Skip to main content
SpringerLink
Log in

Role of the Extracellular Matrix in Tumor Stroma: Barrier or Support?

  • Chapter
  • First Online:
Biomarkers of the Tumor Microenvironment

  • 1477 Accesses

Abstract

Extensive evidence exists to functionally implicate stromal cancer-associated fibroblasts in tumor progression. Data from experimental cancer models has questioned the exclusive tumor-supportive function of the tumor stroma and suggested that the stroma might also act as a barrier to inhibit tumor metastasis. With consideration of this shift in dogma, we discuss the role of a specific part of the tumor stroma, the insoluble extracellular matrix (ECM), in tumor growth and spread. We summarize data from experimental tumor models on the role of fibrillar collagens, the fibronectin EDA splice form, proteoglycans and the matricellular proteins, periostin and tenascins, which are all major components of the tumor stroma. In addition to the composition of the ECM being able to regulate tumorigenesis via integrin-mediated signaling, recent data indicate that the stiffness of the ECM also significantly impacts tumor growth and progression. These two properties add to the complexity of tumor-stroma interactions and have significant implications for gene regulation, matrix remodeling, and tumor metastasis. The role of the tumor stroma is thus extremely complex and highlights the importance of relating findings to tumor-type-, tissue-, and stage-specific effects in addition to considering inter-tumor and intra-tumor heterogeneity. Further work is needed to determine the relative contribution of different ECM proteins to the tumor-supporting and tumor-inhibiting roles of the tumor stroma.

Schematic illustration of the role of extracellular matrix in the tumor microenvironment. The schematic summarizes some of the effects seen for extracellular matrix (ECM) molecules in different forms of cancer. Cancer-associated fibroblasts (CAFs) play a major role in ECM synthesis and ECM reorganization

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 79.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 99.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 139.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Osterholm C, Lu N, Liden A, Karlsen TV, Gullberg D, Reed RK, et al. Fibroblast EXT1-levels influence tumor cell proliferation and migration in composite spheroids. PLoS One. 2012;7(7):e41334.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Lu N, Karlsen TV, Reed RK, Kusche-Gullberg M, Gullberg D. Fibroblast alpha11beta1 integrin regulates tensional homeostasis in fibroblast/A549 carcinoma heterospheroids. PLoS One. 2014;9(7):e103173.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Fatehullah A, Tan SH, Barker N. Organoids as an in vitro model of human development and disease. Nat Cell Biol. 2016;18(3):246–54.

    Article  PubMed  CAS  Google Scholar 

  4. Shi R, Radulovich N, Ng C, Liu N, Notsuda H, Cabanero M, et al. Organoid cultures as preclinical models of non-small cell lung cancer. Clin Cancer Res. 2020;26(5):1162–74.

    Article  PubMed  Google Scholar 

  5. Boj SF, Hwang CI, Baker LA, Chio II, Engle DD, Corbo V, et al. Organoid models of human and mouse ductal pancreatic cancer. Cell. 2015;160(1–2):324–38.

    Article  CAS  PubMed  Google Scholar 

  6. Sachs N, de Ligt J, Kopper O, Gogola E, Bounova G, Weeber F, et al. A living biobank of breast cancer organoids captures disease heterogeneity. Cell. 2018;172(1-2):373–86.e10.

    Article  CAS  PubMed  Google Scholar 

  7. Weaver VM. The microenvironment matters. Mol Biol Cell. 2014;25(21):3254–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Piersma B, Hayward MK, Weaver VM. Fibrosis and cancer: a strained relationship. Biochim Biophys Acta Rev Cancer. 2020;1873(2):188356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zeltz C, Gullberg D. Post-translational modifications of integrin ligands as pathogenic mechanisms in disease. Matrix Biol. 2014;40:5–9.

    Article  CAS  PubMed  Google Scholar 

  10. Levental KR, Yu H, Kass L, Lakins JN, Egeblad M, Erler JT, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell. 2009;139(5):891–906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Azmi AS, Bao B, Sarkar FH. Exosomes in cancer development, metastasis, and drug resistance: a comprehensive review. Cancer Metastasis Rev. 2013;32(3-4):623–42.

    Article  CAS  PubMed  Google Scholar 

  12. Hoshino A, Costa-Silva B, Shen TL, Rodrigues G, Hashimoto A, Tesic Mark M, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015;527(7578):329–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Östman A, Augsten M. Cancer-associated fibroblasts and tumor growth—bystanders turning into key players. Curr Opin Genet Dev. 2009;19(1):67–73.

    Article  PubMed  CAS  Google Scholar 

  14. Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am J Cancer Res. 2011;1(4):482–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med. 2014;211(8):1503–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hu Y, Yan C, Mu L, Huang K, Li X, Tao D, et al. Fibroblast-Derived Exosomes Contribute to Chemoresistance through Priming Cancer Stem Cells in Colorectal Cancer. PLoS One. 2015;10(5):e0125625.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Eberlein C, Rooney C, Ross SJ, Farren M, Weir HM, Barry ST. E-Cadherin and EpCAM expression by NSCLC tumour cells associate with normal fibroblast activation through a pathway initiated by integrin alphavbeta6 and maintained through TGFbeta signalling. Oncogene. 2014;34(6):704–16.

    Article  PubMed  CAS  Google Scholar 

  19. Eberlein C, Kendrew J, McDaid K, Alfred A, Kang JS, Jacobs VN, et al. A human monoclonal antibody 264RAD targeting alphavbeta6 integrin reduces tumour growth and metastasis, and modulates key biomarkers in vivo. Oncogene. 2013;32(37):4406–16.

    Article  CAS  PubMed  Google Scholar 

  20. Klingberg F, Chow ML, Koehler A, Boo S, Buscemi L, Quinn TM, et al. Prestress in the extracellular matrix sensitizes latent TGF-beta1 for activation. J Cell Biol. 2014;207(2):283–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hinz B. The extracellular matrix and transforming growth factor-beta1: tale of a strained relationship. Matrix Biol. 2015;47:54–65.

    Article  CAS  PubMed  Google Scholar 

  22. Henderson NC, Arnold TD, Katamura Y, Giacomini MM, Rodriguez JD, McCarty JH, et al. Targeting of alphav integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat Med. 2013;19(12):1617–24.

    Article  CAS  PubMed  Google Scholar 

  23. Reed NI, Jo H, Chen C, Tsujino K, Arnold TD, DeGrado WF, et al. The alphavbeta1 integrin plays a critical in vivo role in tissue fibrosis. Sci Transl Med. 2015;7(288):288ra79.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Lodyga M, Hinz B. TGF-beta1—a truly transforming growth factor in fibrosis and immunity. Semin Cell Dev Biol. 2020;101:123–39.

    Article  CAS  PubMed  Google Scholar 

  25. Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18(1):10.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Stockis J, Lienart S, Colau D, Collignon A, Nishimura SL, Sheppard D, et al. Blocking immunosuppression by human Tregs in vivo with antibodies targeting integrin alphaVbeta8. Proc Natl Acad Sci U S A. 2017;114(47):E10161–E8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Takasaka N, Seed RI, Cormier A, Bondesson AJ, Lou J, Elattma A, et al. Integrin alphavbeta8-expressing tumor cells evade host immunity by regulating TGF-beta activation in immune cells. JCI Insight. 2018;3(20):e122591.

    Article  PubMed Central  Google Scholar 

  28. Campbell MG, Cormier A, Ito S, Seed RI, Bondesson AJ, Lou J, et al. Cryo-EM reveals integrin-mediated TGF-beta activation without release from latent TGF-beta. Cell. 2020;180(3):490–501.e16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jin S, Lee WC, Aust D, Pilarsky C, Cordes N. beta8 integrin mediates pancreatic cancer cell radiochemoresistance. Mol Cancer Res. 2019;17(10):2126–38.

    Article  CAS  PubMed  Google Scholar 

  30. Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 2007;9(12):1392–400.

    Article  CAS  PubMed  Google Scholar 

  31. Sanz-Moreno V, Gaggioli C, Yeo M, Albrengues J, Wallberg F, Viros A, et al. ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer Cell. 2011;20(2):229–45.

    Article  CAS  PubMed  Google Scholar 

  32. Ozdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell. 2014;25:719–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rhim AD, Oberstein PE, Thomas DH, Mirek ET, Palermo CF, Sastra SA, et al. Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma. Cancer Cell. 2014;25(6):735–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jiang H, Torphy RJ, Steiger K, Hongo H, Ritchie AJ, Kriegsmann M, et al. Pancreatic ductal adenocarcinoma progression is restrained by stromal matrix. J Clin Invest. 2020;130(9):4704–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Zeltz C, Primac I, Erusappan P, Alam J, Noel A, Gullberg D. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins. Semin Cancer Biol. 2020;62:166–81.

    Article  CAS  PubMed  Google Scholar 

  36. Rubashkin MG, Ou G, Weaver VM. Deconstructing signaling in three dimensions. Biochemistry. 2014;53(13):2078–90.

    Article  CAS  PubMed  Google Scholar 

  37. Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3(1):a004978.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Egeblad M, Rasch MG, Weaver VM. Dynamic interplay between the collagen scaffold and tumor evolution. Curr Opin Cell Biol. 2010;22(5):697–706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Dvorak HF. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N Engl J Med. 1986;315(26):1650–9.

    Article  CAS  PubMed  Google Scholar 

  40. Dvorak HF. Tumors: wounds that do not heal-redux. Cancer Immunol Res. 2015;3(1):1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Merkel JR, DiPaolo BR, Hallock GG, Rice DC. Type I and type III collagen content of healing wounds in fetal and adult rats. Proc Soc Exp Biol Med. 1988;187(4):493–7.

    Article  CAS  PubMed  Google Scholar 

  42. Barczyk M, Carracedo S, Gullberg D. Integrins. Cell Tissue Res. 2010;339(1):269–80.

    Article  CAS  PubMed  Google Scholar 

  43. Zeltz C, Gullberg D. The integrin-collagen connection—a glue for tissue repair? J Cell Sci. 2016;129(4):653–64.

    CAS  PubMed  Google Scholar 

  44. Zeltz C, Orgel J, Gullberg D. Molecular composition and function of integrin-based collagen glues-introducing COLINBRIs. Biochim Biophys Acta. 2014;1840(8):2533–48.

    Article  CAS  PubMed  Google Scholar 

  45. Staudinger LA, Spano SJ, Lee W, Coelho N, Rajshankar D, Bendeck MP, et al. Interactions between the discoidin domain receptor 1 and beta1 integrin regulate attachment to collagen. Biol Open. 2013;2(11):1148–59.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Xu H, Bihan D, Chang F, Huang PH, Farndale RW, Leitinger B. Discoidin domain receptors promote alpha1beta1- and alpha2beta1-integrin mediated cell adhesion to collagen by enhancing integrin activation. PLoS One. 2012;7(12):e52209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Abbonante V, Gruppi C, Rubel D, Gross O, Moratti R, Balduini A. Discoidin domain receptor 1 protein is a novel modulator of megakaryocyte-collagen interactions. J Biol Chem. 2013;288(23):16738–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. DuFort CC, Paszek MJ, Weaver VM. Balancing forces: architectural control of mechanotransduction. Nat Rev Mol Cell Biol. 2011;12(5):308–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Gilkes DM, Semenza GL, Wirtz D. Hypoxia and the extracellular matrix: drivers of tumour metastasis. Nat Rev Cancer. 2014;14(6):430–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol. 2015;33(4):230–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Cox TR, Erler JT. Molecular pathways: connecting fibrosis and solid tumor metastasis. Clin Cancer Res. 2014;20(14):3637–43.

    Article  CAS  PubMed  Google Scholar 

  52. Miller BW, Morton JP, Pinese M, Saturno G, Jamieson NB, McGhee E, et al. 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. 2015;7(8):1063–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006;6(5):392–401.

    Article  CAS  PubMed  Google Scholar 

  54. Cooke ME, Sakai T, Mosher DF. Contraction of collagen matrices mediated by a2b1A and avb3 integrins. J Cell Sci. 2000;113(Pt 13):2375–83.

    Article  CAS  PubMed  Google Scholar 

  55. Schulz JN, Zeltz C, Sorensen IW, Barczyk M, Carracedo S, Hallinger R, et al. Reduced granulation tissue and wound strength in the absence of alpha11beta1 integrin. J Invest Dermatol. 2015;135(5):1435–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Gullberg D, Tingstrom A, Thuresson AC, Olsson L, Terracio L, Borg TK, et al. b1 integrin-mediated collagen gel contraction is stimulated by PDGF. Exp Cell Res. 1990;186(2):264–72.

    Article  CAS  PubMed  Google Scholar 

  57. Jokinen J, Dadu E, Nykvist P, Kapyla J, White DJ, Ivaska J, et al. Integrin-mediated cell adhesion to type I collagen fibrils. J Biol Chem. 2004;279(30):31956–63.

    Article  CAS  PubMed  Google Scholar 

  58. Shen B, Vardy K, Hughes P, Tasdogan A, Zhao Z, Yue R, et al. Integrin alpha11 is an Osteolectin receptor and is required for the maintenance of adult skeletal bone mass. elife. 2019;8:e42274.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Velling T, Kusche-Gullberg M, Sejersen T, Gullberg D. cDNA cloning and chromosomal localization of human alpha(11) integrin. A collagen-binding, I domain-containing, beta(1)-associated integrin alpha-chain present in muscle tissues. J Biol Chem. 1999;274(36):25735–42.

    Article  CAS  PubMed  Google Scholar 

  60. Popova SN, Rodriguez-Sanchez B, Liden A, Betsholtz C, Van Den Bos T, Gullberg D. The mesenchymal alpha11beta1 integrin attenuates PDGF-BB-stimulated chemotaxis of embryonic fibroblasts on collagens. Dev Biol. 2004;270(2):427–42.

    Article  CAS  PubMed  Google Scholar 

  61. Popova SN, Barczyk M, Tiger CF, Beertsen W, Zigrino P, Aszodi A, et al. Alpha11 beta1 integrin-dependent regulation of periodontal ligament function in the erupting mouse incisor. Mol Cell Biol. 2007;27(12):4306–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Popov C, Radic T, Haasters F, Prall WC, Aszodi A, Gullberg D, et al. Integrins alpha2beta1 and alpha11beta1 regulate the survival of mesenchymal stem cells on collagen I. Cell Death Dis. 2011;2:e186.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zeltz C, Alam J, Liu H, Erusappan PM, Hoschuetzky H, Molven A, et al. α11β1 integrin is induced in a subset of cancer-associated fibroblasts in desmoplastic tumor stroma and mediates in vitro cell migration. Cancers. 2019;11:765. https://doi.org/10.3390/cancers11060765.

    Article  CAS  PubMed Central  Google Scholar 

  64. Primac I, Maquoi E, Blacher S, Heljasvaara R, Van Deun J, Smeland HY, et al. Stromal integrin alpha11 regulates PDGFR-beta signaling and promotes breast cancer progression. J Clin Invest. 2019;130:4609–28.

    Article  Google Scholar 

  65. Zhu CQ, Popova SN, Brown ER, Barsyte-Lovejoy D, Navab R, Shih W, et al. Integrin alpha 11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells. Proc Natl Acad Sci U S A. 2007;104(28):11754–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Navab R, Strumpf D, To C, Pasko E, Kim KS, Park CJ, et al. Integrin alpha11beta1 regulates cancer stromal stiffness and promotes tumorigenicity and metastasis in non-small cell lung cancer. Oncogene. 2016;35(15):1899–908.

    Article  CAS  PubMed  Google Scholar 

  67. Smeland HY, Askeland C, Wik E, Knutsvik G, Molven A, Edelmann RJ, et al. Integrin alpha11beta1 is expressed in breast cancer stroma and associates with aggressive tumor phenotypes. J Pathol Clin Res. 2020;6(1):69–82.

    Article  CAS  PubMed  Google Scholar 

  68. Barczyk MM, Lu N, Popova SN, Bolstad AI, Gullberg D. alpha11beta1 integrin-mediated MMP-13-dependent collagen lattice contraction by fibroblasts: evidence for integrin-coordinated collagen proteolysis. J Cell Physiol. 2013;228:1108–19.

    Article  CAS  PubMed  Google Scholar 

  69. Ravanti L, Heino J, Lopez-Otin C, Kahari VM. Induction of collagenase-3 (MMP-13) expression in human skin fibroblasts by three-dimensional collagen is mediated by p38 mitogen-activated protein kinase. J Biol Chem. 1999;274(4):2446–55.

    Article  CAS  PubMed  Google Scholar 

  70. Provenzano PP, Eliceiri KW, Keely PJ. Shining new light on 3D cell motility and the metastatic process. Trends Cell Biol. 2009;19(11):638–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Brisson BK, Mauldin EA, Lei W, Vogel LK, Power AM, Lo A, et al. Type III collagen directs stromal organization and limits metastasis in a murine model of breast cancer. Am J Pathol. 2015;185(5):1471–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Radisky D, Muschler J, Bissell MJ. Order and disorder: the role of extracellular matrix in epithelial cancer. Cancer Investig. 2002;20(1):139–53.

    Article  Google Scholar 

  73. Nistico P, Bissell MJ, Radisky DC. Epithelial-mesenchymal transition: general principles and pathological relevance with special emphasis on the role of matrix metalloproteinases. Cold Spring Harb Perspect Biol. 2012;4(2):a011908.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Smith BN, Bhowmick NA. Role of EMT in metastasis and therapy resistance. J Clin Med. 2016;5(2):17.

    Article  PubMed Central  CAS  Google Scholar 

  75. Provenzano PP, Inman DR, Eliceiri KW, Knittel JG, Yan L, Rueden CT, et al. Collagen density promotes mammary tumor initiation and progression. BMC Med. 2008;6:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  76. Xiong G, Deng L, Zhu J, Rychahou PG, Xu R. Prolyl-4-hydroxylase alpha subunit 2 promotes breast cancer progression and metastasis by regulating collagen deposition. BMC Cancer. 2014;14:1.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Chen Y, Terajima M, Yang Y, Sun L, Ahn YH, Pankova D, et al. Lysyl hydroxylase 2 induces a collagen cross-link switch in tumor stroma. J Clin Invest. 2015;125(3):1147–62.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Montgomery AM, Reisfeld RA, Cheresh DA. Integrin alpha v beta 3 rescues melanoma cells from apoptosis in three-dimensional dermal collagen. Proc Natl Acad Sci U S A. 1994;91(19):8856–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Maquoi E, Assent D, Detilleux J, Pequeux C, Foidart JM, Noël A. MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis. Oncogene. 2011;31(4):480–93.

    Article  PubMed  CAS  Google Scholar 

  80. Assent D, Bourgot I, Hennuy B, Geurts P, Noel A, Foidart JM, et al. A membrane-type-1 matrix metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells. PLoS One. 2015;10(3):e0116006.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Nielsen BS, Egeblad M, Rank F, Askautrud HA, Pennington CJ, Pedersen TX, et al. Matrix metalloproteinase 13 is induced in fibroblasts in polyomavirus middle T antigen-driven mammary carcinoma without influencing tumor progression. PLoS One. 2008;3(8):e2959.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Perry SW, Schueckler JM, Burke K, Arcuri GL, Brown EB. Stromal matrix metalloprotease-13 knockout alters Collagen I structure at the tumor-host interface and increases lung metastasis of C57BL/6 syngeneic E0771 mammary tumor cells. BMC Cancer. 2013;13:411.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Krane SM, Byrne MH, Lemaitre V, Henriet P, Jeffrey JJ, Witter JP, et al. Different collagenase gene products have different roles in degradation of type I collagen. J Biol Chem. 1996;271(45):28509–15.

    Article  CAS  PubMed  Google Scholar 

  84. Romanic AM, Adachi E, Kadler KE, Hojima Y, Prockop DJ. Copolymerization of pNcollagen III and collagen I. pNcollagen III decreases the rate of incorporation of collagen I into fibrils, the amount of collagen I incorporated, and the diameter of the fibrils formed. J Biol Chem. 1991;266(19):12703–9.

    Article  CAS  PubMed  Google Scholar 

  85. LeBert DC, Squirrell JM, Rindy J, Broadbridge E, Lui Y, Zakrzewska A, et al. Matrix metalloproteinase 9 modulates collagen matrices and wound repair. Development. 2015;142(12):2136–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Herchenhan A, Uhlenbrock F, Eliasson P, Weis M, Eyre D, Kadler KE, et al. Lysyl oxidase activity is required for ordered collagen fibrillogenesis by tendon cells. J Biol Chem. 2015;290(26):16440–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Sabeh F, Shimizu-Hirota R, Weiss SJ. Protease-dependent versus -independent cancer cell invasion programs: three-dimensional amoeboid movement revisited. J Cell Biol. 2009;185(1):11–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Wolf K, Te Lindert M, Krause M, Alexander S, Te Riet J, Willis AL, et al. Physical limits of cell migration: control by ECM space and nuclear deformation and tuning by proteolysis and traction force. J Cell Biol. 2013;201(7):1069–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Kaur A, Ecker BL, Douglass SM, Kugel CH 3rd, Webster MR, Almeida FV, et al. Remodeling of the collagen matrix in aging skin promotes melanoma metastasis and affects immune cell motility. Cancer Discov. 2019;9(1):64–81.

    Article  CAS  PubMed  Google Scholar 

  90. Nishioka T, Eustace A, West C. Lysyl oxidase: from basic science to future cancer treatment. Cell Struct Funct. 2012;37(1):75–80.

    Article  CAS  PubMed  Google Scholar 

  91. Cox TR, Erler JT. Remodeling and homeostasis of the extracellular matrix: implications for fibrotic diseases and cancer. Dis Model Mech. 2011;4(2):165–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Cox TR, Rumney RM, Schoof EM, Perryman L, Hoye AM, Agrawal A, et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature. 2015;522(7554):106–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Oskarsson T, Acharyya S, Zhang XH, Vanharanta S, Tavazoie SF, Morris PG, et al. Breast cancer cells produce tenascin C as a metastatic niche component to colonize the lungs. Nat Med. 2011;17(7):867–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Oskarsson T, Massague J. Extracellular matrix players in metastatic niches. EMBO J. 2012;31(2):254–6.

    Article  CAS  PubMed  Google Scholar 

  95. Kaplan RN, Riba RD, Zacharoulis S, Bramley AH, Vincent L, Costa C, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438(7069):820–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wilgus ML, Borczuk AC, Stoopler M, Ginsburg M, Gorenstein L, Sonett JR, et al. Lysyl oxidase: a lung adenocarcinoma biomarker of invasion and survival. Cancer. 2011;117(10):2186–91.

    Article  CAS  PubMed  Google Scholar 

  97. Zeltz C, Pasko E, Cox TR, Navab R, Tsao MS. LOXL1 Is regulated by integrin alpha11 and promotes non-small cell lung cancer tumorigenicity. Cancers (Basel). 2019;11(5):705.

    Article  CAS  Google Scholar 

  98. Erler JT, Bennewith KL, Nicolau M, Dornhofer N, Kong C, Le QT, et al. Lysyl oxidase is essential for hypoxia-induced metastasis. Nature. 2006;440(7088):1222–6.

    Article  CAS  PubMed  Google Scholar 

  99. Pupa SM, Menard S, Forti S, Tagliabue E. New insights into the role of extracellular matrix during tumor onset and progression. J Cell Physiol. 2002;192(3):259–67.

    Article  CAS  PubMed  Google Scholar 

  100. Theret N, Musso O, Turlin B, Lotrian D, Bioulac-Sage P, Campion JP, et al. Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Hepatology. 2001;34(1):82–8.

    Article  CAS  PubMed  Google Scholar 

  101. Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996;76(1):69–125.

    Article  CAS  PubMed  Google Scholar 

  102. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  103. Leitinger B, Hohenester E. Mammalian collagen receptors. Matrix Biol. 2007;26(3):146–55.

    Article  CAS  PubMed  Google Scholar 

  104. Chen X, Nadiarynkh O, Plotnikov S, Campagnola PJ. Second harmonic generation microscopy for quantitative analysis of collagen fibrillar structure. Nat Protoc. 2012;7(4):654–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tuer A, Tokarz D, Prent N, Cisek R, Alami J, Dumont DJ, et al. Nonlinear multicontrast microscopy of hematoxylin-and-eosin-stained histological sections. J Biomed Opt. 2010;15(2):026018.

    Article  PubMed  CAS  Google Scholar 

  106. Tuer AE, Akens MK, Krouglov S, Sandkuijl D, Wilson BC, Whyne CM, et al. Hierarchical model of fibrillar collagen organization for interpreting the second-order susceptibility tensors in biological tissue. Biophys J. 2012;103(10):2093–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Tuer AE, Krouglov S, Prent N, Cisek R, Sandkuijl D, Yasufuku K, et al. Nonlinear optical properties of type I collagen fibers studied by polarization dependent second harmonic generation microscopy. J Phys Chem B. 2011;115(44):12759–69.

    Article  CAS  PubMed  Google Scholar 

  108. Amat-Roldan I, Psilodimitrakopoulos S, Loza-Alvarez P, Artigas D. Fast image analysis in polarization SHG microscopy. Opt Express. 2010;18(16):17209–19.

    Article  PubMed  Google Scholar 

  109. Golaraei A, Cisek R, Krouglov S, Navab R, Niu C, Sakashita S, et al. Characterization of collagen in non-small cell lung carcinoma with second harmonic polarization microscopy. Biomed Opt Express. 2014;5(10):3562–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Strupler M, Pena AM, Hernest M, Tharaux PL, Martin JL, Beaurepaire E, et al. Second harmonic imaging and scoring of collagen in fibrotic tissues. Opt Express. 2007;15(7):4054–65.

    Article  CAS  PubMed  Google Scholar 

  111. Rezakhaniha R, Agianniotis A, Schrauwen JT, Griffa A, Sage D, Bouten CV, et al. Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy. Biomech Model Mechanobiol. 2012;11(3-4):461–73.

    Article  CAS  PubMed  Google Scholar 

  112. Zhang J, Wang YL, Gu L, Pan J. Atomic force microscopy of actin. Sheng Wu Hua Xue Yu Sheng Wu Wu Li Xue Bao (Shanghai). 2003;35(6):489–94.

    CAS  Google Scholar 

  113. Paige MF, Rainey JK, Goh MC. A study of fibrous long spacing collagen ultrastructure and assembly by atomic force microscopy. Micron. 2001;32(3):341–53.

    Article  CAS  PubMed  Google Scholar 

  114. Glatzel T, Holscher H, Schimmel T, Baykara MZ, Schwarz UD, Garcia R. Advanced atomic force microscopy techniques. Beilstein J Nanotechnol. 2012;3:893–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Strasser S, Zink A, Janko M, Heckl WM, Thalhammer S. Structural investigations on native collagen type I fibrils using AFM. Biochem Biophys Res Commun. 2007;354(1):27–32.

    Article  CAS  PubMed  Google Scholar 

  116. Lopez JI, Kang I, You WK, McDonald DM, Weaver VM. In situ force mapping of mammary gland transformation. Integr Biol (Camb). 2011;3(9):910–21.

    Article  CAS  Google Scholar 

  117. Braet F, Vermijlen D, Bossuyt V, De Zanger R, Wisse E. Early detection of cytotoxic events between hepatic natural killer cells and colon carcinoma cells as probed with the atomic force microscope. Ultramicroscopy. 2001;89(4):265–73.

    Article  CAS  PubMed  Google Scholar 

  118. Akhtar R, Schwarzer N, Sherratt MJ, Watson RE, Graham HK, Trafford AW, et al. Nanoindentation of histological specimens: mapping the elastic properties of soft tissues. J Mater Res. 2009;24(3):638–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Gueta R, Barlam D, Shneck RZ, Rousso I. Measurement of the mechanical properties of isolated tectorial membrane using atomic force microscopy. Proc Natl Acad Sci U S A. 2006;103(40):14790–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Barbone PE, Bamber JC. Quantitative elasticity imaging: what can and cannot be inferred from strain images. Phys Med Biol. 2002;47(12):2147–64.

    Article  PubMed  Google Scholar 

  121. Jiang T, Olson ES, Nguyen QT, Roy M, Jennings PA, Tsien RY. Tumor imaging by means of proteolytic activation of cell-penetrating peptides. Proc Natl Acad Sci U S A. 2004;101(51):17867–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Scherer RL, VanSaun MN, McIntyre JO, Matrisian LM. Optical imaging of matrix metalloproteinase-7 activity in vivo using a proteolytic nanobeacon. Mol Imaging. 2008;7(3):118–31.

    Article  CAS  PubMed  Google Scholar 

  123. Littlepage LE, Sternlicht MD, Rougier N, Phillips J, Gallo E, Yu Y, et al. Matrix metalloproteinases contribute distinct roles in neuroendocrine prostate carcinogenesis, metastasis, and angiogenesis progression. Cancer Res. 2010;70(6):2224–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Low AF, Tearney GJ, Bouma BE, Jang IK. Technology Insight: optical coherence tomography—current status and future development. Nat Clin Pract Cardiovasc Med. 2006;3(3):154–62. quiz 72

    Article  PubMed  Google Scholar 

  125. Spuentrup E, Buecker A, Katoh M, Wiethoff AJ, Parsons EC Jr, Botnar RM, et al. Molecular magnetic resonance imaging of coronary thrombosis and pulmonary emboli with a novel fibrin-targeted contrast agent. Circulation. 2005;111(11):1377–82.

    Article  CAS  PubMed  Google Scholar 

  126. Stracke CP, Katoh M, Wiethoff AJ, Parsons EC, Spangenberg P, Spuntrup E. Molecular MRI of cerebral venous sinus thrombosis using a new fibrin-specific MR contrast agent. Stroke. 2007;38(5):1476–81.

    Article  CAS  PubMed  Google Scholar 

  127. Miserus RJ, Herias MV, Prinzen L, Lobbes MB, Van Suylen RJ, Dirksen A, et al. Molecular MRI of early thrombus formation using a bimodal alpha2-antiplasmin-based contrast agent. JACC Cardiovasc Imaging. 2009;2(8):987–96.

    Article  PubMed  Google Scholar 

  128. Hynes R. Molecular biology of fibronectin. Annu Rev Cell Biol. 1985;1:67–90.

    Article  CAS  PubMed  Google Scholar 

  129. White ES, Baralle FE, Muro AF. New insights into form and function of fibronectin splice variants. J Pathol. 2008;216(1):1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Astrof S, Crowley D, George EL, Fukuda T, Sekiguchi K, Hanahan D, et al. Direct test of potential roles of EIIIA and EIIIB alternatively spliced segments of fibronectin in physiological and tumor angiogenesis. Mol Cell Biol. 2004;24(19):8662–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Singh P, Reimer CL, Peters JH, Stepp MA, Hynes RO, Van De Water L. The spatial and temporal expression patterns of integrin alpha9beta1 and one of its ligands, the EIIIA segment of fibronectin, in cutaneous wound healing. J Invest Dermatol. 2004;123(6):1176–81.

    Article  CAS  PubMed  Google Scholar 

  132. Bhattacharyya S, Tamaki Z, Wang W, Hinchcliff M, Hoover P, Getsios S, et al. FibronectinEDA promotes chronic cutaneous fibrosis through Toll-like receptor signaling. Sci Transl Med. 2014;6(232):232ra50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  133. Rybinski B, Franco-Barraza J, Cukierman E. The wound healing, chronic fibrosis, and cancer progression triad. Physiol Genomics. 2014;46(7):223–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Rybak JN, Roesli C, Kaspar M, Villa A, Neri D. The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Res. 2007;67(22):10948–57.

    Article  CAS  PubMed  Google Scholar 

  135. Matsumoto E, Yoshida T, Kawarada Y, Sakakura T. Expression of fibronectin isoforms in human breast tissue: production of extra domain A+/extra domain B+ by cancer cells and extra domain A+ by stromal cells. Jpn J Cancer Res. 1999;90(3):320–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Pujuguet P, Hammann A, Moutet M, Samuel JL, Martin F, Martin M. Expression of fibronectin ED-A+ and ED-B+ isoforms by human and experimental colorectal cancer. Contribution of cancer cells and tumor-associated myofibroblasts. Am J Pathol. 1996;148(2):579–92.

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Manabe R, Ohe N, Maeda T, Fukuda T, Sekiguchi K. Modulation of cell-adhesive activity of fibronectin by the alternatively spliced EDA segment. J Cell Biol. 1997;139(1):295–307.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Shinde AV, Bystroff C, Wang C, Vogelezang MG, Vincent PA, Hynes RO, et al. Identification of the peptide sequences within the EIIIA (EDA) segment of fibronectin that mediate integrin alpha9beta1-dependent cellular activities. J Biol Chem. 2008;283(5):2858–70.

    Article  CAS  PubMed  Google Scholar 

  139. Kohan M, Muro AF, White ES, Berkman N. EDA-containing cellular fibronectin induces fibroblast differentiation through binding to alpha4beta7 integrin receptor and MAPK/Erk 1/2-dependent signaling. FASEB J. 2010;24(11):4503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Okamura Y, Watari M, Jerud ES, Young DW, Ishizaka ST, Rose J, et al. The extra domain A of fibronectin activates Toll-like receptor 4. J Biol Chem. 2001;276(13):10229–33.

    Article  CAS  PubMed  Google Scholar 

  141. Kelsh RM, McKeown-Longo PJ, Clark RA. EDA fibronectin in keloids create a vicious cycle of fibrotic tumor formation. J Invest Dermatol. 2015;135(7):1714–8.

    Article  CAS  PubMed  Google Scholar 

  142. Bazigou E, Xie S, Chen C, Weston A, Miura N, Sorokin L, et al. Integrin-alpha9 is required for fibronectin matrix assembly during lymphatic valve morphogenesis. Dev Cell. 2009;17(2):175–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Fukuda T, Yoshida N, Kataoka Y, Manabe R, Mizuno-Horikawa Y, Sato M, et al. Mice lacking the EDB segment of fibronectin develop normally but exhibit reduced cell growth and fibronectin matrix assembly in vitro. Cancer Res. 2002;62(19):5603–10.

    CAS  PubMed  Google Scholar 

  144. Muro AF, Chauhan AK, Gajovic S, Iaconcig A, Porro F, Stanta G, et al. Regulated splicing of the fibronectin EDA exon is essential for proper skin wound healing and normal lifespan. J Cell Biol. 2003;162(1):149–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Astrof S, Crowley D, Hynes RO. Multiple cardiovascular defects caused by the absence of alternatively spliced segments of fibronectin. Dev Biol. 2007;311(1):11–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Danussi C, Del Bel BL, Pivetta E, Modica TM, Muro A, Wassermann B, et al. EMILIN1/alpha9beta1 integrin interaction is crucial in lymphatic valve formation and maintenance. Mol Cell Biol. 2013;33(22):4381–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Serini G, Bochaton-Piallat ML, Ropraz P, Geinoz A, Borsi L, Zardi L, et al. The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1. J Cell Biol. 1998;142(3):873–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Shinde AV, Kelsh R, Peters JH, Sekiguchi K, Van De Water L, PJ MK-L. The alpha4beta1 integrin and the EDA domain of fibronectin regulate a profibrotic phenotype in dermal fibroblasts. Matrix Biol. 2015;41:26–35.

    Article  CAS  PubMed  Google Scholar 

  149. Singh P, Chen C, Pal-Ghosh S, Stepp MA, Sheppard D, Van De Water L. Loss of integrin alpha9beta1 results in defects in proliferation, causing poor re-epithelialization during cutaneous wound healing. J Invest Dermatol. 2009;129(1):217–28.

    Article  CAS  PubMed  Google Scholar 

  150. Nakayama Y, Kon S, Kurotaki D, Morimoto J, Matsui Y, Uede T. Blockade of interaction of alpha9 integrin with its ligands hinders the formation of granulation in cutaneous wound healing. Lab Investig. 2010;90(6):881–94.

    Article  CAS  PubMed  Google Scholar 

  151. Muro AF, Moretti FA, Moore BB, Yan M, Atrasz RG, Wilke CA, et al. An essential role for fibronectin extra type III domain A in pulmonary fibrosis. Am J Respir Crit Care Med. 2008;177(6):638–45.

    Article  CAS  PubMed  Google Scholar 

  152. Arslan F, Smeets MB, Riem Vis PW, Karper JC, Quax PH, Bongartz LG, et al. Lack of fibronectin-EDA promotes survival and prevents adverse remodeling and heart function deterioration after myocardial infarction. Circ Res. 2011;108(5):582–92.

    Article  CAS  PubMed  Google Scholar 

  153. Kelsh-Lasher RM, Ambesi A, Bertram C, McKeown-Longo PJ. Integrin alpha4beta1 and TLR4 Cooperate to Induce Fibrotic Gene Expression in Response to Fibronectin’s EDA Domain. J Invest Dermatol. 2017;137(12):2505–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Jain M, Dhanesha N, Doddapattar P, Chorawala MR, Nayak MK, Cornelissen A, et al. Smooth muscle cell-specific fibronectin-EDA mediates phenotypic switching and neointimal hyperplasia. J Clin Invest. 2020;130(1):295–314.

    Article  CAS  PubMed  Google Scholar 

  155. Klingberg F, Chau G, Walraven M, Boo S, Koehler A, Chow ML, et al. The fibronectin ED-A domain enhances recruitment of latent TGF-beta-binding protein-1 to the fibroblast matrix. J Cell Sci. 2018;131(5):jcs201293.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Liao YF, Gotwals PJ, Koteliansky VE, Sheppard D, Van De Water L. The EIIIA segment of fibronectin is a ligand for integrins alpha 9beta 1 and alpha 4beta 1 providing a novel mechanism for regulating cell adhesion by alternative splicing. J Biol Chem. 2002;277(17):14467–74.

    Article  CAS  PubMed  Google Scholar 

  157. Erdogan B, Ao M, White LM, Means AL, Brewer BM, Yang L, et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J Cell Biol. 2017;216(11):3799–816.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Attieh Y, Clark AG, Grass C, Richon S, Pocard M, Mariani P, et al. Cancer-associated fibroblasts lead tumor invasion through integrin-beta3-dependent fibronectin assembly. J Cell Biol. 2017;216(11):3509–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Franco-Barraza J, Francescone R, Luong T, Shah N, Madhani R, Cukierman G, et al. Matrix-regulated integrin alphavbeta5 maintains alpha5beta1-dependent desmoplastic traits prognostic of neoplastic recurrence. elife. 2017;6:e20600.

    Article  PubMed  PubMed Central  Google Scholar 

  160. Lugano R, Vemuri K, Yu D, Bergqvist M, Smits A, Essand M, et al. CD93 promotes beta1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis. J Clin Invest. 2018;128(8):3280–97.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Rossnagl S, Altrock E, Sens C, Kraft S, Rau K, Milsom MD, et al. EDA-fibronectin originating from osteoblasts inhibits the immune response against cancer. PLoS Biol. 2016;14(9):e1002562.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  162. Gopal S, Veracini L, Grall D, Butori C, Schaub S, Audebert S, et al. Fibronectin-guided migration of carcinoma collectives. Nat Commun. 2017;8:14105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. Berger AJ, Renner CM, Hale I, Yang X, Ponik SM, Weisman PS, et al. Scaffold stiffness influences breast cancer cell invasion via EGFR-linked Mena upregulation and matrix remodeling. Matrix Biol. 2020;85–86:80–93.

    Article  PubMed  CAS  Google Scholar 

  164. Kwon A, Chae IH, You E, Kim SH, Ahn SY, Lee OJ, et al. Extra domain A-containing fibronectin expression in Spin90-deficient fibroblasts mediates cancer-stroma interaction and promotes breast cancer progression. J Cell Physiol. 2020;235(5):4494–507.

    Article  CAS  PubMed  Google Scholar 

  165. Ou J, Deng J, Wei X, Xie G, Zhou R, Yu L, et al. Fibronectin extra domain A (EDA) sustains CD133(+)/CD44(+) subpopulation of colorectal cancer cells. Stem Cell Res. 2013;11(2):820–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Xiang L, Xie G, Ou J, Wei X, Pan F, Liang H. The extra domain A of fibronectin increases VEGF-C expression in colorectal carcinoma involving the PI3K/AKT signaling pathway. PLoS One. 2012;7(4):e35378.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Sun X, Fa P, Cui Z, Xia Y, Sun L, Li Z, et al. The EDA-containing cellular fibronectin induces epithelial-mesenchymal transition in lung cancer cells through integrin alpha9beta1-mediated activation of PI3-K/AKT and Erk1/2. Carcinogenesis. 2014;35(1):184–91.

    CAS  PubMed  Google Scholar 

  168. Ou J, Peng Y, Deng J, Miao H, Zhou J, Zha L, et al. Endothelial cell-derived fibronectin extra domain A promotes colorectal cancer metastasis via inducing epithelial-mesenchymal transition. Carcinogenesis. 2014;35(7):1661–70.

    Article  CAS  PubMed  Google Scholar 

  169. Ou J, Pan F, Geng P, Wei X, Xie G, Deng J, et al. Silencing fibronectin extra domain A enhances radiosensitivity in nasopharyngeal carcinomas involving an FAK/Akt/JNK pathway. Int J Radiat Oncol Biol Phys. 2012;82(4):e685–91.

    Article  CAS  PubMed  Google Scholar 

  170. Mosher DF, Adams JC. Adhesion-modulating/matricellular ECM protein families: a structural, functional and evolutionary appraisal. Matrix Biol. 2012;31(3):155–61.

    Article  CAS  PubMed  Google Scholar 

  171. Wong GS, Rustgi AK. Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis. Br J Cancer. 2013;108(4):755–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Chiquet-Ehrismann R, Tucker RP. Tenascins and the importance of adhesion modulation. Cold Spring Harb Perspect Biol. 2011;3(5):a004960.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  173. Forsberg E, Hirsch E, Frohlich L, Meyer M, Ekblom P, Aszodi A, et al. Skin wounds and severed nerves heal normally in mice lacking tenascin-C. Proc Natl Acad Sci U S A. 1996;93(13):6594–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Talts JF, Wirl G, Dictor M, Muller WJ, Fassler R. Tenascin-C modulates tumor stroma and monocyte/macrophage recruitment but not tumor growth or metastasis in a mouse strain with spontaneous mammary cancer. J Cell Sci. 1999;112(Pt 12):1855–64.

    Article  CAS  PubMed  Google Scholar 

  175. Zuliani-Alvarez L, Marzeda AM, Deligne C, Schwenzer A, McCann FE, Marsden BD, et al. Mapping tenascin-C interaction with toll-like receptor 4 reveals a new subset of endogenous inflammatory triggers. Nat Commun. 2017;8(1):1595.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  176. Bhattacharyya S, Wang W, Morales-Nebreda L, Feng G, Wu M, Zhou X, et al. Tenascin-C drives persistence of organ fibrosis. Nat Commun. 2016;7:11703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Yeo SY, Lee KW, Shin D, An S, Cho KH, Kim SH. A positive feedback loop bi-stably activates fibroblasts. Nat Commun. 2018;9(1):3016.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  178. Fu H, Tian Y, Zhou L, Zhou D, Tan RJ, Stolz DB, et al. Tenascin-C is a major component of the fibrogenic niche in kidney fibrosis. J Am Soc Nephrol. 2017;28(3):785–801.

    Article  CAS  PubMed  Google Scholar 

  179. Orend G, Chiquet-Ehrismann R. Tenascin-C induced signaling in cancer. Cancer Lett. 2006;244(2):143–63.

    Article  CAS  PubMed  Google Scholar 

  180. Martin D, Brown-Luedi M, Chiquet-Ehrismann R. Tenascin-C signaling through induction of 14-3-3 tau. J Cell Biol. 2003;160(2):171–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Ruiz C, Huang W, Hegi ME, Lange K, Hamou MF, Fluri E, et al. Growth promoting signaling by tenascin-C [corrected]. Cancer Res. 2004;64(20):7377–85.

    Article  CAS  PubMed  Google Scholar 

  182. Huang W, Chiquet-Ehrismann R, Moyano JV, Garcia-Pardo A, Orend G. Interference of tenascin-C with syndecan-4 binding to fibronectin blocks cell adhesion and stimulates tumor cell proliferation. Cancer Res. 2001;61(23):8586–94.

    CAS  PubMed  Google Scholar 

  183. Shi M, He X, Wei W, Wang J, Zhang T, Shen X. Tenascin-C induces resistance to apoptosis in pancreatic cancer cell through activation of ERK/NF-kappaB pathway. Apoptosis. 2015;20(6):843–57.

    Article  CAS  PubMed  Google Scholar 

  184. Nagaharu K, Zhang X, Yoshida T, Katoh D, Hanamura N, Kozuka Y, et al. Tenascin C induces epithelial-mesenchymal transition-like change accompanied by SRC activation and focal adhesion kinase phosphorylation in human breast cancer cells. Am J Pathol. 2011;178(2):754–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Katoh D, Nagaharu K, Shimojo N, Hanamura N, Yamashita M, Kozuka Y, et al. Binding of alphavbeta1 and alphavbeta6 integrins to tenascin-C induces epithelial-mesenchymal transition-like change of breast cancer cells. Oncogenesis. 2013;2:e65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Ghahhari NM, Babashah S. Interplay between microRNAs and WNT/beta-catenin signalling pathway regulates epithelial-mesenchymal transition in cancer. Eur J Cancer. 2015;51(12):1638–49.

    Article  CAS  PubMed  Google Scholar 

  187. Saupe F, Schwenzer A, Jia Y, Gasser I, Spenle C, Langlois B, et al. Tenascin-C downregulates wnt inhibitor dickkopf-1, promoting tumorigenesis in a neuroendocrine tumor model. Cell Rep. 2013;5(2):482–92.

    Article  CAS  PubMed  Google Scholar 

  188. Beiter K, Hiendlmeyer E, Brabletz T, Hlubek F, Haynl A, Knoll C, et al. beta-Catenin regulates the expression of tenascin-C in human colorectal tumors. Oncogene. 2005;24(55):8200–4.

    Article  CAS  PubMed  Google Scholar 

  189. Nong Y, Wu D, Lin Y, Zhang Y, Bai L, Tang H. Tenascin-C expression is associated with poor prognosis in hepatocellular carcinoma (HCC) patients and the inflammatory cytokine TNF-alpha-induced TNC expression promotes migration in HCC cells. Am J Cancer Res. 2015;5(2):782–91.

    PubMed  PubMed Central  Google Scholar 

  190. Grahovac J, Becker D, Wells A. Melanoma cell invasiveness is promoted at least in part by the epidermal growth factor-like repeats of tenascin-C. J Invest Dermatol. 2013;133(1):210–20.

    Article  CAS  PubMed  Google Scholar 

  191. Kaariainen E, Nummela P, Soikkeli J, Yin M, Lukk M, Jahkola T, et al. Switch to an invasive growth phase in melanoma is associated with tenascin-C, fibronectin, and procollagen-I forming specific channel structures for invasion. J Pathol. 2006;210(2):181–91.

    Article  CAS  PubMed  Google Scholar 

  192. Kalembeyi I, Inada H, Nishiura R, Imanaka-Yoshida K, Sakakura T, Yoshida T. Tenascin-C upregulates matrix metalloproteinase-9 in breast cancer cells: direct and synergistic effects with transforming growth factor beta1. Int J Cancer. 2003;105(1):53–60.

    Article  CAS  PubMed  Google Scholar 

  193. Hancox RA, Allen MD, Holliday DL, Edwards DR, Pennington CJ, Guttery DS, et al. Tumour-associated tenascin-C isoforms promote breast cancer cell invasion and growth by matrix metalloproteinase-dependent and independent mechanisms. Breast Cancer Res. 2009;11(2):R24.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Calvo A, Catena R, Noble MS, Carbott D, Gil-Bazo I, Gonzalez-Moreno O, et al. Identification of VEGF-regulated genes associated with increased lung metastatic potential: functional involvement of tenascin-C in tumor growth and lung metastasis. Oncogene. 2008;27(40):5373–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. O’Connell JT, Sugimoto H, Cooke VG, MacDonald BA, Mehta AI, LeBleu VS, et al. VEGF-A and Tenascin-C produced by S100A4+ stromal cells are important for metastatic colonization. Proc Natl Acad Sci U S A. 2011;108(38):16002–7.

    Article  PubMed  PubMed Central  Google Scholar 

  196. Gocheva V, Naba A, Bhutkar A, Guardia T, Miller KM, Li CM, et al. Quantitative proteomics identify Tenascin-C as a promoter of lung cancer progression and contributor to a signature prognostic of patient survival. Proc Natl Acad Sci U S A. 2017;114(28):E5625–E34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Katoh D, Kozuka Y, Noro A, Ogawa T, Imanaka-Yoshida K, Yoshida T. Tenascin-C induces phenotypic changes in fibroblasts to myofibroblasts with high contractility through the integrin alphavbeta1/TGF-beta/SMAD signaling axis in human breast cancer. Am J Pathol. 2020;190(10):2123–35.

    Article  CAS  PubMed  Google Scholar 

  198. Spenle C, Loustau T, Murdamoothoo D, Erne W, la Forest B-d, Divonne S, Veber R, et al. Tenascin-C orchestrates an immune-suppressive tumor microenvironment in oral squamous cell carcinoma. Cancer Immunol Res. 2020;8(9):1122–38.

    Article  CAS  PubMed  Google Scholar 

  199. Chiovaro F, Martina E, Bottos A, Scherberich A, Hynes NE, Chiquet-Ehrismann R. Transcriptional regulation of tenascin-W by TGF-beta signaling in the bone metastatic niche of breast cancer cells. Int J Cancer. 2015;137(8):1842–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Degen M, Brellier F, Kain R, Ruiz C, Terracciano L, Orend G, et al. Tenascin-W is a novel marker for activated tumor stroma in low-grade human breast cancer and influences cell behavior. Cancer Res. 2007;67(19):9169–79.

    Article  CAS  PubMed  Google Scholar 

  201. Degen M, Brellier F, Schenk S, Driscoll R, Zaman K, Stupp R, et al. Tenascin-W, a new marker of cancer stroma, is elevated in sera of colon and breast cancer patients. Int J Cancer. 2008;122(11):2454–61.

    Article  CAS  PubMed  Google Scholar 

  202. Scherberich A, Tucker RP, Degen M, Brown-Luedi M, Andres AC, Chiquet-Ehrismann R. Tenascin-W is found in malignant mammary tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF-alpha induced expression in vitro. Oncogene. 2005;24(9):1525–32.

    Article  CAS  PubMed  Google Scholar 

  203. Brellier F, Martina E, Degen M, Heuze-Vourc’h N, Petit A, Kryza T, et al. Tenascin-W is a better cancer biomarker than tenascin-C for most human solid tumors. BMC Clin Pathol. 2012;12:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Matsumoto K, Saga Y, Ikemura T, Sakakura T, Chiquet-Ehrismann R. The distribution of tenascin-X is distinct and often reciprocal to that of tenascin-C. J Cell Biol. 1994;125(2):483–93.

    Article  CAS  PubMed  Google Scholar 

  205. Chiquet-Ehrismann R, Chiquet M. Tenascins: regulation and putative functions during pathological stress. J Pathol. 2003;200(4):488–99.

    Article  CAS  PubMed  Google Scholar 

  206. Geffrotin C, Horak V, Crechet F, Tricaud Y, Lethias C, Vincent-Naulleau S, et al. Opposite regulation of tenascin-C and tenascin-X in MeLiM swine heritable cutaneous malignant melanoma. Biochim Biophys Acta. 2000;1524(2-3):196–202.

    Article  CAS  PubMed  Google Scholar 

  207. Matsumoto K, Takayama N, Ohnishi J, Ohnishi E, Shirayoshi Y, Nakatsuji N, et al. Tumour invasion and metastasis are promoted in mice deficient in tenascin-X. Genes Cells. 2001;6(12):1101–11.

    Article  CAS  PubMed  Google Scholar 

  208. Matsumoto K, Minamitani T, Orba Y, Sato M, Sawa H, Ariga H. Induction of matrix metalloproteinase-2 by tenascin-X deficiency is mediated through the c-Jun N-terminal kinase and protein tyrosine kinase phosphorylation pathway. Exp Cell Res. 2004;297(2):404–14.

    Article  CAS  PubMed  Google Scholar 

  209. Alcaraz LB, Exposito JY, Chuvin N, Pommier RM, Cluzel C, Martel S, et al. Tenascin-X promotes epithelial-to-mesenchymal transition by activating latent TGF-beta. J Cell Biol. 2014;205(3):409–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Rios H, Koushik SV, Wang H, Wang J, Zhou HM, Lindsley A, et al. periostin null mice exhibit dwarfism, incisor enamel defects, and an early-onset periodontal disease-like phenotype. Mol Cell Biol. 2005;25(24):11131–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Conway SJ, Izuhara K, Kudo Y, Litvin J, Markwald R, Ouyang G, et al. The role of periostin in tissue remodeling across health and disease. Cell Mol Life Sci. 2014;71(7):1279–88.

    Article  CAS  PubMed  Google Scholar 

  212. Elliott CG, Wang J, Guo X, Sw X, Eastwood M, Guan J, et al. Periostin modulates myofibroblast differentiation during full-thickness cutaneous wound repair. J Cell Sci. 2012;125(1):121–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Shimazaki M, Nakamura K, Kii I, Kashima T, Amizuka N, Li M, et al. Periostin is essential for cardiac healing after acute myocardial infarction. J Exp Med. 2008;205(2):295–303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Lorts A, Schwanekamp JA, Baudino TA, McNally EM, Molkentin JD. Deletion of periostin reduces muscular dystrophy and fibrosis in mice by modulating the transforming growth factor-beta pathway. Proc Natl Acad Sci U S A. 2012;109(27):10978–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Norris RA, Damon B, Mironov V, Kasyanov V, Ramamurthi A, Moreno-Rodriguez R, et al. Periostin regulates collagen fibrillogenesis and the biomechanical properties of connective tissues. J Cell Biochem. 2007;101(3):695–711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Egbert M, Ruetze M, Sattler M, Wenck H, Gallinat S, Lucius R, et al. The matricellular protein periostin contributes to proper collagen function and is downregulated during skin aging. J Dermatol Sci. 2014;73(1):40–8.

    Article  CAS  PubMed  Google Scholar 

  217. Shimazaki M, Kudo A. Impaired capsule formation of tumors in periostin-null mice. Biochem Biophys Res Commun. 2008;367(4):736–42.

    Article  CAS  PubMed  Google Scholar 

  218. Kikuchi Y, Kunita A, Iwata C, Komura D, Nishiyama T, Shimazu K, et al. The niche component periostin is produced by cancer-associated fibroblasts, supporting growth of gastric cancer through ERK activation. Am J Pathol. 2014;184(3):859–70.

    Article  CAS  PubMed  Google Scholar 

  219. Fukuda K, Sugihara E, Ohta S, Izuhara K, Funakoshi T, Amagai M, et al. Periostin is a key niche component for wound metastasis of melanoma. PLoS One. 2015;10(6):e0129704.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Zhou W, Ke SQ, Huang Z, Flavahan W, Fang X, Paul J, et al. Periostin secreted by glioblastoma stem cells recruits M2 tumour-associated macrophages and promotes malignant growth. Nat Cell Biol. 2015;17(2):170–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Malanchi I, Santamaria-Martinez A, Susanto E, Peng H, Lehr HA, Delaloye JF, et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature. 2012;481(7379):85–9.

    Article  CAS  Google Scholar 

  222. Sonongbua J, Siritungyong S, Thongchot S, Kamolhan T, Utispan K, Thuwajit P, et al. Periostin induces epithelialtomesenchymal transition via the integrin alpha5beta1/TWIST2 axis in cholangiocarcinoma. Oncol Rep. 2020;43(4):1147–58.

    CAS  PubMed  PubMed Central  Google Scholar 

  223. Ma H, Wang J, Zhao X, Wu T, Huang Z, Chen D, et al. Periostin promotes colorectal tumorigenesis through integrin-FAK-Src pathway-mediated YAP/TAZ activation. Cell Rep. 2020;30(3):793–806 e6.

    Article  CAS  PubMed  Google Scholar 

  224. Zenitani M, Nojiri T, Hosoda H, Kimura T, Uehara S, Miyazato M, et al. Chemotherapy can promote liver metastasis by enhancing metastatic niche formation in mice. J Surg Res. 2018;224:50–7.

    Article  CAS  PubMed  Google Scholar 

  225. Wegrowski Y, Maquart FX. Involvement of stromal proteoglycans in tumour progression. Crit Rev Oncol Hematol. 2004;49(3):259–68.

    Article  PubMed  Google Scholar 

  226. Theocharis AD, Skandalis SS, Tzanakakis GN, Karamanos NK. Proteoglycans in health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. FEBS J. 2010;277(19):3904–23.

    Article  CAS  PubMed  Google Scholar 

  227. Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med. 2011;15(5):1013–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Sarrazin S, Lamanna WC, Esko JD. Heparan sulfate proteoglycans. Cold Spring Harb Perspect Biol. 2011;3(7):a004952.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  229. Li JP, Kusche-Gullberg M. Heparan sulfate: biosynthesis, structure, and function. Int Rev Cell Mol Biol. 2016;325:215–73.

    Article  CAS  PubMed  Google Scholar 

  230. Bishop JR, Schuksz M, Esko JD. Heparan sulphate proteoglycans fine-tune mammalian physiology. Nature. 2007;446(7139):1030–7.

    Article  CAS  PubMed  Google Scholar 

  231. Ai X, Do AT, Lozynska O, Kusche-Gullberg M, Lindahl U, Emerson CP Jr. QSulf1 remodels the 6-O sulfation states of cell surface heparan sulfate proteoglycans to promote Wnt signaling. J Cell Biol. 2003;162(2):341–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Billings PC, Pacifici M. Interactions of signaling proteins, growth factors and other proteins with heparan sulfate: mechanisms and mysteries. Connect Tissue Res. 2015;56(4):272–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Lau EK, Paavola CD, Johnson Z, Gaudry JP, Geretti E, Borlat F, et al. Identification of the glycosaminoglycan binding site of the CC chemokine, MCP-1: implications for structure and function in vivo. J Biol Chem. 2004;279(21):22294–305.

    Article  CAS  PubMed  Google Scholar 

  234. Dowsland MH, Harvey JR, Lennard TW, Kirby JA, Ali S. Chemokines and breast cancer: a gateway to revolutionary targeted cancer treatments? Curr Med Chem. 2003;10(7):579–92.

    Article  CAS  PubMed  Google Scholar 

  235. Iozzo RV, Schaefer L. Proteoglycan form and function: a comprehensive nomenclature of proteoglycans. Matrix Biol. 2015;42:11–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Choi Y, Chung H, Jung H, Couchman JR, Oh ES. Syndecans as cell surface receptors: unique structure equates with functional diversity. Matrix Biol. 2011;30(2):93–9.

    Article  CAS  PubMed  Google Scholar 

  237. Couchman JR, Gopal S, Lim HC, Norgaard S, Multhaupt HA. Syndecans: from peripheral coreceptors to mainstream regulators of cell behaviour. Int J Exp Pathol. 2015;96(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  238. Yao W, Rose JL, Wang W, Seth S, Jiang H, Taguchi A, et al. Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer. Nature. 2019;568(7752):410–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  239. Chute C, Yang X, Meyer K, Yang N, O’Neil K, Kasza I, et al. Syndecan-1 induction in lung microenvironment supports the establishment of breast tumor metastases. Breast Cancer Res. 2018;20(1):66.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  240. Gondelaud F, Ricard-Blum S. Structures and interactions of syndecans. FEBS J. 2019;286(15):2994–3007.

    Article  CAS  PubMed  Google Scholar 

  241. Vuoriluoto K, Hognas G, Meller P, Lehti K, Ivaska J. Syndecan-1 and -4 differentially regulate oncogenic K-ras dependent cell invasion into collagen through alpha2beta1 integrin and MT1-MMP. Matrix Biol. 2011;30(3):207–17.

    Article  CAS  PubMed  Google Scholar 

  242. Chronopoulos A, Thorpe SD, Cortes E, Lachowski D, Rice AJ, Mykuliak VV, et al. Syndecan-4 tunes cell mechanics by activating the kindlin-integrin-RhoA pathway. Nat Mater. 2020;19(6):669–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Ihrcke NS, Platt JL. Shedding of heparan sulfate proteoglycan by stimulated endothelial cells: evidence for proteolysis of cell-surface molecules. J Cell Physiol. 1996;168(3):625–37.

    Article  CAS  PubMed  Google Scholar 

  244. Manon-Jensen T, Multhaupt HA, Couchman JR. Mapping of matrix metalloproteinase cleavage sites on syndecan-1 and syndecan-4 ectodomains. FEBS J. 2013;280(10):2320–31.

    Article  CAS  PubMed  Google Scholar 

  245. Choi S, Kim JY, Park JH, Lee ST, Han IO, Oh ES. The matrix metalloproteinase-7 regulates the extracellular shedding of syndecan-2 from colon cancer cells. Biochem Biophys Res Commun. 2012;417(4):1260–4.

    Article  CAS  PubMed  Google Scholar 

  246. Manon-Jensen T, Itoh Y, Couchman JR. Proteoglycans in health and disease: the multiple roles of syndecan shedding. FEBS J. 2010;277(19):3876–89.

    Article  CAS  PubMed  Google Scholar 

  247. Ding K, Lopez-Burks M, Sanchez-Duran JA, Korc M, Lander AD. Growth factor-induced shedding of syndecan-1 confers glypican-1 dependence on mitogenic responses of cancer cells. J Cell Biol. 2005;171(4):729–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Tan X, Khalil N, Tesarik C, Vanapalli K, Yaputra V, Alkhouri H, et al. Th1 cytokine-induced syndecan-4 shedding by airway smooth muscle cells is dependent on mitogen-activated protein kinases. Am J Physiol Lung Cell Mol Physiol. 2012;302(7):L700–10.

    Article  CAS  PubMed  Google Scholar 

  249. Yang Y, Macleod V, Miao HQ, Theus A, Zhan F, Shaughnessy JD Jr, et al. Heparanase enhances syndecan-1 shedding: a novel mechanism for stimulation of tumor growth and metastasis. J Biol Chem. 2007;282(18):13326–33.

    Article  CAS  PubMed  Google Scholar 

  250. Joensuu H, Anttonen A, Eriksson M, Makitaro R, Alfthan H, Kinnula V, et al. Soluble syndecan-1 and serum basic fibroblast growth factor are new prognostic factors in lung cancer. Cancer Res. 2002;62(18):5210–7.

    CAS  PubMed  Google Scholar 

  251. Ramani VC, Sanderson RD. Chemotherapy stimulates syndecan-1 shedding: a potentially negative effect of treatment that may promote tumor relapse. Matrix Biol. 2014;35:215–22.

    Article  CAS  PubMed  Google Scholar 

  252. Stewart MD, Ramani VC, Sanderson RD. Shed syndecan-1 translocates to the nucleus of cells delivering growth factors and inhibiting histone acetylation: a novel mechanism of tumor-host cross-talk. J Biol Chem. 2015;290(2):941–9.

    Article  CAS  PubMed  Google Scholar 

  253. Su G, Blaine SA, Qiao D, Friedl A. Membrane type 1 matrix metalloproteinase-mediated stromal syndecan-1 shedding stimulates breast carcinoma cell proliferation. Cancer Res. 2008;68(22):9558–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. Su G, Blaine SA, Qiao D, Friedl A. Shedding of syndecan-1 by stromal fibroblasts stimulates human breast cancer cell proliferation via FGF2 activation. J Biol Chem. 2007;282(20):14906–15.

    Article  CAS  PubMed  Google Scholar 

  255. Nikolova V, Koo CY, Ibrahim SA, Wang Z, Spillmann D, Dreier R, et al. Differential roles for membrane-bound and soluble syndecan-1 (CD138) in breast cancer progression. Carcinogenesis. 2009;30(3):397–407.

    Article  CAS  PubMed  Google Scholar 

  256. Choi S, Choi Y, Jun E, Kim IS, Kim SE, Jung SA, et al. Shed syndecan-2 enhances tumorigenic activities of colon cancer cells. Oncotarget. 2015;6(6):3874–86.

    Article  PubMed  PubMed Central  Google Scholar 

  257. Wang X, Zuo D, Chen Y, Li W, Liu R, He Y, et al. Shed Syndecan-1 is involved in chemotherapy resistance via the EGFR pathway in colorectal cancer. Br J Cancer. 2014;111(10):1965–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  258. Chen S, Birk DE. The regulatory roles of small leucine-rich proteoglycans in extracellular matrix assembly. FEBS J. 2013;280(10):2120–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Cawthorn TR, Moreno JC, Dharsee M, Tran-Thanh D, Ackloo S, Zhu PH, et al. Proteomic analyses reveal high expression of decorin and endoplasmin (HSP90B1) are associated with breast cancer metastasis and decreased survival. PLoS One. 2012;7(2):e30992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Sainio A, Nyman M, Lund R, Vuorikoski S, Bostrom P, Laato M, et al. Lack of decorin expression by human bladder cancer cells offers new tools in the therapy of urothelial malignancies. PLoS One. 2013;8(10):e76190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  261. Henke A, Grace OC, Ashley GR, Stewart GD, Riddick AC, Yeun H, et al. Stromal expression of decorin, Semaphorin6D, SPARC, Sprouty1 and Tsukushi in developing prostate and decreased levels of decorin in prostate cancer. PLoS One. 2012;7(8):e42516.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Campioni M, Ambrogi V, Pompeo E, Citro G, Castelli M, Spugnini EP, et al. Identification of genes down-regulated during lung cancer progression: a cDNA array study. J Exp Clin Cancer Res. 2008;27:38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  263. Bostrom P, Sainio A, Kakko T, Savontaus M, Soderstrom M, Jarvelainen H. Localization of decorin gene expression in normal human breast tissue and in benign and malignant tumors of the human breast. Histochem Cell Biol. 2013;139(1):161–71.

    Article  PubMed  CAS  Google Scholar 

  264. Oda G, Sato T, Ishikawa T, Kawachi H, Nakagawa T, Kuwayama T, et al. Significance of stromal decorin expression during the progression of breast cancer. Oncol Rep. 2012;28(6):2003–8.

    Article  PubMed  Google Scholar 

  265. Troup S, Njue C, Kliewer EV, Parisien M, Roskelley C, Chakravarti S, et al. Reduced expression of the small leucine-rich proteoglycans, lumican, and decorin is associated with poor outcome in node-negative invasive breast cancer. Clin Cancer Res. 2003;9(1):207–14.

    CAS  PubMed  Google Scholar 

  266. Horvath Z, Kovalszky I, Fullar A, Kiss K, Schaff Z, Iozzo RV, et al. Decorin deficiency promotes hepatic carcinogenesis. Matrix Biol. 2014;35:194–205.

    Article  CAS  PubMed  Google Scholar 

  267. Xu W, Neill T, Yang Y, Hu Z, Cleveland E, Wu Y, et al. The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. Gene Ther. 2015;22(3):31–40.

    Article  CAS  Google Scholar 

  268. Nyman MC, Sainio AO, Pennanen MM, Lund RJ, Vuorikoski S, Sundstrom JT, et al. Decorin in human colon cancer: localization in vivo and effect on cancer cell behavior in vitro. J Histochem Cytochem. 2015;63(9):710–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Buraschi S, Neill T, Owens RT, Iniguez LA, Purkins G, Vadigepalli R, et al. Decorin protein core affects the global gene expression profile of the tumor microenvironment in a triple-negative orthotopic breast carcinoma xenograft model. PLoS One. 2012;7(9):e45559.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Goldoni S, Iozzo RV. Tumor microenvironment: modulation by decorin and related molecules harboring leucine-rich tandem motifs. Int J Cancer. 2008;123(11):2473–9.

    Article  CAS  PubMed  Google Scholar 

  271. Buraschi S, Pal N, Tyler-Rubinstein N, Owens RT, Neill T, Iozzo RV. Decorin antagonizes Met receptor activity and down-regulates {beta}-catenin and Myc levels. J Biol Chem. 2010;285(53):42075–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Neill T, Torres A, Buraschi S, Owens RT, Hoek JB, Baffa R, et al. Decorin induces mitophagy in breast carcinoma cells via peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) and mitostatin. J Biol Chem. 2014;289(8):4952–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Neill T, Painter H, Buraschi S, Owens RT, Lisanti MP, Schaefer L, et al. Decorin antagonizes the angiogenic network: concurrent inhibition of Met, hypoxia inducible factor 1alpha, vascular endothelial growth factor A, and induction of thrombospondin-1 and TIMP3. J Biol Chem. 2012;287(8):5492–506.

    Article  CAS  PubMed  Google Scholar 

  274. Buraschi S, Neill T, Goyal A, Poluzzi C, Smythies J, Owens RT, et al. Decorin causes autophagy in endothelial cells via Peg3. Proc Natl Acad Sci U S A. 2013;110(28):E2582–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Morcavallo A, Buraschi S, Xu SQ, Belfiore A, Schaefer L, Iozzo RV, et al. Decorin differentially modulates the activity of insulin receptor isoform A ligands. Matrix Biol. 2014;35:82–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Koninger J, Giese NA, di Mola FF, Berberat P, Giese T, Esposito I, et al. Overexpressed decorin in pancreatic cancer: potential tumor growth inhibition and attenuation of chemotherapeutic action. Clin Cancer Res. 2004;10(14):4776–83.

    Article  PubMed  Google Scholar 

  277. Kasamatsu A, Uzawa K, Minakawa Y, Ishige S, Kasama H, Endo-Sakamoto Y, et al. Decorin in human oral cancer: a promising predictive biomarker of S-1 neoadjuvant chemosensitivity. Biochem Biophys Res Commun. 2015;457(1):71–6.

    Article  CAS  PubMed  Google Scholar 

  278. Zhu YH, Yang F, Zhang SS, Zeng TT, Xie X, Guan XY. High expression of biglycan is associated with poor prognosis in patients with esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2013;6(11):2497–505.

    PubMed  PubMed Central  Google Scholar 

  279. Aprile G, Avellini C, Reni M, Mazzer M, Foltran L, Rossi D, et al. Biglycan expression and clinical outcome in patients with pancreatic adenocarcinoma. Tumour Biol. 2013;34(1):131–7.

    Article  CAS  PubMed  Google Scholar 

  280. Hu L, Duan YT, Li JF, Su LP, Yan M, Zhu ZG, et al. Biglycan enhances gastric cancer invasion by activating FAK signaling pathway. Oncotarget. 2014;5(7):1885–96.

    Article  PubMed  PubMed Central  Google Scholar 

  281. Niedworok C, Rock K, Kretschmer I, Freudenberger T, Nagy N, Szarvas T, et al. Inhibitory role of the small leucine-rich proteoglycan biglycan in bladder cancer. PLoS One. 2013;8(11):e80084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Weber CK, Sommer G, Michl P, Fensterer H, Weimer M, Gansauge F, et al. Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines. Gastroenterology. 2001;121(3):657–67.

    Article  CAS  PubMed  Google Scholar 

  283. Nikitovic D, Papoutsidakis A, Karamanos NK, Tzanakakis GN. Lumican affects tumor cell functions, tumor-ECM interactions, angiogenesis and inflammatory response. Matrix Biol. 2014;35:206–14.

    Article  CAS  PubMed  Google Scholar 

  284. Brezillon S, Pietraszek K, Maquart FX, Wegrowski Y. Lumican effects in the control of tumour progression and their links with metalloproteinases and integrins. FEBS J. 2013;280(10):2369–81.

    Article  CAS  PubMed  Google Scholar 

  285. Seya T, Tanaka N, Shinji S, Yokoi K, Koizumi M, Teranishi N, et al. Lumican expression in advanced colorectal cancer with nodal metastasis correlates with poor prognosis. Oncol Rep. 2006;16(6):1225–30.

    CAS  PubMed  Google Scholar 

  286. de Wit M, Belt EJ, Delis-van Diemen PM, Carvalho B, Coupe VM, Stockmann HB, et al. Lumican and versican are associated with good outcome in stage II and III colon cancer. Ann Surg Oncol. 2013;20(Suppl 3):S348–59.

    Article  PubMed  Google Scholar 

  287. Panis C, Pizzatti L, Herrera AC, Cecchini R, Abdelhay E. Putative circulating markers of the early and advanced stages of breast cancer identified by high-resolution label-free proteomics. Cancer Lett. 2013;330(1):57–66.

    Article  CAS  PubMed  Google Scholar 

  288. Karamanou K, Franchi M, Onisto M, Passi A, Vynios DH, Brezillon S. Evaluation of lumican effects on morphology of invading breast cancer cells, expression of integrins and downstream signaling. FEBS J. 2020;287:4862–80.

    Article  CAS  PubMed  Google Scholar 

  289. Ishiwata T, Cho K, Kawahara K, Yamamoto T, Fujiwara Y, Uchida E, et al. Role of lumican in cancer cells and adjacent stromal tissues in human pancreatic cancer. Oncol Rep. 2007;18(3):537–43.

    CAS  PubMed  Google Scholar 

  290. Li X, Truty MA, Kang Y, Chopin-Laly X, Zhang R, Roife D, et al. Extracellular lumican inhibits pancreatic cancer cell growth and is associated with prolonged survival after surgery. Clin Cancer Res. 2014;20(24):6529–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  291. Matsuda Y, Yamamoto T, Kudo M, Kawahara K, Kawamoto M, Nakajima Y, et al. Expression and roles of lumican in lung adenocarcinoma and squamous cell carcinoma. Int J Oncol. 2008;33(6):1177–85.

    CAS  PubMed  Google Scholar 

  292. Brezillon S, Venteo L, Ramont L, D’Onofrio MF, Perreau C, Pluot M, et al. Expression of lumican, a small leucine-rich proteoglycan with antitumour activity, in human malignant melanoma. Clin Exp Dermatol. 2007;32(4):405–16.

    Article  CAS  PubMed  Google Scholar 

  293. Brezillon S, Radwanska A, Zeltz C, Malkowski A, Ploton D, Bobichon H, et al. Lumican core protein inhibits melanoma cell migration via alterations of focal adhesion complexes. Cancer Lett. 2009;283(1):92–100.

    Article  CAS  PubMed  Google Scholar 

  294. Zeltz C, Brezillon S, Perreau C, Ramont L, Maquart FX, Wegrowski Y. Lumcorin: a leucine-rich repeat 9-derived peptide from human lumican inhibiting melanoma cell migration. FEBS Lett. 2009;583(18):3027–32.

    Article  CAS  PubMed  Google Scholar 

  295. Zeltz C, Brezillon S, Kapyla J, Eble JA, Bobichon H, Terryn C, et al. Lumican inhibits cell migration through alpha2beta1 integrin. Exp Cell Res. 2010;316(17):2922–31.

    Article  CAS  PubMed  Google Scholar 

  296. Pietraszek K, Chatron-Colliet A, Brezillon S, Perreau C, Jakubiak-Augustyn A, Krotkiewski H, et al. Lumican: a new inhibitor of matrix metalloproteinase-14 activity. FEBS Lett. 2014;588(23):4319–24.

    Article  CAS  PubMed  Google Scholar 

  297. Coulson-Thomas VJ, Coulson-Thomas YM, Gesteira TF, Andrade de Paula CA, Carneiro CR, Ortiz V, et al. Lumican expression, localization and antitumor activity in prostate cancer. Exp Cell Res. 2013;319(7):967–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. Radwanska A, Litwin M, Nowak D, Baczynska D, Wegrowski Y, Maquart FX, et al. Overexpression of lumican affects the migration of human colon cancer cells through up-regulation of gelsolin and filamentous actin reorganization. Exp Cell Res. 2012;318(18):2312–23.

    Article  CAS  PubMed  Google Scholar 

  299. Oldberg A, Kalamajski S, Salnikov AV, Stuhr L, Morgelin M, Reed RK, et al. Collagen-binding proteoglycan fibromodulin can determine stroma matrix structure and fluid balance in experimental carcinoma. Proc Natl Acad Sci U S A. 2007;104(35):13966–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Hildebrand A, Romaris M, Rasmussen LM, Heinegard D, Twardzik DR, Border WA, et al. Interaction of the small interstitial proteoglycans biglycan, decorin and fibromodulin with transforming growth factor beta. Biochem J. 1994;302(Pt 2):527–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  301. Maris P, Blomme A, Palacios AP, Costanza B, Bellahcene A, Bianchi E, et al. Asporin Is a Fibroblast-Derived TGF-beta1 Inhibitor and a Tumor Suppressor Associated with Good Prognosis in Breast Cancer. PLoS Med. 2015;12(9):e1001871.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  302. Lohler J, Timpl R, Jaenisch R. Embryonic lethal mutation in mouse collagen I gene causes rupture of blood vessels and is associated with erythropoietic and mesenchymal cell death. Cell. 1984;38(2):597–607.

    Article  CAS  PubMed  Google Scholar 

  303. Andrikopoulos K, Liu X, Keene DR, Jaenisch R, Ramirez F. Targeted mutation in the col5a2 gene reveals a regulatory role for type V collagen during matrix assembly. Nat Genet. 1995;9(1):31–6.

    Article  CAS  PubMed  Google Scholar 

  304. Wenstrup RJ, Florer JB, Brunskill EW, Bell SM, Chervoneva I, Birk DE. Type V collagen controls the initiation of collagen fibril assembly. J Biol Chem. 2004;279(51):53331–7.

    Article  CAS  PubMed  Google Scholar 

  305. Provenzano PP, Eliceiri KW, Campbell JM, Inman DR, White JG, Keely PJ. Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 2006;4(1):38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  306. Liu X, Wu H, Byrne M, Krane S, Jaenisch R. Type III collagen is crucial for collagen I fibrillogenesis and for normal cardiovascular development. Proc Natl Acad Sci U S A. 1997;94(5):1852–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  307. Saga Y, Yagi T, Ikawa Y, Sakakura T, Aizawa S. Mice develop normally without tenascin. Genes Dev. 1992;6:1821–31.

    Article  CAS  PubMed  Google Scholar 

  308. Hendaoui I, Tucker RP, Zingg D, Bichet S, Schittny J, Chiquet-Ehrismann R. Tenascin-C is required for normal Wnt/beta-catenin signaling in the whisker follicle stem cell niche. Matrix Biol. 2014;40:46–53.

    Article  CAS  PubMed  Google Scholar 

  309. Kii I, Amizuka N, Minqi L, Kitajima S, Saga Y, Kudo A. Periostin is an extracellular matrix protein required for eruption of incisors in mice. Biochem Biophys Res Commun. 2006;342(3):766–72.

    Article  CAS  PubMed  Google Scholar 

  310. Ontsuka K, Kotobuki Y, Shiraishi H, Serada S, Ohta S, Tanemura A, et al. Periostin, a matricellular protein, accelerates cutaneous wound repair by activating dermal fibroblasts. Exp Dermatol. 2012;21(5):331–6.

    Article  CAS  PubMed  Google Scholar 

  311. Ishiba T, Nagahara M, Nakagawa T, Sato T, Ishikawa T, Uetake H, et al. Periostin suppression induces decorin secretion leading to reduced breast cancer cell motility and invasion. Sci Rep. 2014;4:7069.

    Article  PubMed  PubMed Central  Google Scholar 

  312. Danielson KG, Baribault H, Holmes DF, Graham H, Kadler KE, Iozzo RV. Targeted disruption of decorin leads to abnormal collagen fibril morphology and skin fragility. J Cell Biol. 1997;136(3):729–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  313. Neill T, Schaefer L, Iozzo RV. Decorin: a guardian from the matrix. Am J Pathol. 2012;181(2):380–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  314. Yamaguchi Y, Mann DM, Ruoslahti E. Negative regulation of transforming growth factor-beta by the proteoglycan decorin. Nature. 1990;346(6281):281–4.

    Article  CAS  PubMed  Google Scholar 

  315. Merline R, Moreth K, Beckmann J, Nastase MV, Zeng-Brouwers J, Tralhao JG, et al. Signaling by the matrix proteoglycan decorin controls inflammation and cancer through PDCD4 and MicroRNA-21. Sci Signal. 2011;4(199):ra75.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  316. Chakravarti S, Magnuson T, Lass JH, Jepsen KJ, LaMantia C, Carroll H. Lumican regulates collagen fibril assembly: skin fragility and corneal opacity in the absence of lumican. J Cell Biol. 1998;141(5):1277–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  317. Beauvais DM, Ell BJ, McWhorter AR, Rapraeger AC. Syndecan-1 regulates {alpha}v{beta}3 and {alpha}v{beta}5 integrin activation during angiogenesis and is blocked by synstatin, a novel peptide inhibitor. J Exp Med. 2009;16:691–705.

    Article  CAS  Google Scholar 

  318. Theocharis AD, Karamanos NK. Proteoglycans remodeling in cancer: underlying molecular mechanisms. Matrix Biol. 2019;75-76:220–59.

    Article  CAS  PubMed  Google Scholar 

  319. Multhaupt HA, Leitinger B, Gullberg D, Couchman JR. Extracellular matrix component signaling in cancer. Adv Drug Deliv Rev. 2016;97:28–40.

    Article  CAS  PubMed  Google Scholar 

  320. Guilluy C, Dolega ME. Syndecan-4 forces integrins to cooperate. Nat Mater. 2020;19(6):587–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge the useful comments from Sandy Der (University Health Network, Toronto).

Supported by grants to DG from the Research Council of Norway (Norwegian Center of Excellence grant, grants 223250) and Nasjonalföreningen for folkhelsen (Project 16216).

Author information

Authors and Affiliations

  1. Department of Biomedicine, Centre for Cancer Biomarkers, University of Bergen, Bergen, Norway

    Cédric Zeltz, Ning Lu, Marion Kusche-Gullberg & Donald Gullberg

  2. Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada

    Roya Navab & Ming-Sound Tsao

Authors
  1. Cédric Zeltz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Roya Navab
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ning Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marion Kusche-Gullberg
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ming-Sound Tsao
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald Gullberg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Donald Gullberg .

Editor information

Editors and Affiliations

  1. Centre for Cancer Biomarkers CCBIO Department of Clinical Medicine, University of Bergen, Bergen, Norway

    Lars A. Akslen

  2. Department of Surgery, Harvard Medical School, Vascular Biology Program, Boston Children’s Hospital, Boston, USA

    Randolph S. Watnick

Rights and permissions

Reprints and permissions

Copyright information

© 2022 The Author(s), under exclusive license to Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Zeltz, C., Navab, R., Lu, N., Kusche-Gullberg, M., Tsao, MS., Gullberg, D. (2022). Role of the Extracellular Matrix in Tumor Stroma: Barrier or Support?. In: Akslen, L.A., Watnick, R.S. (eds) Biomarkers of the Tumor Microenvironment. Springer, Cham. https://doi.org/10.1007/978-3-030-98950-7_5

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-98950-7_5

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-98949-1

  • Online ISBN: 978-3-030-98950-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation