Cancer and Metastasis Reviews

, Volume 35, Issue 4, pp 655–667 | Cite as

From transformation to metastasis: deconstructing the extracellular matrix in breast cancer

  • Shelly Kaushik
  • Michael W Pickup
  • Valerie M Weaver


The extracellular matrix (ECM) is a guiding force that regulates various developmental stages of the breast. In addition to providing structural support for the cells, it mediates epithelial-stromal communication and provides cues for cell survival, proliferation, and differentiation. Perturbations in ECM architecture profoundly influence breast tumor progression and metastasis. Understanding how a dysregulated ECM can facilitate malignant transformation is crucial to designing treatments to effectively target the tumor microenvironment. Here, we address the contribution of ECM mechanics to breast cancer progression, metastasis, and treatment resistance and discuss potential therapeutic strategies targeting the ECM.


Extracellular matrix (ECM) Breast cancer Desmoplasia Mechanosignaling Metastasis Treatment resistance 



The authors apologize to all colleagues whose work could not be cited due to space limitations. The authors would like to thank Dr. Janna Mouw for her insightful review of the manuscript. This work was supported by NIH grant RO1CA192914, USMRAA (DOD) grant BC122990, U54 grant CA210184, and UO1 grant CA202241-01.


  1. 1.
    Wiseman, B. S., & Werb, Z. (2002). Stromal effects on mammary gland development and breast cancer. Science (New York, N.Y.), 296(5570), 1046–1049. doi: 10.1126/science.1067431.CrossRefGoogle Scholar
  2. 2.
    Robinson, G. W., Karpf, a. B., & Kratochwil, K. (1999). Regulation of mammary gland development by tissue interaction. Journal of Mammary Gland Biology and Neoplasia, 4(1), 9–19. doi: 10.1023/A:1018748418447.PubMedCrossRefGoogle Scholar
  3. 3.
    Wicha, M. S., Liotta, L. A., Vonderhaar, B. K., & Kidwell, W. R. (1980). Effects of inhibition of basement membrane collagen deposition on rat mammary gland development. Developmental Biology, 80(2), 253–266. doi: 10.1016/0012-1606(80)90402-9.PubMedCrossRefGoogle Scholar
  4. 4.
    Silberstein, G. B., & Daniel, C. W. (1982). Glycosaminoglycans in the basal lamina and extracellular matrix of the developing mouse mammary duct. Developmental Biology, 90(1), 215–222. doi: 10.1016/0012-1606(82)90228-7.PubMedCrossRefGoogle Scholar
  5. 5.
    Fata, J. E., Werb, Z., & Bissell, M. J. (2004). Regulation of mammary gland branching morphogenesis by the extracellular matrix and its remodeling enzymes. Breast cancer research: BCR, 6(1), 1–11. doi: 10.1186/bcr634.PubMedGoogle Scholar
  6. 6.
    Paszek, M. J., & Weaver, V. M. (2004). The tension mounts: mechanics meets morphogenesis and malignancy. Journal of Mammary Gland Biology and Neoplasia. doi: 10.1007/s10911-004-1404-x.PubMedGoogle Scholar
  7. 7.
    Schedin, P., & Keely, P. J. (2011). Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harbor Perspectives in Biology, 3(1), 1–22. doi: 10.1101/cshperspect.a003228.CrossRefGoogle Scholar
  8. 8.
    Schedin, P., & Keely, P. J. (2011). and Mechanosignaling in normal development and tumor progression, 1–22. doi: 10.1101/cshperspect.a003228.
  9. 9.
    Schedin, P., Mitrenga, T., McDaniel, S., & Kaeck, M. (2004). Mammary ECM composition and function are altered by reproductive state. Molecular Carcinogenesis, 41(4), 207–220. doi: 10.1002/mc.20058.PubMedCrossRefGoogle Scholar
  10. 10.
    Hynes, R. O. (2009). The extracellular matrix: not just pretty fibrils. Science (New York, N.Y.), 326(5957), 1216–1219. doi: 10.1126/science.1176009.CrossRefGoogle Scholar
  11. 11.
    Pickup, M. W., Mouw, J. K., & Weaver, V. M. (2014). The extracellular matrix modulates the hallmarks of cancer TL - 15. EMBO Reports, 15 VN-r(12). doi: 10.15252/embr.201439246.
  12. 12.
    Sweet, D. T., Chen, Z., Wiley, D. M., Bautch, V. L., & Tzima, E. (2012). The adaptor protein Shc integrates growth factor and ECM signaling during postnatal angiogenesis. Blood, 119(8), 1946–1955. doi: 10.1182/blood-2011-10-384560.PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Newman, a. C., Nakatsu, M. N., Chou, W., Gershon, P. D., & Hughes, C. C. W. (2011). The requirement for fibroblasts in angiogenesis: fibroblast-derived matrix proteins are essential for endothelial cell lumen formation. Molecular Biology of the Cell, 22(20), 3791–3800. doi: 10.1091/mbc.E11-05-0393.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Myers, K. A., Applegate, K. T., Danuser, G., Fischer, R. S., & Waterman, C. M. (2011). Distinct ECM mechanosensing pathways regulate microtubule dynamics to control endothelial cell branching morphogenesis. Journal of Cell Biology, 192(2), 321–334. doi: 10.1083/jcb.201006009.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Sorokin, L. (2010). The impact of the extracellular matrix on inflammation. Nature reviews. Immunology, 10(10), 712–723. doi: 10.1038/nri2852.PubMedGoogle Scholar
  16. 16.
    Lu, P., Weaver, V. M., & Werb, Z. (2012). The extracellular matrix: a dynamic niche in cancer progression. Journal of Cell Biology, 196(4), 395–406. doi: 10.1083/jcb.201102147.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Egeblad, M., Rasch, M. G., & Weaver, V. M. (2010). Dynamic interplay between the collagen scaffold and tumor evolution. Current Opinion in Cell Biology. doi: 10.1016/ Scholar
  18. 18.
    Provenzano, P. P., Eliceiri, K. W., Campbell, J. M., Inman, D. R., White, J. G., & Keely, P. J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine, 4(1), 38. doi: 10.1186/1741-7015-4-38.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Huijbers, I. J., Iravani, M., Popov, S., Robertson, D., Al-Sarraj, S., Jones, C., & Isacke, C. M. (2010). A role for fibrillar collagen deposition and the collagen internalization receptor endo180 in glioma invasion. PloS One, 5(3). doi: 10.1371/journal.pone.0009808.
  20. 20.
    Zhu, G. G., Risteli, L., Makinen, M., Risteli, J., Kauppila, A., & Stenback, F. (1995). Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. Cancer, 75(4), 1010–1017. doi: 10.1002/1097-0142(19950215)75:4<1010::AID-CNCR2820750417>3.0.CO;2-O.PubMedCrossRefGoogle Scholar
  21. 21.
    Kauppila, S., Stenbäck, F., Risteli, J., Jukkola, A., & Risteli, L. (1998). Aberrant type I and type III collagen gene expression in human breast cancer in vivo. The Journal of Pathology, 186(3), 262–268. doi: 10.1002/(SICI)1096-9896(1998110)186:3<262::AID-PATH191>3.0.CO;2-3.PubMedCrossRefGoogle Scholar
  22. 22.
    Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., … Weaver, V. M. (2005). Tensional homeostasis and the malignant phenotype. Cancer cell, 8(3), 241–54. doi:  10.1016/j.ccr.2005.08.010
  23. 23.
    Lu, P., Takai, K., Weaver, V. M., & Werb, Z. (2011). Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor Perspectives in Biology, 3(12), 1–24. doi: 10.1101/cshperspect.a005058.CrossRefGoogle Scholar
  24. 24.
    Lopez, J. I., Kang, I., You, W.-K., McDonald, D. M., & Weaver, V. M. (2011). In situ force mapping of mammary gland transformation. Integrative biology: quantitative biosciences from nano to macro, 3(9), 910–921. doi: 10.1039/c1ib00043h.CrossRefGoogle Scholar
  25. 25.
    Hu, M., Yao, J., Carroll, D. K., Weremowicz, S., Chen, H., Carrasco, D., … Polyak, K. (2008). Regulation of in situ to invasive breast carcinoma transition. Cancer Cell, 13(5), 394–406. doi:  10.1016/j.ccr.2008.03.007
  26. 26.
    Lerwill, M. F. (2004). Current practical applications of diagnostic immunohistochemistry in breast pathology. The American Journal of Surgical Pathology, 28, 1076–1091. doi: 10.1097/01.pas.0000126780.10029.f0.PubMedCrossRefGoogle Scholar
  27. 27.
    Ursin, G., Hovanessian-Larsen, L., Parisky, Y. R., Pike, M. C., & Wu, A. H. (2005). Greatly increased occurrence of breast cancers in areas of mammographically dense tissue. Breast Cancer Research, 7(5), R605–R608. doi: 10.1186/bcr1260.PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Acerbi, I., Cassereau, L., Dean, I., Shi, Q., Au, A., Park, C., … Weaver, V. M. (2015). Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integrative biology: quantitative biosciences from nano to macro, 7(10), 1120–34. doi:  10.1039/c5ib00040h
  29. 29.
    Conklin, M. W., Eickhoff, J. C., Riching, K. M., Pehlke, C. A., Eliceiri, K. W., Provenzano, P. P., … Keely, P. J. (2011). Aligned collagen is a prognostic signature for survival in human breast carcinoma. American Journal of Pathology, 178(3), 1221–1232. doi:  10.1016/j.ajpath.2010.11.076
  30. 30.
    Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Erler, J. T., Fong, S. F. T., … Weaver, V. M. (2010). NIH Public Access, 139(5), 891–906. doi:  10.1016/j.cell.2009.10.027.Matrix
  31. 31.
    Ding, J., Warren, R., Girling, A., Thompson, D., & Easton, D. (n.d.). Mammographic density, estrogen receptor status and other breast cancer tumor characteristics. The Breast Journal, 16(3), 279–289. doi: 10.1111/j.1524-4741.2010.00907.x.
  32. 32.
    Conroy, S. M., Butler, L. M., Harvey, D., Gold, E. B., Sternfeld, B., Greendale, G. A., & Habel, L. A. (2011). Metabolic syndrome and mammographic density: the Study of Women’s Health Across the Nation. International Journal of Cancer, 129(7), 1699–1707. doi: 10.1002/ijc.25790.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Yaghjyan, L., Colditz, G. A., Collins, L. C., Schnitt, S. J., Rosner, B., Vachon, C., & Tamimi, R. M. (2011). Mammographic breast density and subsequent risk of breast cancer in postmenopausal women according to tumor characteristics. Journal of the National Cancer Institute, 103(15), 1179–1189. doi: 10.1093/jnci/djr225.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    Hugh, J., Hanson, J., Cheang, M. C. U., Nielsen, T. O., Perou, C. M., Dumontet, C., … Vogel, C. (2009). Breast cancer subtypes and response to docetaxel in node-positive breast cancer: use of an immunohistochemical definition in the BCIRG 001 trial. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 27(8), 1168–76. doi:  10.1200/JCO.2008.18.1024
  35. 35.
    Chang, R.-F., Chen, H.-H., Chang, Y.-C., Huang, C.-S., Chen, J.-H., & Lo, C.-M. (2016). Quantification of breast tumor heterogeneity for ER status, HER2 status, and TN molecular subtype evaluation on DCE-MRI. Magnetic Resonance Imaging, 34(6), 809–819. doi: 10.1016/j.mri.2016.03.001.PubMedCrossRefGoogle Scholar
  36. 36.
    Park, S. Y., Kim, H. M., & Koo, J. S. (2015). Differential expression of cancer-associated fibroblast-related proteins according to molecular subtype and stromal histology in breast cancer. Breast Cancer Research and Treatment, 149(3), 727–741. doi: 10.1007/s10549-015-3291-9.PubMedCrossRefGoogle Scholar
  37. 37.
    Afik, R., Zigmond, E., Vugman, M., Klepfish, M., Shimshoni, E., Pasmanik-Chor, M., … Varol, C. (2016). Tumor macrophages are pivotal constructors of tumor collagenous matrix. Journal of Experimental Medicine.Google Scholar
  38. 38.
    Tchou, J., Kossenkov, A. V, Chang, L., Satija, C., Herlyn, M., Showe, L. C., … Gelmon, K. (2012). Human breast cancer associated fibroblasts exhibit subtype specific gene expression profiles. BMC Medical Genomics, 5(1), 39. doi:  10.1186/1755-8794-5-39
  39. 39.
    Galbraith, C. G., Yamada, K. M., & Sheetz, M. P. (2002). The relationship between force and focal complex development. Journal of Cell Biology, 159(4), 695–705. doi: 10.1083/jcb.200204153.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    White, D. E., Kurpios, N. A., Zuo, D., Hassell, J. A., Blaess, S., Mueller, U., & Muller, W. J. (2004). Targeted disruption of beta1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction. Cancer Cell, 6(2), 159–170. doi:10.1016/j.ccr.2004.06.025\rS1535610804002077 [pii].PubMedCrossRefGoogle Scholar
  41. 41.
    Wozniak, M. a., Desai, R., Solski, P. a., Der, C. J., & Keely, P. J. (2003). ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. The Journal of Cell Biology, 163(3), 583–595. doi: 10.1083/jcb.200305010.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Provenzano, P. P., Inman, D. R., Eliceiri, K. W., & Keely, P. J. (2009). Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage. Oncogene, 28(49), 4326–4343. doi: 10.1038/onc.2009.299.PubMedPubMedCentralCrossRefGoogle Scholar
  43. 43.
    Rubashkin, M. G., Cassereau, L., Bainer, R., DuFort, C. C., Yui, Y., Ou, G., … Weaver, V. M. (2014). Force engages vinculin and promotes tumor progression by enhancing PI3K activation of phosphatidylinositol (3,4,5)-triphosphate. Cancer Research, 74(17), 4597–4611. doi:  10.1158/0008-5472.CAN-13-3698
  44. 44.
    Mouw, J. K., Yui, Y., Damiano, L., Bainer, R. O., Lakins, J. N., Acerbi, I., … Weaver, V. M. (2014). Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nature medicine, 20(4), 360–7. doi:  10.1038/nm.3497
  45. 45.
    Gehler, S., Ponik, S. M., Riching, K. M., & Keely, P. J. (2013). Bi-directional signaling: extracellular matrix and integrin regulation of breast tumor progression. Critical Reviews in Eukaryotic Gene Expression, 23(2), 139–157. doi: 10.1615/CritRevEukarGeneExpr.2013006647.PubMedPubMedCentralCrossRefGoogle Scholar
  46. 46.
    Zhu, J., Xiong, G., Trinkle, C., & Xu, R. (2014). Integrated extracellular matrix signaling in mammary gland development and breast cancer progression. Histology and Histopathology, 29(9), 1083–1092. doi: 10.1002/jcp.24872.The.PubMedPubMedCentralGoogle Scholar
  47. 47.
    Franco, C., Hou, G., Ahmad, P. J., Fu, E. Y. K., Koh, L., Vogel, W. F., & Bendeck, M. P. (2008). Discoidin domain receptor 1 (Ddr1) deletion decreases atherosclerosis by accelerating matrix accumulation and reducing inflammation in low-density lipoprotein receptor-deficient mice. Circulation Research, 102(10), 1202–1211. doi: 10.1161/CIRCRESAHA.107.170662.PubMedCrossRefGoogle Scholar
  48. 48.
    Meyaard, L. (2008). The inhibitory collagen receptor LAIR-1 (CD305). Journal of Leukocyte Biology, 83(4), 799–803. doi: 10.1189/jlb.0907609.PubMedCrossRefGoogle Scholar
  49. 49.
    Houghton, A. M., Quintero, P. A., Perkins, D. L., Kobayashi, D. K., Kelley, D. G., Marconcini, L. A., … Shapiro, S. D. (2006). Elastin fragments drive disease progression in a murine model of emphysema. Journal of Clinical Investigation, 116(3), 753–759. doi:  10.1172/JCI25617
  50. 50.
    Krishnan, R., & Cleary, E. G. (1990). Elastin gene expression in elastotic human breast cancers and epithelial cell lines. Cancer Research, 50(7), 2164–2171.PubMedGoogle Scholar
  51. 51.
    García-Mendoza, M. G., Inman, D. R., Ponik, S. M., Jeffery, J. J., Sheerar, D. S., Van Doorn, R. R., & Keely, P. J. (2016). Neutrophils drive accelerated tumor progression in the collagen-dense mammary tumor microenvironment. Breast cancer research: BCR, 18(1), 49. doi: 10.1186/s13058-016-0703-7.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Coussens, L. M., & Werb, Z. (2002). Inflammation and cancer. Nature, 420(6917), 860–867. doi: 10.1038/nature01322.PubMedPubMedCentralCrossRefGoogle Scholar
  53. 53.
    Sieminski, A. L., Hebbel, R. P., & Gooch, K. J. (2004). The relative magnitudes of endothelial force generation and matrix stiffness modulate capillary morphogenesis in vitro. Experimental Cell Research, 297(2), 574–584. doi: 10.1016/j.yexcr.2004.03.035.PubMedCrossRefGoogle Scholar
  54. 54.
    Teo, N. B., Shoker, B. S., Jarvis, C., Martin, L., Sloane, J. P., & Holcombe, C. (2002). Vascular density and phenotype around ductal carcinoma in situ (DCIS) of the breast. British Journal of Cancer, 86(6), 905–911. doi: 10.1038/sj.bjc.6600053.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Mason, B. N., Starchenko, A., Williams, R. M., Bonassar, L. J., & Reinhart-King, C. A. (2013). Tuning three-dimensional collagen matrix stiffness independently of collagen concentration modulates endothelial cell behavior. Acta Biomaterialia, 9(1), 4635–4644. doi: 10.1016/j.actbio.2012.08.007.PubMedCrossRefGoogle Scholar
  56. 56.
    Kohn, J. C., Zhou, D. W., Bordeleau, F., Zhou, A. L., Mason, B. N., Mitchell, M. J., … Reinhart-King, C. A. (2015). Cooperative effects of matrix stiffness and fluid shear stress on endothelial cell behavior. Biophysical Journal, 108(3), 471–478. doi:  10.1016/j.bpj.2014.12.023
  57. 57.
    Kaplan, R. N., Rafii, S., & Lyden, D. (2006). Preparing the “soil”: the premetastatic niche. Cancer Research. doi: 10.1158/0008-5472.CAN-06-2407.PubMedCentralGoogle Scholar
  58. 58.
    Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature reviews. Cancer, 2(8), 563–572. doi: 10.1038/nrc865.PubMedGoogle Scholar
  59. 59.
    Nguyen, D. X., Bos, P. D., & Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature reviews. Cancer, 9(4), 274–284. doi: 10.1038/nrc2622.PubMedGoogle Scholar
  60. 60.
    Cox, T. R., Rumney, R. M., Schoof, E. M., Perryman, L., Hoye, A. M., Agrawal, A., … Erler, J. T. (2015). The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature, 522(7554), 106–110. doi:  10.1038/nature14492
  61. 61.
    Miller, B. W., Morton, J. P., Pinese, M., Saturno, G., Jamieson, N. B., McGhee, E., … Sansom, O. J. (2015). Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. EMBO Mol Med, 7, 1063–1076. doi:  10.15252/emmm
  62. 62.
    Erler, J. T., & Weaver, V. M. (2009). Three-dimensional context regulation of metastasis. Clinical and Experimental Metastasis, 26(1), 35–49. doi: 10.1007/s10585-008-9209-8.PubMedCrossRefGoogle Scholar
  63. 63.
    Giles, A. J., Reid, C. M., De Wayne Evans, J., Murgai, M., Vicioso, Y., Highfill, S. L., … Kaplan, R. N. (2016). Activation of hematopoietic stem/progenitor cells promotes immunosuppression within the pre-metastatic niche. Cancer Research, 76(6), 1335–1347. doi:  10.1158/0008-5472.CAN-15-0204
  64. 64.
    Gao, D., Joshi, N., Choi, H., Ryu, S., Hahn, M., Catena, R., … Mittal, V. (2012). Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research, 72(6), 1384–1394. doi:  10.1158/0008-5472.CAN-11-2905
  65. 65.
    Kagan, H. M., & Li, W. (2003). Lysyl oxidase: properties, specificity, and biological roles inside and outside of the cell. Journal of Cellular Biochemistry, 88(4), 660–672. doi: 10.1002/jcb.10413.PubMedCrossRefGoogle Scholar
  66. 66.
    Pfeiffer, B. J., Franklin, C. L., Hsieh, F. H., Bank, R. A., & Phillips, C. L. (2005). Alpha 2(I) collagen deficient oim mice have altered biomechanical integrity, collagen content, and collagen crosslinking of their thoracic aorta. Matrix Biology, 24(7), 451–458. doi: 10.1016/j.matbio.2005.07.001.PubMedCrossRefGoogle Scholar
  67. 67.
    Erler, J. T., Bennewith, K. L., Cox, T. R., Lang, G., Bird, D., Koong, A., … Giaccia, A. J. (2009). Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell, 15(1), 35–44. doi:  10.1016/j.ccr.2008.11.012
  68. 68.
    Kaplan, R. N., Riba, R. D., Zacharoulis, S., Anna, H., Vincent, L., Costa, C., … Lyden, D. (2005). VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature, 438(7069), 820–827. doi:  10.1038/nature04186.VEGFR1-positive
  69. 69.
    Erler, J. T., Bennewith, K. L., Nicolau, M., Dornhöfer, N., Kong, C., Le, Q.-T., … Giaccia, A. J. (2006). Lysyl oxidase is essential for hypoxia-induced metastasis. Nature, 440(7088), 1222–6. doi:  10.1038/nature04695
  70. 70.
    Wong, C. C.-L., Gilkes, D. M., Zhang, H., Chen, J., Wei, H., Chaturvedi, P., … Semenza, G. L. (2011). Hypoxia-inducible factor 1 is a master regulator of breast cancer metastatic niche formation. Proceedings of the National Academy of Sciences of the United States of America, 108(39), 16369–74. doi:  10.1073/pnas.1113483108
  71. 71.
    Fogelgren, B., Polgár, N., Szauter, K. M., Újfaludi, Z., Laczkó, R., Fong, K. S. K., & Csiszar, K. (2005). Cellular fibronectin binds to lysyl oxidase with high affinity and is critical for its proteolytic activation. Journal of Biological Chemistry, 280(26), 24690–24697. doi: 10.1074/jbc.M412979200.PubMedCrossRefGoogle Scholar
  72. 72.
    Høye, A. M., & Erler, J. T. (2016). Structural ECM components in the pre-metastatic and metastatic niche. American Journal of Physiology. Cell Physiology, 1(73) ajpcell.00326.2015. doi: 10.1152/ajpcell.00326.2015.
  73. 73.
    Hoshino, A., Costa-Silva, B., Shen, T.-L., Rodrigues, G., Hashimoto, A., Tesic Mark, M., … Lyden, D. (2015). Tumour exosome integrins determine organotropic metastasis. Nature, 527(7578), 329–35. doi:  10.1038/nature15756
  74. 74.
    Hsemann, Y., Geigl, J. B., Schubert, F., Musiani, P., Meyer, M., Burghart, E., … Klein, C. A. (2008). Systemic spread is an early step in breast cancer. Cancer Cell, 13(1), 58–68. doi:  10.1016/j.ccr.2007.12.003
  75. 75.
    Kennecke, H., Yerushalmi, R., Woods, R., Cheang, M. C. U., Voduc, D., Speers, C. H., … Gelmon, K. (2010). Metastatic behavior of breast cancer subtypes. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 28(20), 3271–7. doi:  10.1200/JCO.2009.25.9820
  76. 76.
    Rizwan, A., Bulte, C., Kalaichelvan, A., Cheng, M., Krishnamachary, B., Bhujwalla, Z. M., … Tyers, M. (2015). Metastatic breast cancer cells in lymph nodes increase nodal collagen density. Scientific Reports, 5, 10002. doi:  10.1038/srep10002
  77. 77.
    Koyama, T., Hasebe, T., Tsuda, H., Hirohashi, S., Sasaki, S., Fukutomi, T., … Mukai, K. (1999). Histological factors associated with initial bone metastasis of invasive ductal carcinoma of the breast. Japanese Journal of Cancer Research, 90(3), 294–300. doi:  10.1111/j.1349-7006.1999.tb00747.x
  78. 78.
    Lawson, D. A., Bhakta, N. R., Kessenbrock, K., Prummel, K. D., Yu, Y., Takai, K., … Werb, Z. (2015). Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature, 526(7571), 131–135. doi:  10.1038/nature15260
  79. 79.
    Oskarsson, T., Acharyya, S., Zhang, X. H.-F., Vanharanta, S., Tavazoie, S. F., Morris, P. G., … Massagué, J. (2011). Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nature medicine, 17(7), 867–74. doi:  10.1038/nm.2379
  80. 80.
    O’Connell, J. T., Sugimoto, H., Cooke, V. G., MacDonald, B. A., Mehta, A. I., LeBleu, V. S., … Kalluri, R. (2011). VEGF-A and tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proceedings of the National Academy of Sciences of the United States of America, 108(38), 16002–7. doi:  10.1073/pnas.1109493108
  81. 81.
    Malanchi, I., Santamaria-Martínez, A., Susanto, E., Peng, H., Lehr, H.-A., Delaloye, J.-F., & Huelsken, J. (2011). Interactions between cancer stem cells and their niche govern metastatic colonization. Nature, 481(7379), 85–89. doi: 10.1038/nature10694.PubMedCrossRefGoogle Scholar
  82. 82.
    Aguirre-Ghiso, J. A., Liu, D., Mignatti, A., Kovalski, K., & Ossowski, L. (2001). Urokinase receptor and fibronectin regulate the ERK(MAPK) to p38(MAPK) activity ratios that determine carcinoma cell proliferation or dormancy in vivo. Molecular Biology of the Cell, 12(4), 863–879.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Barkan, D., Green, J. E., & Chambers, A. F. (2010). Extracellular matrix: a gatekeeper in the transition from dormancy to metastatic growth. European Journal of Cancer, 46(7), 1181–1188. doi: 10.1016/j.ejca.2010.02.027.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Hayashi, M., Yamamoto, Y., Ibusuki, M., Fujiwara, S., Yamamoto, S., Tomita, S., … Iwase, H. (2012). Evaluation of tumor stiffness by elastography is predictive for pathologic complete response to neoadjuvant chemotherapy in patients with breast cancer. Annals of Surgical Oncology, 19(9), 3042–3049. doi:  10.1245/s10434-012-2343-1
  85. 85.
    Giussani, M., Merlino, G., Cappelletti, V., Tagliabue, E., & Daidone, M. G. (2015). Tumor-extracellular matrix interactions: identification of tools associated with breast cancer progression. Seminars in Cancer Biology. doi: 10.1016/j.semcancer.2015.09.012.PubMedGoogle Scholar
  86. 86.
    Magzoub, M., Jin, S., & Verkman, a. S. (2008). Enhanced macromolecule diffusion deep in tumors after enzymatic digestion of extracellular matrix collagen and its associated proteoglycan decorin. The FASEB journal: official publication of the Federation of American Societies for Experimental Biology, 22(1), 276–284. doi: 10.1096/fj.07-9150com.CrossRefGoogle Scholar
  87. 87.
    Netti, P. A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J., & Jain, R. K. (2000). Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Research, 60(9), 2497–2503. doi: 10.1126/science.271.5252.1079.PubMedGoogle Scholar
  88. 88.
    Erikson, A., Andersen, H. N., Naess, S. N., Sikorski, P., & Davies, C. D. L. (2008). Physical and chemical modifications of collagen gels: impact on diffusion. Biopolymers, 89(2), 135–143. doi: 10.1002/bip.20874.PubMedCrossRefGoogle Scholar
  89. 89.
    Farmer, P., Bonnefoi, H., Anderle, P., Cameron, D., Wirapati, P., Becette, V., … Delorenzi, M. (2009). A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nature medicine, 15(1), 68–74. doi:  10.1038/nm0209-220a
  90. 90.
    Misra, S., Obeid, L. M., Hannun, Y. A., Minamisawa, S., Berger, F. G., Markwald, R. R., … Ghatak, S. (2008). Hyaluronan constitutively regulates activation of COX-2-mediated cell survival activity in intestinal epithelial and colon carcinoma cells. Journal of Biological Chemistry, 283(21), 14335–14344. doi:  10.1074/jbc.M703811200
  91. 91.
    Jansen, M. P. H. M., Foekens, J. a, van Staveren, I. L., Dirkzwager-Kiel, M. M., Ritstier, K., Look, M. P., … Berns, E. M. J. J. (2005). Molecular classification of tamoxifen-resistant breast carcinomas by gene expression profiling. Journal of clinical oncology: official journal of the American Society of Clinical Oncology, 23(4), 732–40. doi:  10.1200/JCO.2005.05.145
  92. 92.
    Thurber, G. M., Schmidt, M. M., & Wittrup, K. D. (2008). Antibody tumor penetration: transport opposed by systemic and antigen-mediated clearance. Advanced Drug Delivery Reviews. doi: 10.1016/j.addr.2008.04.012.PubMedPubMedCentralGoogle Scholar
  93. 93.
    Holle, A. W., Young, J. L., & Spatz, J. P. (2016). In vitro cancer cell-ECM interactions inform in vivo cancer treatment. Advanced Drug Delivery Reviews. doi: 10.1016/j.addr.2015.10.007.PubMedGoogle Scholar
  94. 94.
    Chrenek, M. a., Wong, P., & Weaver, V. M. (2001). Tumour-stromal interactions. Integrins and cell adhesions as modulators of mammary cell survival and transformation. Breast cancer research: BCR, 3(4), 224–229. doi: 10.1186/bcr300.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Sloan, E. K., Pouliot, N., Stanley, K. L., Chia, J., Moseley, J. M., Hards, D. K., & Anderson, R. L. (2006). Tumor-specific expression of αvβ3 integrin promotes spontaneous metastasis of breast cancer to bone. Breast Cancer Research, 8(2), R20. doi: 10.1186/bcr1398.PubMedPubMedCentralCrossRefGoogle Scholar
  96. 96.
    Seguin, L., Kato, S., Franovic, A., Camargo, M. F., Lesperance, J., Elliott, K. C., … Cheresh, D. A. (2014). An integrin β3-KRAS-RalB complex drives tumour stemness and resistance to EGFR inhibition. Nature cell biology, 16(5), 457–68. doi:  10.1038/ncb2953
  97. 97.
    Barkan, D., & Chambers, A. F. (2011). B1-integrin: a potential therapeutic target in the battle against cancer recurrence. Clinical Cancer Research. doi: 10.1158/1078-0432.CCR-11-0642.PubMedGoogle Scholar
  98. 98.
    Das, S., Ongusaha, P. P., Yang, Y. S., Park, J.-M., Aaronson, S. a., & Lee, S. W. (2006). Discoidin domain receptor 1 receptor tyrosine kinase induces cyclooxygenase-2 and promotes chemoresistance through nuclear factor-kappaB pathway activation. Cancer Research, 66, 8123–8130. doi: 10.1158/0008-5472.CAN-06-1215.PubMedCrossRefGoogle Scholar
  99. 99.
    Rammal, H., Saby, C., Magnien, K., Van-Gulick, L., Garnotel, R., Buache, E., … Morjani, H. (2016). Discoidin domain receptors: potential actors and targets in cancer. Frontiers in Pharmacology. doi:  10.3389/fphar.2016.00055
  100. 100.
    Bertout, J. A., Patel, S. A., & Simon, M. C. (2008). The impact of O2 availability on human cancer. Nature reviews. Cancer, 8(12), 967–975. doi: 10.1038/nrc2540.PubMedPubMedCentralGoogle Scholar
  101. 101.
    Pang, M.-F., Siedlik, M. J., Han, S., Stallings-Mann, M., Radisky, D. C., & Nelson, C. M. (2016). Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast cancer stem-like cells. Cancer research. doi: 10.1158/0008-5472.CAN-16-0579.Google Scholar
  102. 102.
    Al-Ejeh, F., Smart, C. E., Morrison, B. J., Chenevix-Trench, G., López, J. A., Lakhani, S. R., … Khanna, K. K. (2011). Breast cancer stem cells: treatment resistance and therapeutic opportunities. Carcinogenesis. doi:  10.1093/carcin/bgr028
  103. 103.
    Naumov, G. N., Townson, J. L., MacDonald, I. C., Wilson, S. M., Bramwell, V. H. C., Groom, A. C., & Chambers, A. F. (2003). Ineffectiveness of doxorubicin treatment on solitary dormant mammary carcinoma cells or late-developing metastases. Breast Cancer Research and Treatment, 82(3), 199–206. doi: 10.1023/B:BREA.0000004377.12288.3c.PubMedCrossRefGoogle Scholar
  104. 104.
    Barkan, D., Kleinman, H., Simmons, J. L., Asmussen, H., Kamaraju, A. K., Hoenorhoff, M. J., … Green, J. E. (2008). Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Research, 68(15), 6241–6250. doi:  10.1158/0008-5472.CAN-07-6849
  105. 105.
    Schrader, J., Gordon-Walker, T. T., Aucott, R. L., van Deemter, M., Quaas, A., Walsh, S., … Iredale, J. P. (2011). Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology, 53(4), 1192–1205. doi:  10.1002/hep.24108
  106. 106.
    Tilghman, R. W., Blais, E. M., Cowan, C. R., Sherman, N. E., Grigera, P. R., Jeffery, E. D., … Parsons, J. T. (2012). Matrix rigidity regulates cancer cell growth by modulating cellular metabolism and protein synthesis. PLoS ONE, 7(5). doi:  10.1371/journal.pone.0037231
  107. 107.
    Pupa, S. M., Giuffré, S., Castiglioni, F., Bertola, L., Cantú, M., Bongarzone, I., … Tagliabue, E. (2007). Regulation of breast cancer response to chemotherapy by fibulin-1. Cancer Research, 67(9), 4271–4277. doi:  10.1158/0008-5472.CAN-06-4162
  108. 108.
    Peiris-Pagès, M., Sotgia, F., & Lisanti, M. P. (2015). Chemotherapy induces the cancer-associated fibroblast phenotype, activating paracrine Hedgehog-GLI signalling in breast cancer cells. Oncotarget, 6(13), 10728–10745. doi: 10.18632/oncotarget.3828.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature reviews. Cancer, 6(5), 392–401. doi: 10.1038/nrc1877.PubMedCrossRefGoogle Scholar
  110. 110.
    Shen, C. J., Sharma, A., Vuong, D.-V., Erler, J. T., Pruschy, M., & Broggini-Tenzer, A. (2014). Ionizing radiation induces tumor cell lysyl oxidase secretion. BMC Cancer, 14(1), 532. doi: 10.1186/1471-2407-14-532.PubMedPubMedCentralCrossRefGoogle Scholar
  111. 111.
    Liu, J., Liao, S., Diop-Frimpong, B., Chen, W., Goel, S., Naxerova, K., … Xu, L. (2012). TGF-β blockade improves the distribution and efficacy of therapeutics in breast carcinoma by normalizing the tumor stroma. Proceedings of the National Academy of Sciences of the United States of America, 109(41), 16618–23. doi:  10.1073/pnas.1117610109
  112. 112.
    Bondareva, A., Downey, C. M., Ayres, F., Liu, W., Boyd, S. K., Hallgrimsson, B., & Jirik, F. R. (2009). The lysyl oxidase inhibitor, beta-aminopropionitrile, diminishes the metastatic colonization potential of circulating breast cancer cells. PloS One, 4(5), e5620. doi: 10.1371/journal.pone.0005620.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Beckenlehner, K., Bannke, S., Spruss, T., Bernhardt, G., Schönenberg, H., & Schiess, W. (1992). Hyaluronidase enhances the activity of adriamycin in breast cancer models in vitro and in vivo. Journal of Cancer Research and Clinical Oncology, 118(8), 591–596.PubMedCrossRefGoogle Scholar
  114. 114.
    Shuster, S., Frost, G. I., Csoka, A. B., Formby, B., & Stern, R. (2002). Hyaluronidase reduces human breast cancer xenografts in SCID mice. International Journal of Cancer, 102(2), 192–197. doi: 10.1002/ijc.10668.PubMedCrossRefGoogle Scholar
  115. 115.
    Pickup, M. W., Laklai, H., Acerbi, I., Owens, P., Gorska, A. E., Chytil, A., … Moses, H. L. (2013). Stromally derived lysyl oxidase promotes metastasis of transforming growth factor-β-deficient mouse mammary carcinomas. Cancer Research, 73(17), 5336–5346. doi:  10.1158/0008-5472.CAN-13-0012
  116. 116.
    Barry-Hamilton, V., Spangler, R., Marshall, D., McCauley, S., Rodriguez, H. M., Oyasu, M., … Smith, V. (2010). Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment. Nature medicine, 16(9), 1009–17. doi:  10.1038/nm.2208
  117. 117.
    Chan, N., Willis, A., Kornhauser, N., Ward, M. M., Lee, S. B., Nackos, E., … Vahdat, L. (2016). Influencing the tumor microenvironment: phase 2 study of copper depletion with tetrathiomolybdate in high risk breast cancer and preclinical models of lung metastases. Clinical Cancer Research.Google Scholar
  118. 118.
    Golubovskaya, V. M., & Cance, W. G. (2007). Focal adhesion kinase and p53 signaling in cancer cells. International Review of Cytology, 263(7), 103–153. doi: 10.1016/S0074-7696(07)63003-4.PubMedCrossRefGoogle Scholar
  119. 119.
    Mitra, S. K., & Schlaepfer, D. D. (2006). Integrin-regulated FAK-Src signaling in normal and cancer cells. Current Opinion in Cell Biology, 18(5), 516–523. doi: 10.1016/ Scholar
  120. 120.
    Tanjoni, I., Walsh, C., Uryu, S., Tomar, A., Nam, J.-O., Mielgo, A., … Schlaepfer, D. D. (2010). PND-1186 FAK inhibitor selectively promotes tumor cell apoptosis in three-dimensional environments. Cancer biology & therapy, 9(10), 764–77.Google Scholar
  121. 121.
    Walsh, C., Tanjoni, I., Uryu, S., Tomar, A., Nam, J.-O., Luo, H., … Schlaepfer, D. D. (2010). Oral delivery of PND-1186 FAK inhibitor decreases tumor growth and spontaneous breast to lung metastasis in pre-clinical models. Cancer biology & therapy, 9(10), 778–90.Google Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Shelly Kaushik
    • 1
  • Michael W Pickup
    • 1
  • Valerie M Weaver
    • 1
    • 2
    • 3
    • 4
    • 5
    • 6
  1. 1.Center for Bioengineering and Tissue Regeneration, Department of SurgeryUCSFSan FranciscoUSA
  2. 2.Department of AnatomyUCSFSan FranciscoUSA
  3. 3.Department of Bioengineering and Therapeutic SciencesUCSFSan FranciscoUSA
  4. 4.Department of Radiation OncologyUCSFSan FranciscoUSA
  5. 5.UCSF Helen Diller Comprehensive Cancer CenterUCSFSan FranciscoUSA
  6. 6.Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell ResearchUCSFSan FranciscoUSA

Personalised recommendations