Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Opinion
  • Published:

Hypoxia and the extracellular matrix: drivers of tumour metastasis

Nature Reviews Cancer volume 14, pages 430–439 (2014)Cite this article

Subjects

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Biosynthesis of fibrillar collagens.
Figure 2: Hypoxia promotes ECM remodelling to facilitate metastasis.
Figure 3: Hypoxia recruits and reprogrammes cells to produce fibrillar collagen.

Similar content being viewed by others

References

  1. Vaupel, P., Mayer, A. & Hockel, M. Tumour hypoxia and malignant progression. Methods Enzymol. 381, 335–354 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Sorg, B. S., Hardee, M. E., Agarwal, N., Moeller, B. J. & Dewhirst, M. W. Spectral imaging facilitates visualization and measurements of unstable and abnormal microvascular oxygen transport in tumours. J. Biomed. Opt. 13, 014026 (2008).

    Article  PubMed  CAS  Google Scholar 

  3. Vaupel, P. Prognostic potential of the pre-therapeutic tumour oxygenation status. Adv. Exp. Med. Biol. 645, 241–246 (2009).

    Article  PubMed  Google Scholar 

  4. Vaupel, P., Hockel, M. & Mayer, A. Detection and characterization of tumour hypoxia using pO2 histography. Antioxid. Redox Signal. 9, 1221–1235 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Semenza, G. L. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. 9, 47–71 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nature Rev. Cancer 8, 967–975 (2008).

    Article  CAS  Google Scholar 

  7. Finger, E. C. & Giaccia, A. J. Hypoxia, inflammation, and the tumour microenvironment in metastatic disease. Cancer Metastasis Rev. 29, 285–293 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Semenza, G. L. Defining the role of hypoxia-inducible factor 1 in cancer biology and therapeutics. Oncogene 29, 625–634 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Semenza, G. L. Molecular mechanisms mediating metastasis of hypoxic breast cancer cells. Trends Mol. Med. 18, 534–543 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Semenza, G. L. Hypoxia-inducible factors: mediators of cancer progression and targets for cancer therapy. Trends Pharmacol. Sci. 33, 207–214 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Semenza, G. L. Cancer-stromal cell interactions mediated by hypoxia-inducible factors promote angiogenesis, lymphangiogenesis, and metastasis. Oncogene 32, 4057–4063 (2013).

    Article  CAS  PubMed  Google Scholar 

  12. Casazza, A. et al. Tumour stroma: a complexity dictated by the hypoxic tumour microenvironment. Oncogene 33, 1743–1754 (2014).

    Article  CAS  PubMed  Google Scholar 

  13. Lu, P., Weaver, V. M. & Werb, Z. The extracellular matrix: a dynamic niche in cancer progression. J. Cell Biol. 196, 395–406 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bissell, M. J., Radisky, D. C., Rizki, A., Weaver, V. M. & Petersen, O. W. The organizing principle: microenvironmental influences in the normal and malignant breast. Differentiation 70, 537–546 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  16. Cretu, A. & Brooks, P. C. Impact of the non-cellular tumour microenvironment on metastasis: potential therapeutic and imaging opportunities. J. Cell. Physiol. 213, 391–402 (2007).

    Article  CAS  PubMed  Google Scholar 

  17. van Kempen, L. C., Ruiter, D. J., van Muijen, G. N. & Coussens, L. M. The tumour microenvironment: a critical determinant of neoplastic evolution. Eur. J. Cell Biol. 82, 539–548 (2003).

    Article  PubMed  Google Scholar 

  18. Lochter, A. & Bissell, M. J. Involvement of extracellular matrix constituents in breast cancer. Semin. Cancer Biol. 6, 165–173 (1995).

    Article  CAS  PubMed  Google Scholar 

  19. Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumour extracellular matrices. Mol. Cell Proteomics 11, M111.014647 (2012).

    Article  PubMed  CAS  Google Scholar 

  20. Gilkes, D. M. et al. Procollagen lysyl hydroxylase 2 is essential for hypoxia-induced breast cancer metastasis. Mol. Cancer Res. 11, 456–466 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Gilkes, D. M. et al. Collagen prolyl hydroxylases are essential for breast cancer metastasis. Cancer Res. 73, 3285–3296 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hielscher, A. C., Qiu, C. & Gerecht, S. Breast cancer cell-derived matrix supports vascular morphogenesis. Am. J. Physiol. Cell Physiol. 302, C1243–C1256 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Langness, U. & Udenfriend, S. Collagen biosynthesis in nonfibroblastic cell lines. Proc. Natl Acad. Sci. USA 71, 50–51 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Wyckoff, J. B. et al. Direct visualization of macrophage-assisted tumour cell intravasation in mammary tumours. Cancer Res. 67, 2649–2656 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Provenzano, P. P. et al. Collagen reorganization at the tumour-stromal interface facilitates local invasion. BMC Med. 4, 38 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Trier, S. M. & Keely, P. J. Contact guidance mediated three-dimensional cell migration is regulated by Rho/ROCK-dependent matrix reorganization. Biophys. J. 95, 5374–5384 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Frantz, C., Stewart, K. M. & Weaver, V. M. The extracellular matrix at a glance. J. Cell Sci. 123, 4195–4200 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Ramaswamy, S., Ross, K. N., Lander, E. S. & Golub, T. R. A molecular signature of metastasis in primary solid tumours. Nature Genet. 33, 49–54 (2003).

    Article  CAS  PubMed  Google Scholar 

  30. Eckhardt, B. L. et al. Genomic analysis of a spontaneous model of breast cancer metastasis to bone reveals a role for the extracellular matrix. Mol. Cancer Res. 3, 1–13 (2005).

    CAS  PubMed  Google Scholar 

  31. Allinen, M. et al. Molecular characterization of the tumour microenvironment in breast cancer. Cancer Cell 6, 17–32 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Finak, G. et al. Stromal gene expression predicts clinical outcome in breast cancer. Nature Med. 14, 518–527 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Qiu, T. H. et al. Global expression profiling identifies signatures of tumour virulence in MMTV-PyMT-transgenic mice: Correlation to human disease. Cancer Res. 64, 5973–5981 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Ma, X. J., Dahiya, S., Richardson, E., Erlander, M. & Sgroi, D. C. Gene expression profiling of the tumour microenvironment during breast cancer progression. Breast Cancer Res. 11, R7 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Chang, H. Y. et al. Robustness, scalability, and integration of a wound-response gene expression signature in predicting breast cancer survival. Proc. Natl Acad. Sci. USA 102, 3738–3743 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Chang, H. Y. et al. Gene expression signature of fibroblast serum response predicts human cancer progression: similarities between tumours and wounds. PLoS Biol. 2, E7 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Artinian, V. & Kvale, P. A. Cancer and interstitial lung disease. Curr. Opin. Pulm. Med. 10, 425–434 (2004).

    Article  PubMed  Google Scholar 

  38. Bartow, S. A., Pathak, D. R. & Mettler, F. A. Radiographic microcalcification and parenchymal patterns as indicators of histologic 'high-risk' benign breast disease. Cancer 66, 1721–1725 (1990).

    Article  CAS  PubMed  Google Scholar 

  39. Bataller, R. & Brenner, D. A. Liver fibrosis. J. Clin. Invest. 115, 209–218 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Bissell, D. M. Chronic liver injury, TGFβ, and cancer. Exp. Mol. Med. 33, 179–190 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Boyd, N. F., Jensen, H. M., Cooke, G. & Han, H. L. Relationship between mammographic and histological risk factors for breast cancer. J. Natl Cancer Inst. 84, 1170–1179 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Boyd, N. F. et al. 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. 9, 15–24 (2000).

    Article  CAS  PubMed  Google Scholar 

  43. Boyd, N. F. et al. Heritability of mammographic density, a risk factor for breast cancer. N. Engl. J. Med. 347, 886–894 (2002).

    Article  PubMed  Google Scholar 

  44. Shapiro, F. D. & Eyre, D. R. Collagen polymorphism in extracellular matrix of human osteosarcoma. J. Natl Cancer Inst. 69, 1009–1016 (1982).

    CAS  PubMed  Google Scholar 

  45. Coussens, L. M. et al. Inflammatory mast cells upregulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Jussila, T., Kauppila, S., Risteli, L., Risteli, J. & Stenback, F. Collagen formation in extracellular matrix of transplants of human transformed keratinocyte cell lines. Anticancer Res. 22, 1705–1711 (2002).

    CAS  PubMed  Google Scholar 

  47. Gould, V. E., Koukoulis, G. K. & Virtanen, I. Extracellular matrix proteins and their receptors in the normal, hyperplastic and neoplastic breast. Cell Differ. Dev. 32, 409–416 (1990).

    Article  CAS  PubMed  Google Scholar 

  48. Zhu, G. G. et al. Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. Cancer 75, 1010–1017 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Kauppila, S., Stenback, F., Risteli, J., Jukkola, A. & Risteli, L. Aberrant type I and type III collagen gene expression in human breast cancer in vivo. J. Pathol. 186, 262–268 (1998).

    Article  CAS  PubMed  Google Scholar 

  50. Huijbers, I. J. et al. A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PLoS ONE 5, e9808 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Colpaert, C. G. et al. 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. 81, 137–147 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Trastour, C. et al. HIF1α and CA IX staining in invasive breast carcinomas: prognosis and treatment outcome. Int. J. Cancer 120, 1451–1458 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Hasebe, T., Tsuda, H., Tsubono, Y., Imoto, S. & Mukai, K. Fibrotic focus in invasive ductal carcinoma of the breast: a histopathological prognostic parameter for tumour recurrence and tumour death within three years after the initial operation. Jpn J. Cancer Res. 88, 590–599 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. van der Rest, M. & Garrone, R. Collagen family of proteins. FASEB J. 5, 2814–2823 (1991).

    Article  CAS  PubMed  Google Scholar 

  55. Fraley, S. I. et al. A distinctive role for focal adhesion proteins in three-dimensional cell motility. Nature Cell Biol. 12, 598–604 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Fraley, S. I., Feng, Y., Giri, A., Longmore, G. D. & Wirtz, D. Dimensional and temporal controls of three-dimensional cell migration by zyxin and binding partners. Nature Commun. 3, 719 (2012).

    Article  CAS  Google Scholar 

  57. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    Article  CAS  PubMed  Google Scholar 

  58. Levental, K. R. et al. Matrix crosslinking forces tumour progression by enhancing integrin signalling. Cell 139, 891–906 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Liu, X. et al. A targeted mutation at the known collagenase cleavage site in mouse type I collagen impairs tissue remodelling. J. Cell Biol. 130, 227–237 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Provenzano, P. P. et al. Collagen density promotes mammary tumour initiation and progression. BMC Med. 6, 11 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  61. Lin, E. Y. et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am. J. Pathol. 163, 2113–2126 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  62. Mao, Y., Keller, E. T., Garfield, D. H., Shen, K. & Wang, J. Stromal cells in tumour microenvironment and breast cancer. Cancer Metastasis Rev. 32, 303–315 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  63. Kalluri, R. & Zeisberg, M. Fibroblasts in cancer. Nature Rev. Cancer 6, 392–401 (2006).

    Article  CAS  Google Scholar 

  64. Shekhar, M. P., Pauley, R. & Heppner, G. Host microenvironment in breast cancer development: extracellular matrix-stromal cell contribution to neoplastic phenotype of epithelial cells in the breast. Breast Cancer Res. 5, 130–135 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Cox, T. R. et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–1732 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Erler, J. T. et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature 440, 1222–1226 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Eisinger-Mathason, T. S. et al. Hypoxia-dependent modification of collagen networks promotes sarcoma metastasis. Cancer Discov. 3, 1190–1205 (2013).

    Article  CAS  PubMed  Google Scholar 

  68. Xiong, G., Deng, L., Zhu, J., Rychahou, P. G. & Xu, R. Prolyl-4-hydroxylase α–subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition. BMC Cancer 14, 1 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Halberg, N. et al. Hypoxia-inducible factor 1α induces fibrosis and insulin resistance in white adipose tissue. Mol. Cell. Biol. 29, 4467–4483 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Higgins, D. F. et al. Hypoxia promotes fibrogenesis in vivo via HIF1 stimulation of epithelial-to-mesenchymal transition. J. Clin. Invest. 117, 3810–3820 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Moon, J. O., Welch, T. P., Gonzalez, F. J. & Copple, B. L. Reduced liver fibrosis in hypoxia-inducible factor-1α-deficient mice. Am. J. Physiol. Gastrointest. Liver Physiol. 296, G582–G592 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Falanga, V. et al. Low oxygen tension increases mRNA levels of α1 (I) procollagen in human dermal fibroblasts. J. Cell. Physiol. 157, 408–412 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Tamamori, M., Ito, H., Hiroe, M., Marumo, F. & Hata, R. I. 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. 21, 175–180 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Norman, J. T., Clark, I. M. & Garcia, P. L. Hypoxia promotes fibrogenesis in human renal fibroblasts. Kidney Int. 58, 2351–2366 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Berg, J. T., Breen, E. C., Fu, Z., Mathieu-Costello, O. & West, J. B. Alveolar hypoxia increases gene expression of extracellular matrix proteins and platelet-derived growth factor-B in lung parenchyma. Am. J. Respir. Crit. Care Med. 158, 1920–1928 (1998).

    Article  CAS  PubMed  Google Scholar 

  76. Myllyharju, J. & Kivirikko, K. I. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 20, 33–43 (2004).

    Article  CAS  PubMed  Google Scholar 

  77. Kivirikko, K. I. & Pihlajaniemi, T. Collagen hydroxylases and the protein disulphide isomerase subunit of prolyl 4-hydroxylases. Adv. Enzymol. Relat. Areas Mol. Biol. 72, 325–398 (1998).

    CAS  PubMed  Google Scholar 

  78. Myllyharju, J. Prolyl 4-hydroxylases, the key enzymes of collagen biosynthesis. Matrix Biol. 22, 15–24 (2003).

    Article  CAS  PubMed  Google Scholar 

  79. Annunen, P. et al. Cloning of the human prolyl 4-hydroxylase-α subunit isoform-α(II) and characterization of the type II enzyme tetramer. The-α(I) and-α(II) subunits do not form a mixed-α(I)α(II)β2 tetramer. J. Biol. Chem. 272, 17342–17348 (1997).

    Article  CAS  PubMed  Google Scholar 

  80. Kukkola, L., Hieta, R., Kivirikko, K. I. & Myllyharju, J. Identification and characterization of a third human, rat, and mouse collagen prolyl 4-hydroxylase isoenzyme. J. Biol. Chem. 278, 47685–47693 (2003).

    Article  CAS  PubMed  Google Scholar 

  81. van der Slot, A. J. et al. Increased formation of pyridinoline crosslinks due to higher telopeptide lysyl hydroxylase levels is a general fibrotic phenomenon. Matrix Biol. 23, 251–257 (2004).

    Article  CAS  PubMed  Google Scholar 

  82. Gilkes, D. M., Bajpai, S., Chaturvedi, P., Wirtz, D. & Semenza, G. L. Hypoxia-inducible factor 1 (HIF1) promotes extracellular matrix remodeling under hypoxic conditions by inducing P4HA1, P4HA2, and PLOD2 expression in fibroblasts. J. Biol. Chem. 288, 10819–10829 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Hofbauer, K. H. et al. Oxygen tension regulates the expression of a group of procollagen hydroxylases. Eur. J. Biochem. 270, 4515–4522 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Elvidge, G. P. et al. Concordant regulation of gene expression by hypoxia and 2-oxoglutarate-dependent dioxygenase inhibition: the role of HIF1α, HIF2α, and other pathways. J. Biol. Chem. 281, 15215–15226 (2006).

    Article  CAS  PubMed  Google Scholar 

  85. Aro, E. et al. Hypoxia-inducible factor 1 (HIF1) but not HIF2 is essential for hypoxic induction of collagen prolyl 4-hydroxylases in primary newborn mouse epiphyseal growth plate chondrocytes. J. Biol. Chem. 287, 37134–37144 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Bentovim, L., Amarilio, R. & Zelzer, E. HIF1α is a central regulator of collagen hydroxylation and secretion under hypoxia during bone development. Development 139, 4473–4483 (2012).

    Article  CAS  PubMed  Google Scholar 

  87. Gordon, M. K. & Hahn, R. A. Collagens. Cell Tissue Res. 339, 247–257 (2010).

    Article  CAS  PubMed  Google Scholar 

  88. Tanjore, H. & Kalluri, R. The role of type IV collagen and basement membranes in cancer progression and metastasis. Am. J. Pathol. 168, 715–717 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Wong, C. C. et al. Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proc. Natl Acad. Sci. USA 108, 16369–16374 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Wong, C. C. et al. Inhibitors of hypoxia-inducible factor 1 block breast cancer metastatic niche formation and lung metastasis. J. Mol. Med. 90, 803–815 (2012).

    Article  CAS  PubMed  Google Scholar 

  91. Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Schietke, R. et al. The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF1. J. Biol. Chem. 285, 6658–6669 (2010).

    Article  CAS  PubMed  Google Scholar 

  93. Barker, H. E., Cox, T. R. & Erler, J. T. The rationale for targeting the LOX family in cancer. Nature Rev. Cancer 12, 540–552 (2012).

    Article  CAS  Google Scholar 

  94. Munoz-Najar, U. M., Neurath, K. M., Vumbaca, F. & Claffey, K. P. Hypoxia stimulates breast carcinoma cell invasion through MT1-MMP and MMP2 activation. Oncogene 25, 2379–2392 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Krishnamachary, B. et al. Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1. Cancer Res. 63, 1138–1143 (2003).

    CAS  PubMed  Google Scholar 

  96. Choi, J. Y., Jang, Y. S., Min, S. Y. & Song, J. Y. Overexpression of MMP9 and HIF1α in breast cancer cells under hypoxic conditions. J. Breast Cancer 14, 88–95 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Petrella, B. L., Lohi, J. & Brinckerhoff, C. E. Identification of membrane type-1 matrix metalloproteinase as a target of hypoxia-inducible factor 2α in von Hippel–Lindau renal cell carcinoma. Oncogene 24, 1043–1052 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Graham, C. H., Forsdike, J., Fitzgerald, C. J. & Macdonald-Goodfellow, S. Hypoxia-mediated stimulation of carcinoma cell invasiveness via upregulation of urokinase receptor expression. Int. J. Cancer 80, 617–623 (1999).

    Article  CAS  PubMed  Google Scholar 

  99. Buchler, P. et al. Transcriptional regulation of urokinase-type plasminogen activator receptor by hypoxia-inducible factor 1 is crucial for invasion of pancreatic and liver cancer. Neoplasia 11, 196–206 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Kim, J., Yu, W., Kovalski, K. & Ossowski, L. Requirement for specific proteases in cancer cell intravasation as revealed by a novel semiquantitative PCR-based assay. Cell 94, 353–362 (1998).

    Article  CAS  PubMed  Google Scholar 

  101. Dvorak, H. F. Tumours: wounds that do not heal. Similarities between tumour stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  102. Lokmic, Z., Musyoka, J., Hewitson, T. D. & Darby, I. A. in International Review of Cell and Molecular Biology Vol. 296 Ch.3 (ed. Kwang, W. J.) 139–185 (Academic Press, 2012).

    Google Scholar 

  103. Zhang, X. et al. Impaired angiogenesis and mobilization of circulating angiogenic cells in HIF-1α heterozygous-null mice after burn wounding. Wound Repair Regen. 18, 193–201 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Velnar, T., Bailey, T. & Smrkolj, V. The wound healing process: an overview of the cellular and molecular mechanisms. J. Int. Med. Res. 37, 1528–1542 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Rey, S. & Semenza, G. L. Hypoxia-inducible factor 1-dependent mechanisms of vascularization and vascular remodelling. Cardiovasc. Res. 86, 236–242 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Schito, L. et al. Hypoxia-inducible factor 1-dependent expression of platelet-derived growth factor B promotes lymphatic metastasis of hypoxic breast cancer cells. Proc. Natl Acad. Sci. USA 109, E2707–E2716 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Manalo, D. J. et al. Transcriptional regulation of vascular endothelial cell responses to hypoxia by HIF1. Blood 105, 659–669 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Kelly, B. D. et al. 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. 93, 1074–1081 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Forsythe, J. A. et al. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell. Biol. 16, 4604–4613 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Ceradini, D. J. et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF1 induction of SDF1. Nature Med. 10, 858–864 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Simon, M. P., Tournaire, R. & Pouyssegur, J. The angiopoietin-2 gene of endothelial cells is upregulated in hypoxia by a HIF binding site located in its first intron and by the central factors GATA2 and ETS1. J. Cell. Physiol. 217, 809–818 (2008).

    Article  CAS  PubMed  Google Scholar 

  112. Chaturvedi, P. et al. Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signalling promotes metastasis. J. Clin. Invest. 123, 189–205 (2013).

    Article  CAS  PubMed  Google Scholar 

  113. Kondo, S. et al. Connective tissue growth factor increased by hypoxia may initiate angiogenesis in collaboration with matrix metalloproteinases. Carcinogenesis 23, 769–776 (2002).

    Article  CAS  PubMed  Google Scholar 

  114. Higgins, D. F. et al. Hypoxic induction of CTGF is directly mediated by HIF1. Am. J. Physiol. Renal Physiol. 287, F1223–F1232 (2004).

    Article  CAS  PubMed  Google Scholar 

  115. Le, Y. J. & Corry, P. M. Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway. Mol. Cell Biochem. 202, 1–8 (1999).

    Article  CAS  PubMed  Google Scholar 

  116. Lappi-Blanco, E., Soini, Y., Kinnula, V. & Paakko, P. VEGF and bFGF are highly expressed in intraluminal fibromyxoid lesions in bronchiolitis obliterans organizing pneumonia. J. Pathol. 196, 220–227 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Lasky, J. A. et al. Connective tissue growth factor mRNA expression is upregulated in bleomycin-induced lung fibrosis. Am. J. Physiol. 275, L365–371 (1998).

    CAS  PubMed  Google Scholar 

  118. Bonner, J. C. Regulation of PDGF and its receptors in fibrotic diseases. Cytokine Growth Factor Rev. 15, 255–273 (2004).

    Article  CAS  PubMed  Google Scholar 

  119. Phillips, R. J. et al. Circulating fibrocytes traffic to the lungs in response to CXCL12 and mediate fibrosis. J. Clin. Invest. 114, 438–446 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Hayashida, K. et al. Bone marrow-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced pulmonary hypertension. Chest 127, 1793–1798 (2005).

    Article  PubMed  Google Scholar 

  121. Mehrad, B., Burdick, M. D. & Strieter, R. M. Fibrocyte CXCR4 regulation as a therapeutic target in pulmonary fibrosis. Int. J. Biochem. Cell Biol. 41, 1708–1718 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Karnoub, A. E. et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449, 557–563 (2007).

    Article  CAS  PubMed  Google Scholar 

  123. Brown, L. F. et al. Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast. Clin. Cancer Res. 5, 1041–1056 (1999).

    CAS  PubMed  Google Scholar 

  124. Wels, J., Kaplan, R. N., Rafii, S. & Lyden, D. Migratory neighbours and distant invaders: tumour-associated niche cells. Genes Dev. 22, 559–574 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Murdoch, C., Giannoudis, A. & Lewis, C. E. Mechanisms regulating the recruitment of macrophages into hypoxic areas of tumours and other ischemic tissues. Blood 104, 2224–2234 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Cramer, T. et al. HIF1α is essential for myeloid cell-mediated inflammation. Cell 112, 645–657 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Rezvani, H. R. et al. HIF1α in epidermis: oxygen sensing, cutaneous angiogenesis, cancer, and non-cancer disorders. J. Invest. Dermatol. 131, 1793–1805 (2011).

    Article  CAS  PubMed  Google Scholar 

  128. Casazza, A. et al. Impeding macrophage entry into hypoxic tumour areas by SEMA3A/NRP1 signalling blockade inhibits angiogenesis and restores antitumor immunity. Cancer Cell 24, 695–709 (2013).

    Article  CAS  PubMed  Google Scholar 

  129. Wynn, T. A. & Barron, L. Macrophages: master regulators of inflammation and fibrosis. Semin. Liver Dis. 30, 245–257 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Joyce, J. A. & Pollard, J. W. Microenvironmental regulation of metastasis. Nature Rev. Cancer 9, 239–252 (2009).

    Article  CAS  Google Scholar 

  131. Wirtz, D., Konstantopoulos, K. & Searson, P. C. The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nature Rev. Cancer 11, 512–522 (2011).

    Article  CAS  Google Scholar 

  132. Clarijs, R., Ruiter, D. J. & De Waal, R. M. Pathophysiological implications of stroma pattern formation in uveal melanoma. J. Cell. Physiol. 194, 267–271 (2003).

    Article  CAS  PubMed  Google Scholar 

  133. Lopez, J. I., Kang, I., You, W. K., McDonald, D. M. & Weaver, V. M. In situ force mapping of mammary gland transformation. Integr. Biol. 3, 910–921 (2011).

    Article  CAS  Google Scholar 

  134. Kim, D. H. et al. Actin cap associated focal adhesions and their distinct role in cellular mechanosensing. Sci. Rep. 2, 555 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Samuel, M. S. et al. Actomyosin-mediated cellular tension drives increased tissue stiffness and beta-catenin activation to induce epidermal hyperplasia and tumour growth. Cancer Cell 19, 776–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Wozniak, M. A., Desai, R., Solski, P. A., Der, C. J. & Keely, P. J. ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. J. Cell Biol. 163, 583–595 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Sahai, E. & Marshall, C. J. Differing modes of tumour cell invasion have distinct requirements for Rho/ROCK signalling and extracellular proteolysis. Nature Cell Biol. 5, 711–719 (2003).

    Article  CAS  PubMed  Google Scholar 

  138. Kim, D. H. & Wirtz, D. Focal adhesion size uniquely predicts cell migration. FASEB J. 27, 1351–1361 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Provenzano, P. P. & Keely, P. J. The role of focal adhesion kinase in tumour initiation and progression. Cell Adh. Migr. 3, 347–350 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  140. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., Beggs, H. E. & Keely, P. J. Mammary epithelial-specific disruption of focal adhesion kinase retards tumour formation and metastasis in a transgenic mouse model of human breast cancer. Am. J. Pathol. 173, 1551–1565 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Lahlou, H. et al. Mammary epithelial-specific disruption of the focal adhesion kinase blocks mammary tumour progression. Proc. Natl Acad. Sci. USA 104, 20302–20307 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Baker, A. M., Bird, D., Lang, G., Cox, T. R. & Erler, J. T. Lysyl oxidase enzymatic function increases stiffness to drive colorectal cancer progression through FAK. Oncogene 32, 1863–1868 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nature Cell Biol. 15, 637–646 (2013).

    Article  CAS  PubMed  Google Scholar 

  144. Tamimi, S. O. & Ahmed, A. Stromal changes in early invasive and non-invasive breast carcinoma: an ultrastructural study. J. Pathol. 150, 43–49 (1986).

    Article  CAS  PubMed  Google Scholar 

  145. Tamimi, S. O. & Ahmed, A. Stromal changes in invasive breast carcinoma: an ultrastructural study. J. Pathol. 153, 163–170 (1987).

    Article  CAS  PubMed  Google Scholar 

  146. Conklin, M. W. & Keely, P. J. Why the stroma matters in breast cancer: insights into breast cancer patient outcomes through the examination of stromal biomarkers. Cell Adh. Migr. 6, 249–260 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  147. Ruiter, D., Bogenrieder, T., Elder, D. & Herlyn, M. Melanoma–stroma interactions: structural and functional aspects. Lancet Oncol. 3, 35–43 (2002).

    Article  CAS  PubMed  Google Scholar 

  148. Wang, W. et al. Single cell behaviour in metastatic primary mammary tumours correlated with gene expression patterns revealed by molecular profiling. Cancer Res. 62, 6278–6288 (2002).

    CAS  PubMed  Google Scholar 

  149. Goetz, J. G. et al. Biomechanical remodeling of the microenvironment by stromal caveolin 1 favours tumour invasion and metastasis. Cell 146, 148–163 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Wang, Y. et al. Hypoxia promotes ligand-independent EGF receptor signalling via hypoxia-inducible factor-mediated upregulation of caveolin 1. Proc. Natl Acad. Sci. USA 109, 4892–4897 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Gilkes, D. M. et al. Hypoxia-inducible factors mediate coordinated RhoA-ROCK1 expression and signalling in breast cancer cells. Proc. Natl Acad. Sci. USA 111, E384–E393 (2014).

    Article  CAS  PubMed  Google Scholar 

  152. Keith, B., Johnson, R. S. & Simon, M. C. HIF1α and HIF2α: sibling rivalry in hypoxic tumour growth and progression. Nature Rev. Cancer 12, 9–22 (2012).

    Article  CAS  Google Scholar 

  153. Semenza, G. L. Targeting HIF1 for cancer therapy. Nature Rev. Cancer 3, 721–732 (2003).

    Article  CAS  Google Scholar 

  154. Shen, C. et al. Genetic and functional studies implicate HIF1α as a 14q kidney cancer suppressor gene. Cancer Discov. 1, 222–235 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Semenza, G. L. HIF1 mediates metabolic responses to intratumoural hypoxia and oncogenic mutations. J. Clin. Invest. 123, 3664–3671 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Liao, D., Corle, C., Seagroves, T. N. & Johnson, R. S. Hypoxia-inducible factor 1α is a key regulator of metastasis in a transgenic model of cancer initiation and progression. Cancer Res. 67, 563–572 (2007).

    Article  CAS  PubMed  Google Scholar 

  157. Zhang, H. et al. HIF1-dependent expression of angiopoietin-like 4 and L1CAM mediates vascular metastasis of hypoxic breast cancer cells to the lungs. Oncogene 31, 1757–1770 (2012).

    Article  CAS  PubMed  Google Scholar 

  158. Tang, N. et al. Loss of HIF1α in endothelial cells disrupts a hypoxia-driven VEGF autocrine loop necessary for tumorigenesis. Cancer Cell 6, 485–495 (2004).

    Article  CAS  PubMed  Google Scholar 

  159. Yamashita, T. et al. Hypoxia-inducible transcription factor 2α in endothelial cells regulates tumour neovascularization through activation of ephrin A1. J. Biol. Chem. 283, 18926–18936 (2008).

    Article  CAS  PubMed  Google Scholar 

  160. Mazzone, M. et al. Heterozygous deficiency of PHD2 restores tumour oxygenation and inhibits metastasis via endothelial normalization. Cell 136, 839–851 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Leite de Oliveira, R. et al. Gene-targeting of PHD2 improves tumour response to chemotherapy and prevents side-toxicity. Cancer Cell 22, 263–277 (2012).

    Article  CAS  PubMed  Google Scholar 

  162. Acker, T. et al. Genetic evidence for a tumour suppressor role of HIF2α. Cancer Cell 8, 131–141 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Mazumdar, J. et al. HIF2α deletion promotes KRAS-driven lung tumour development. Proc. Natl Acad. Sci. USA 107, 14182–14187 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Kummar, S. et al. Multihistology, target-driven pilot trial of oral topotecan as an inhibitor of hypoxia-inducible factor 1α in advanced solid tumours. Clin. Cancer Res. 17, 5123–5131 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sun, K., Tordjman, J., Clément, K. & Scherer, Philipp, E. Fibrosis and adipose tissue dysfunction. Cell Metab. 18, 470–477 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Rose, N. R., McDonough, M. A., King, O. N., Kawamura, A. & Schofield, C. J. Inhibition of 2-oxoglutarate dependent oxygenases. Chem. Soc. Rev. 40, 4364–4397 (2011).

    Article  CAS  PubMed  Google Scholar 

  167. Murad, S., Walker, L. C., Tajima, S. & Pinnell, S. R. Minimum structural requirements for minoxidil inhibition of lysyl hydroxylase in cultured fibroblasts. Arch. Biochem. Biophys. 308, 42–47 (1994).

    Article  CAS  PubMed  Google Scholar 

  168. Tang, S. S., Trackman, P. C. & Kagan, H. M. Reaction of aortic lysyl oxidase with β-aminopropionitrile. J. Biol. Chem. 258, 4331–4338 (1983).

    Article  CAS  PubMed  Google Scholar 

  169. Siegel, R. C. Collagen crosslinking. Effect of d-penicillamine on crosslinking in vitro. J. Biol. Chem. 252, 254–259 (1977).

    Article  CAS  PubMed  Google Scholar 

  170. Barry-Hamilton, V. et al. Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nature Med. 16, 1009–1017 (2010).

    Article  CAS  PubMed  Google Scholar 

  171. Zardavas, D., Baselga, J. & Piccart, M. Emerging targeted agents in metastatic breast cancer. Nature Rev. Clin. Oncol. 10, 191–210 (2013).

    Article  CAS  Google Scholar 

  172. Liu, G., Nellaiappan, K. & Kagan, H. M. Irreversible inhibition of lysyl oxidase by homocysteine thiolactone and its selenium and oxygen analogues: Implications for homocystinuria. J. Biol. Chem. 272, 32370–32377 (1997).

    Article  CAS  PubMed  Google Scholar 

  173. Gilkes, D. M. & Semenza, G. L. Role of hypoxia-inducible factors in breast cancer metastasis. Future Oncol. 9, 1623–1636 (2013).

    Article  CAS  PubMed  Google Scholar 

  174. Entenberg, D. et al. in Current Protocols in Cell Biology. Ch. 19, 19.7.1–19.7.19 (Wiley, 2013).

    Google Scholar 

  175. Giampuzzi, M. et al. Downregulation of lysyl oxidase-induced tumorigenic transformation in NRK-49F cells characterized by constitutive activation of RAS proto-oncogene. J. Biol. Chem. 276, 29226–29232 (2001).

    Article  CAS  PubMed  Google Scholar 

  176. Kadler, K. E., Hill, A. & Canty-Laird, E. G. Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr. Opin. Cell Biol. 20, 495–501 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Zhang, K. et al. The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis. Nature Cell Biol. 15, 677–687 (2013).

    Article  CAS  PubMed  Google Scholar 

  178. Wang, G. L., Jiang, B. H., Rue, E. A. & Semenza, G. L. Hypoxia-inducible factor 1 is a basic-helix–loop–helix-PAS heterodimer regulated by cellular O2 tension. Proc. Natl Acad. Sci. USA 92, 5510–5514 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Wang, G. L. & Semenza, G. L. Purification and characterization of hypoxia-inducible factor 1. J. Biol. Chem. 270, 1230–1237 (1995).

    Article  CAS  PubMed  Google Scholar 

  180. Semenza, G. L. et al. 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. 271, 32529–32537 (1996).

    Article  CAS  PubMed  Google Scholar 

  181. Kaelin, W. G. Jr & Ratcliffe, P. J. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30, 393–402 (2008).

    Article  CAS  PubMed  Google Scholar 

  182. Tian, H., McKnight, S. L. & Russell, D. W. Endothelial PAS domain protein 1 (EPAS1), a transcription factor selectively expressed in endothelial cells. Genes Dev. 11, 72–82 (1997).

    Article  CAS  PubMed  Google Scholar 

  183. Wiesener, M. S. et al. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1α. Blood 92, 2260–2268 (1998).

    Article  CAS  PubMed  Google Scholar 

  184. Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).

    Article  CAS  PubMed  Google Scholar 

  185. Zundel, W. et al. Loss of PTEN facilitates HIF1-mediated gene expression. Genes Dev. 14, 391–396 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Akakura, N. et al. Constitutive expression of hypoxia-inducible factor-1α renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 61, 6548–6554 (2001).

    CAS  PubMed  Google Scholar 

  187. Zhong, H. et al. Modulation of hypoxia-inducible factor 1α expression by the epidermal growth factor/phosphatidylinositol 3-kinase/PTEN/AKT/FRAP pathway in human prostate cancer cells: implications for tumour angiogenesis and therapeutics. Cancer Res. 60, 1541–1545 (2000).

    CAS  PubMed  Google Scholar 

  188. Rajkumar, T. et al. Identification and validation of genes involved in cervical tumorigenesis. BMC Cancer 11, 80 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  189. Dong, S. et al. Histology-based expression profiling yields novel prognostic markers in human glioblastoma. J. Neuropathol. Exp. Neurol. 64, 948–955 (2005).

    Article  PubMed  Google Scholar 

  190. Arao, T. et al. ZD6474 inhibits tumour growth and intraperitoneal dissemination in a highly metastatic orthotopic gastric cancer model. Int. J. Cancer 118, 483–489 (2006).

    Article  CAS  PubMed  Google Scholar 

  191. Bos, P. D. et al. Genes that mediate breast cancer metastasis to the brain. Nature 459, 1005–1009 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Kavak, E., Unlu, M., Nister, M. & Koman, A. Meta-analysis of cancer gene expression signatures reveals new cancer genes, SAGE tags and tumour associated regions of co-regulation. Nucleic Acids Res. 38, 7008–7021 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Chang, K. P. et al. 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. 10, 4935–4947 (2011).

    Article  CAS  PubMed  Google Scholar 

  194. Jarzab, B. et al. Gene expression profile of papillary thyroid cancer: sources of variability and diagnostic implications. Cancer Res. 65, 1587–1597 (2005).

    Article  CAS  PubMed  Google Scholar 

  195. Brigstock, D. R. Connective tissue growth factor (CCN2, CTGF) and organ fibrosis: lessons from transgenic animals. J. Cell Commun. Signal. 4, 1–4 (2010).

    Article  PubMed  Google Scholar 

  196. Vlodavsky, I. et al. Extracellular matrix-resident growth factors and enzymes: possible involvement in tumour metastasis and angiogenesis. Cancer Metastasis Rev. 9, 203–226 (1990).

    Article  CAS  PubMed  Google Scholar 

  197. Swigris, J. & Brown, K. The role of endothelin 1 in the pathogenesis of idiopathic pulmonary fibrosis. BioDrugs 24, 49–54 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Kagami, S., Border, W. A., Miller, D. E. & Noble, N. A. Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor-β expression in rat glomerular mesangial cells. J. Clin. Invest. 93, 2431–2437 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Wang, Z. et al. Hypoxia-inducible factor 1α contributes to the profibrotic action of angiotensin II in renal medullary interstitial cells. Kidney Int. 79, 300–310 (2011).

    Article  CAS  PubMed  Google Scholar 

  200. Grotendorst, G. R., Rahmanie, H. & Duncan, M. R. Combinatorial signalling pathways determine fibroblast proliferation and myofibroblast differentiation. FASEB J. 18, 469–479 (2004).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

D.M.G. is supported by funding from the National Cancer Institute (NCI) (K99CA181352) and is a Susan G. Komen postdoctoral fellow. Cancer research in the Wirtz laboratory is supported by the US National Insititutes of Health (grants U54-CA143868 and R01-CA174388). Cancer Research in the Semenza laboratory is supported by the American Cancer Society, NCI grant U54-CA143868, the Department of Defense Breast Cancer Research Program and the Johns Hopkins Institute for Cell Engineering. G.L.S. is the C. Michael Armstrong Professor at the Johns Hopkins University School of Medicine, USA, and an American Cancer Society Research Professor. D.W. is the T.H. Smoot Professor and Vice Provost for Research at Johns Hopkins University.

Author information

Authors and Affiliations

  1. Vascular Program, Institute for Cell Engineering, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Daniele M. Gilkes & Gregg L. Semenza

  2. Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, 21218, Maryland, USA

    Daniele M. Gilkes & Gregg L. Semenza

  3. Departments of Pediatrics, Oncology, Medicine, Radiation Oncology and Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Gregg L. Semenza

  4. Johns Hopkins Physical Sciences-Oncology Center, The Johns Hopkins University, Baltimore, 21218, Maryland, USA

    Denis Wirtz

  5. Department of Chemical and Biomolecular Engineering, The Johns Hopkins University, Baltimore, 21218, Maryland, USA

    Denis Wirtz

  6. Departments of Oncology and Pathology and Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Denis Wirtz

Authors
  1. Daniele M. Gilkes
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gregg L. Semenza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Denis Wirtz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Denis Wirtz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gilkes, D., Semenza, G. & Wirtz, D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer 14, 430–439 (2014). https://doi.org/10.1038/nrc3726

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc3726

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer