721-32 PMID: 23345161
  47. Identification of PRDX4 and P4HA2 as metastasis-associated proteins in oral cavity squamous cell carcinoma by comparative tissue proteomics of microdissected specimens using iTRAQ technology.
    J Proteome Res. 2011 Nov 4;10(11):4935-47 PMID: 21859152
  48. A molecular signature of metastasis in primary solid tumors.
    Nat Genet. 2003 Jan;33(1):49-54 PMID: 12469122
  49. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis.
    Genes Dev. 1999 Jun 1;13(11):1382-97 PMID: 10364156
  50. HIF-1α in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders.
    J Invest Dermatol. 2011 Sep;131(9):1793-805 PMID: 21633368
  51. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway.
    Mol Cell. 2008 May 23;30(4):393-402 PMID: 18498744
  52. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF-1.
    Blood. 2005 Jan 15;105(2):659-69 PMID: 15374877
  53. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression.
    Nat Rev Cancer. 2011 Dec 15;12(1):9-22 PMID: 22169972
  54. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumor progression.
    Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20302-7 PMID: 18056629
  55. Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer.
    Neoplasia. 2009 Feb;11(2):196-206 PMID: 19177204
  56. Molecular characterization of the tumor microenvironment in breast cancer.
    Cancer Cell. 2004 Jul;6(1):17-32 PMID: 15261139
  57. Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases.
    Carcinogenesis. 2002 May;23(5):769-76 PMID: 12016149
  58. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.
    N Engl J Med. 1986 Dec 25;315(26):1650-9 PMID: 3537791
  59. Fibroblasts in cancer.
    Nat Rev Cancer. 2006 May;6(5):392-401 PMID: 16572188
  60. Chronic liver injury, TGF-beta, and cancer.
    Exp Mol Med. 2001 Dec 31;33(4):179-90 PMID: 11795478
  61. Hypoxia-inducible factor-1 (HIF-1) but not HIF-2 is essential for hypoxic induction of collagen prolyl 4-hydroxylases in primary newborn mouse epiphyseal growth plate chondrocytes.
    J Biol Chem. 2012 Oct 26;287(44):37134-44 PMID: 22930750
  62. Involvement of extracellular matrix constituents in breast cancer.
    Semin Cancer Biol. 1995 Jun;6(3):165-73 PMID: 7495985
  63. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche.
    Cancer Cell. 2009 Jan 6;15(1):35-44 PMID: 19111879
  64. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation.
    Proc Natl Acad Sci U S A. 2011 Sep 27;108(39):16369-74 PMID: 21911388
  65. Collagen family of proteins.
    FASEB J. 1991 Oct;5(13):2814-23 PMID: 1916105
  66. Hypoxia, inflammation, and the tumor microenvironment in metastatic disease.
    Cancer Metastasis Rev. 2010 Jun;29(2):285-93 PMID: 20393783
  67. Hypoxia promotes ligand-independent EGF receptor signaling via hypoxia-inducible factor-mediated upregulation of caveolin-1.
    Proc Natl Acad Sci U S A. 2012 Mar 27;109(13):4892-7 PMID: 22411794
  68. Mammary epithelial-specific disruption of focal adhesion kinase retards tumor formation and metastasis in a transgenic mouse model of human breast cancer.
    Am J Pathol. 2008 Nov;173(5):1551-65 PMID: 18845837
  69. Collagen reorganization at the tumor-stromal interface facilitates local invasion.
    BMC Med. 2006 Dec 26;4(1):38 PMID: 17190588
  70. Inhibition of 2-oxoglutarate dependent oxygenases.
    Chem Soc Rev. 2011 Aug;40(8):4364-97 PMID: 21390379
  71. Stromal gene expression predicts clinical outcome in breast cancer.
    Nat Med. 2008 May;14(5):518-27 PMID: 18438415
  72. Prolyl-4-hydroxylase α subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition.
    BMC Cancer. 2014 Jan 02;14:1 PMID: 24383403
  73. Purification and characterization of hypoxia-inducible factor 1.
    J Biol Chem. 1995 Jan 20;270(3):1230-7 PMID: 7836384
  74. Cell type-specific regulation of angiogenic growth factor gene expression and induction of angiogenesis in nonischemic tissue by a constitutively active form of hypoxia-inducible factor 1.
    Circ Res. 2003 Nov 28;93(11):1074-81 PMID: 14576200
  75. Down-regulation of lysyl oxidase-induced tumorigenic transformation in NRK-49F cells characterized by constitutive activation of ras proto-oncogene.
    J Biol Chem. 2001 Aug 3;276(31):29226-32 PMID: 11323426
  76. Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension.
    Chest. 2005 May;127(5):1793-8 PMID: 15888860
  77. The rationale for targeting the LOX family in cancer.
    Nat Rev Cancer. 2012 Jul 19;12(8):540-52 PMID: 22810810
  78. HIF-1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs.
    Oncogene. 2012 Apr 5;31(14):1757-70 PMID: 21860410
  79. Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway.
    Mol Cell Biochem. 1999 Dec;202(1-2):1-8 PMID: 10705989
  80. Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers.
    Cell Adh Migr. 2012 May-Jun;6(3):249-60 PMID: 22568982
  81. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors.
    Cancer Res. 2007 Mar 15;67(6):2649-56 PMID: 17363585
  82. Hypoxia-inducible factor 1 (HIF-1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts.
    J Biol Chem. 2013 Apr 12;288(15):10819-29 PMID: 23423382
  83. Histology-based expression profiling yields novel prognostic markers in human glioblastoma.
    J Neuropathol Exp Neurol. 2005 Nov;64(11):948-55 PMID: 16254489
  84. Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast.
    Breast Cancer Res. 2003;5(3):130-5 PMID: 12793893
  85. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis.
    J Clin Invest. 2013 Jan;123(1):189-205 PMID: 23318994
  86. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization.
    Biophys J. 2008 Dec;95(11):5374-84 PMID: 18775961
  87. Meta-analysis of cancer gene expression signatures reveals new cancer genes, SAGE tags and tumor associated regions of co-regulation.
    Nucleic Acids Res. 2010 Nov;38(20):7008-21 PMID: 20621981
  88. Collagen cross-linking. Effect of D-penicillamine on cross-linking in vitro.
    J Biol Chem. 1977 Jan 10;252(1):254-9 PMID: 13066
  89. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor-2 alpha in von Hippel-Lindau renal cell carcinoma.
    Oncogene. 2005 Feb 3;24(6):1043-52 PMID: 15592504
  90. Macrophages: master regulators of inflammation and fibrosis.
    Semin Liver Dis. 2010 Aug;30(3):245-57 PMID: 20665377
  91. Aberrant type I and type III collagen gene expression in human breast cancer in vivo.
    J Pathol. 1998 Nov;186(3):262-8 PMID: 10211114
  92. Impeding macrophage entry into hypoxic tumor areas by Sema3A/Nrp1 signaling blockade inhibits angiogenesis and restores antitumor immunity.
    Cancer Cell. 2013 Dec 9;24(6):695-709 PMID: 24332039
  93. The angiopoietin-2 gene of endothelial cells is up-regulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA-2 and Ets-1.
    J Cell Physiol. 2008 Dec;217(3):809-18 PMID: 18720385
  94. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.
    Cancer Cell. 2011 Jun 14;19(6):776-91 PMID: 21665151
  95. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.
    Nat Cell Biol. 2013 Jun;15(6):677-87 PMID: 23644467
  96. Collagen biosynthesis in nonfibroblastic cell lines.
    Proc Natl Acad Sci U S A. 1974 Jan;71(1):50-1 PMID: 4359330
  97. Pathophysiological implications of stroma pattern formation in uveal melanoma.
    J Cell Physiol. 2003 Mar;194(3):267-71 PMID: 12548547
  98. Microenvironmental regulation of metastasis.
    Nat Rev Cancer. 2009 Apr;9(4):239-52 PMID: 19279573
  99. The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1.
    J Biol Chem. 2010 Feb 26;285(9):6658-69 PMID: 20026874
  100. Minimum structural requirements for minoxidil inhibition of lysyl hydroxylase in cultured fibroblasts.
    Arch Biochem Biophys. 1994 Jan;308(1):42-7 PMID: 8311472
  101. Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signaling in breast cancer cells.
    Proc Natl Acad Sci U S A. 2014 Jan 21;111(3):E384-93 PMID: 24324133
  102. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts.
    Nat Cell Biol. 2013 Jun;15(6):637-46 PMID: 23708000
  103. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis.
    Nature. 2007 Oct 4;449(7162):557-63 PMID: 17914389
  104. Actin cap associated focal adhesions and their distinct role in cellular mechanosensing.
    Sci Rep. 2012;2:555 PMID: 22870384
  105. Genetic evidence for a tumor suppressor role of HIF-2alpha.
    Cancer Cell. 2005 Aug;8(2):131-41 PMID: 16098466
  106. A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion.
    PLoS One. 2010 Mar 22;5(3):e9808 PMID: 20339555
  107. HIF-1alpha and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome.
    Int J Cancer. 2007 Apr 1;120(7):1451-8 PMID: 17245699
  108. Hypoxia-inducible factor-1-dependent mechanisms of vascularization and vascular remodelling.
    Cardiovasc Res. 2010 May 1;86(2):236-42 PMID: 20164116
  109. Stimulation of collagen synthesis in rat cardiac fibroblasts by exposure to hypoxic culture conditions and suppression of the effect by natriuretic peptides.
    Cell Biol Int. 1997 Mar;21(3):175-80 PMID: 9151994
  110. Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay.
    Cell. 1998 Aug 7;94(3):353-62 PMID: 9708737
  111. Liver fibrosis.
    J Clin Invest. 2005 Feb;115(2):209-18 PMID: 15690074
  112. Low oxygen tension increases mRNA levels of alpha 1 (I) procollagen in human dermal fibroblasts.
    J Cell Physiol. 1993 Nov;157(2):408-12 PMID: 8227170
  113. HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development.
    Development. 2012 Dec 1;139(23):4473-83 PMID: 23095889
  114. The role of type IV collagen and basement membranes in cancer progression and metastasis.
    Am J Pathol. 2006 Mar;168(3):715-7 PMID: 16507886
  115. Hypoxia-inducible factor-1α contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells.
    Kidney Int. 2011 Feb;79(3):300-10 PMID: 20881940
  116. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK.
    Oncogene. 2013 Apr 4;32(14):1863-8 PMID: 22641216
  117. Radiographic microcalcification and parenchymal patterns as indicators of histologic "high-risk" benign breast disease.
    Cancer. 1990 Oct 15;66(8):1721-5 PMID: 2208027
  118. Irreversible inhibition of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues. Implications for homocystinuria.
    J Biol Chem. 1997 Dec 19;272(51):32370-7 PMID: 9405445
  119. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases.
    Am J Pathol. 2003 Nov;163(5):2113-26 PMID: 14578209
  120. Hypoxia-inducible factor 1alpha induces fibrosis and insulin resistance in white adipose tissue.
    Mol Cell Biol. 2009 Aug;29(16):4467-83 PMID: 19546236
  121. Extracellular matrix-resident growth factors and enzymes: possible involvement in tumor metastasis and angiogenesis.
    Cancer Metastasis Rev. 1990 Nov;9(3):203-26 PMID: 1705486
  122. Fibrosis and adipose tissue dysfunction.
    Cell Metab. 2013 Oct 1;18(4):470-7 PMID: 23954640
  123. Mammographic densities and the prevalence and incidence of histological types of benign breast disease. Reference Pathologists of the Canadian National Breast Screening Study.
    Eur J Cancer Prev. 2000 Feb;9(1):15-24 PMID: 10777006
  124. Hypoxia response elements in the aldolase A, enolase 1, and lactate dehydrogenase A gene promoters contain essential binding sites for hypoxia-inducible factor 1.
    J Biol Chem. 1996 Dec 20;271(51):32529-37 PMID: 8955077
  125. Hypoxia-inducible transcription factor-2alpha in endothelial cells regulates tumor neovascularization through activation of ephrin A1.
    J Biol Chem. 2008 Jul 4;283(27):18926-36 PMID: 18434321
  126. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor-1α in advanced solid tumors.
    Clin Cancer Res. 2011 Aug 1;17(15):5123-31 PMID: 21673063
  127. Cloning of the human prolyl 4-hydroxylase alpha subunit isoform alpha(II) and characterization of the type II enzyme tetramer. The alpha(I) and alpha(II) subunits do not form a mixed alpha(I)alpha(II)beta2 tetramer.
    J Biol Chem. 1997 Jul 11;272(28):17342-8 PMID: 9211872
  128. Impact of the non-cellular tumor microenvironment on metastasis: potential therapeutic and imaging opportunities.
    J Cell Physiol. 2007 Nov;213(2):391-402 PMID: 17657728
  129. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation.
    Cancer Res. 2001 Sep 1;61(17):6548-54 PMID: 11522653
  130. Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms.
    Cancer. 1995 Feb 15;75(4):1010-7 PMID: 7842402
  131. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology.
    Annu Rev Pathol. 2014;9:47-71 PMID: 23937437
  132. Hypoxia promotes fibrogenesis in human renal fibroblasts.
    Kidney Int. 2000 Dec;58(6):2351-66 PMID: 11115069
  133. Lysyl oxidase is essential for hypoxia-induced metastasis.
    Nature. 2006 Apr 27;440(7088):1222-6 PMID: 16642001
  134. Aligned collagen is a prognostic signature for survival in human breast carcinoma.
    Am J Pathol. 2011 Mar;178(3):1221-32 PMID: 21356373
  135. Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals.
    J Cell Commun Signal. 2010 Mar;4(1):1-4 PMID: 19798591
  136. Cancer and interstitial lung disease.
    Curr Opin Pulm Med. 2004 Sep;10(5):425-34 PMID: 15316443
  137. The role of focal adhesion kinase in tumor initiation and progression.
    Cell Adh Migr. 2009 Oct-Dec;3(4):347-50 PMID: 19690467
  138. Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1alpha heterozygous-null mice after burn wounding.
    Wound Repair Regen. 2010 Mar-Apr;18(2):193-201 PMID: 20163569
  139. The tumor microenvironment: a critical determinant of neoplastic evolution.
    Eur J Cell Biol. 2003 Nov;82(11):539-48 PMID: 14703010
  140. Gene expression profiling of the tumor microenvironment during breast cancer progression.
    Breast Cancer Res. 2009;11(1):R7 PMID: 19187537
  141. HIF-1alpha is essential for myeloid cell-mediated inflammation.
    Cell. 2003 Mar 7;112(5):645-57 PMID: 12628185
  142. The physics of cancer: the role of physical interactions and mechanical forces in metastasis.
    Nat Rev Cancer. 2011 Jun 24;11(7):512-22 PMID: 21701513
  143. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis.
    J Mol Med (Berl). 2012 Jul;90(7):803-15 PMID: 22231744
  144. Extracellular matrix proteins and their receptors in the normal, hyperplastic and neoplastic breast.
    Cell Differ Dev. 1990 Dec 2;32(3):409-16 PMID: 1711920
  145. The extracellular matrix: not just pretty fibrils.
    Science. 2009 Nov 27;326(5957):1216-9 PMID: 19965464
  146. Collagen density promotes mammary tumor initiation and progression.
    BMC Med. 2008 Apr 28;6:11 PMID: 18442412
  147. Genes that mediate breast cancer metastasis to the brain.
    Nature. 2009 Jun 18;459(7249):1005-9 PMID: 19421193
  148. Oxygen tension regulates the expression of a group of procollagen hydroxylases.
    Eur J Biochem. 2003 Nov;270(22):4515-22 PMID: 14622280
  149. Heritability of mammographic density, a risk factor for breast cancer.
    N Engl J Med. 2002 Sep 19;347(12):886-94 PMID: 12239257
  150. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP-2 activation.
    Oncogene. 2006 Apr 13;25(16):2379-92 PMID: 16369494
  151. Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme.
    J Biol Chem. 2003 Nov 28;278(48):47685-93 PMID: 14500733
  152. Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators.
    Curr Opin Cell Biol. 2008 Oct;20(5):495-501 PMID: 18640274
  153. The extracellular matrix at a glance.
    J Cell Sci. 2010 Dec 15;123(Pt 24):4195-200 PMID: 21123617
  154. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene.
    Cancer Discov. 2011 Aug;1(3):222-35 PMID: 22037472
  155. Role of hypoxia-inducible factors in breast cancer metastasis.
    Future Oncol. 2013 Nov;9(11):1623-36 PMID: 24156323
  156. Emerging targeted agents in metastatic breast cancer.
    Nat Rev Clin Oncol. 2013 Apr;10(4):191-210 PMID: 23459626
  157. Tensional homeostasis and the malignant phenotype.
    Cancer Cell. 2005 Sep;8(3):241-54 PMID: 16169468
  158. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells.
    Trends Mol Med. 2012 Sep;18(9):534-43 PMID: 22921864
  159. HIF-1 mediates metabolic responses to intratumoral hypoxia and oncogenic mutations.
    J Clin Invest. 2013 Sep;123(9):3664-71 PMID: 23999440
  160. The organizing principle: microenvironmental influences in the normal and malignant breast.
    Differentiation. 2002 Dec;70(9-10):537-46 PMID: 12492495
  161. Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis.
    Int J Biochem Cell Biol. 2009 Aug-Sep;41(8-9):1708-18 PMID: 19433312
  162. Collagens, modifying enzymes and their mutations in humans, flies and worms.
    Trends Genet. 2004 Jan;20(1):33-43 PMID: 14698617
  163. Reaction of aortic lysyl oxidase with beta-aminopropionitrile.
    J Biol Chem. 1983 Apr 10;258(7):4331-8 PMID: 6131892
  164. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis.
    Am J Physiol. 1998 Aug;275(2):L365-71 PMID: 9700098
  165. Increased formation of pyridinoline cross-links due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon.
    Matrix Biol. 2004 Jul;23(4):251-7 PMID: 15296939
  166. Migratory neighbors and distant invaders: tumor-associated niche cells.
    Genes Dev. 2008 Mar 1;22(5):559-74 PMID: 18316475
  167. Hypoxia and hypoxia signaling in tissue repair and fibrosis.
    Int Rev Cell Mol Biol. 2012;296:139-85 PMID: 22559939
  168. The role of endothelin-1 in the pathogenesis of idiopathic pulmonary fibrosis.
    BioDrugs. 2010 Feb 1;24(1):49-54 PMID: 20055532
  169. Heterozygous deficiency of PHD2 restores tumor oxygenation and inhibits metastasis via endothelial normalization.
    Cell. 2009 Mar 6;136(5):839-851 PMID: 19217150
  170. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis.
    Cancer Discov. 2013 Oct;3(10):1190-205 PMID: 23906982
  171. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumors and other ischemic tissues.
    Blood. 2004 Oct 15;104(8):2224-34 PMID: 15231578
  172. Tumor stroma: a complexity dictated by the hypoxic tumor microenvironment.
    Oncogene. 2014 Apr 3;33(14):1743-54 PMID: 23604130
  173. A distinctive role for focal adhesion proteins in three-dimensional cell motility.
    Nat Cell Biol. 2010 Jun;12(6):598-604 PMID: 20473295
  174. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications.
    Cancer Res. 2005 Feb 15;65(4):1587-97 PMID: 15735049
  175. Stromal changes in invasive breast carcinoma: an ultrastructural study.
    J Pathol. 1987 Oct;153(2):163-70 PMID: 3694320
  176. Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis.
    Mol Cancer Res. 2013 May;11(5):456-66 PMID: 23378577
  177. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis.
    Nat Cell Biol. 2003 Aug;5(8):711-9 PMID: 12844144
  178. Relationship between mammographic and histological risk factors for breast cancer.
    J Natl Cancer Inst. 1992 Aug 5;84(15):1170-9 PMID: 1635085
  179. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics.
    Oncogene. 2010 Feb 4;29(5):625-34 PMID: 19946328
  180. Melanoma-stroma interactions: structural and functional aspects.
    Lancet Oncol. 2002 Jan;3(1):35-43 PMID: 11905603
  181. Stromal changes in early invasive and non-invasive breast carcinoma: an ultrastructural study.
    J Pathol. 1986 Sep;150(1):43-9 PMID: 3023597
  182. Collagen formation in extracellular matrix of transplants of human transformed keratinocyte cell lines.
    Anticancer Res. 2002 May-Jun;22(3):1705-11 PMID: 12168857
  183. Gene-targeting of Phd2 improves tumor response to chemotherapy and prevents side-toxicity.
    Cancer Cell. 2012 Aug 14;22(2):263-77 PMID: 22897855
  184. The extracellular matrix: a dynamic niche in cancer progression.
    J Cell Biol. 2012 Feb 20;196(4):395-406 PMID: 22351925
  185. Loss of HIF-1alpha in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis.
    Cancer Cell. 2004 Nov;6(5):485-95 PMID: 15542432
  186. Stromal cells in tumor microenvironment and breast cancer.
    Cancer Metastasis Rev. 2013 Jun;32(1-2):303-15 PMID: 23114846
  187. The impact of O2 availability on human cancer.
    Nat Rev Cancer. 2008 Dec;8(12):967-75 PMID: 18987634
  188. Combinatorial signaling pathways determine fibroblast proliferation and myofibroblast differentiation.
    FASEB J. 2004 Mar;18(3):469-79 PMID: 15003992
  189. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells.
    Genes Dev. 1997 Jan 1;11(1):72-82 PMID: 9000051
  190. 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 Oct 2;109(40):E2707-16 PMID: 23012449
  191. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1.
    Cancer Res. 2003 Mar 1;63(5):1138-43 PMID: 12615733
  192. Prognostic potential of the pre-therapeutic tumor oxygenation status.
    Adv Exp Med Biol. 2009;645:241-6 PMID: 19227477
  193. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis.
    Oncogene. 2013 Aug 29;32(35):4057-63 PMID: 23222717
  194. Fibrotic focus in invasive ductal carcinoma of the breast: a histopathological prognostic parameter for tumor recurrence and tumor death within three years after the initial operation.
    Jpn J Cancer Res. 1997 Jun;88(6):590-9 PMID: 9263537
  195. Identification and validation of genes involved in cervical tumourigenesis.
    BMC Cancer. 2011 Feb 22;11:80 PMID: 21338529
  196. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumors and wounds.
    PLoS Biol. 2004 Feb;2(2):E7 PMID: 14737219
  197. Hypoxia-inducible factor-1alpha is a key regulator of metastasis in a transgenic model of cancer initiation and progression.
    Cancer Res. 2007 Jan 15;67(2):563-72 PMID: 17234764
  198. ZD6474 inhibits tumor growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model.
    Int J Cancer. 2006 Jan 15;118(2):483-9 PMID: 16052530
  199. Collagen prolyl hydroxylases are essential for breast cancer metastasis.
    Cancer Res. 2013 Jun 1;73(11):3285-96 PMID: 23539444
Article Info
Journal
Nature reviews. Cancer
Abbr.
Nat Rev Cancer
ISSN
1474-1768
DOI
10.1038/nrc3726
Published
2014-00-00
Epub
2014-00-15
Pages
430-9
Language
English
Region
England
NLM ID
101124168
PMCID
PMC4283800
Subset
IM
Grants
NCI NIH HHS · K99 CA181352 · United States
NCI NIH HHS · R01 CA174388 · United States
External Links
PubMed source DOI: 10.1038/nrc3726 PMC Full Text View journal details
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