Skip to main content

Novel Approaches for Extracellular Matrix Targeting in Disease Treatment

  • Protocol
The Extracellular Matrix

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1952))

Abstract

Extracellular matrix (ECM) macromolecules, apart from structural role for the surrounding tissue, have also been defined as crucial mediators in several cell mechanisms. The proteolytic and cross-linking cascades of ECM have fundamental importance in health and disease, which is increasingly becoming acknowledged. However, formidable challenges remain to identify the diverse and novel role of ECM molecules, especially with regard to their distinct biophysical, biochemical, and structural properties. Considering the heterogeneous, dynamic, and hierarchical nature of ECM, the characterization of 3D functional molecular view of ECM in atomic detail will be very useful for further ECM-related studies. Nowadays, the creation of a pioneer ECM multidisciplinary integrated platform in order to decipher ECM homeostasis is more possible than ever. The access to cutting-edge technologies, such as optical imaging and electron and atomic force microscopies, along with diffraction and X-ray-based spectroscopic methods can integrate spanning wide ranges of spatial and time resolutions. Subsequently, ECM image-guided site-directed proteomics can reveal molecular compositions in defined native and reconstituted ECM microenvironments. In addition, the use of highly selective ECM enzyme inhibitors enables the comparative molecular analyses within pre-classified remodeled ECM microenvironments. Mechanistic information which will be derived can be used to develop novel protein-based inhibitors for effective diagnostic and/or therapeutic modalities targeting ECM reactions within tissue microenvironment.

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

Access this chapter

Protocol
USD 49.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
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. Theocharis AD, Karamanos NK (2017) Proteoglycans remodeling in cancer: underlying molecular mechanisms. Matrix Biol. https://doi.org/10.1016/j.matbio.2017.10.008

  2. Karamanos NK, Passi A (2014) Novel insights into matrix pathobiology regulatory mechanisms in health and disease. FEBS J 281(22):4978–4979. https://doi.org/10.1111/febs.13106

    Article  CAS  PubMed  Google Scholar 

  3. Lu P, Takai K, Weaver VM, Werb Z (2011) Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb Perspect Biol 3(12). https://doi.org/10.1101/cshperspect.a005058

  4. Page-McCaw A, Ewald AJ, Werb Z (2007) Matrix metalloproteinases and the regulation of tissue remodelling. Nat Rev Mol Cell Biol 8(3):221–233. https://doi.org/10.1038/nrm2125

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Engler AJ, Humbert PO, Wehrle-Haller B, Weaver VM (2009) Multiscale modeling of form and function. Science 324(5924):208–212. https://doi.org/10.1126/science.1170107

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Muschler J, Streuli CH (2010) Cell-matrix interactions in mammary gland development and breast cancer. Cold Spring Harb Perspect Biol 2(10):a003202. https://doi.org/10.1101/cshperspect.a003202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Egeblad M, Nakasone ES, Werb Z (2010) Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 18(6):884–901. https://doi.org/10.1016/j.devcel.2010.05.012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brix K, Dunkhorst A, Mayer K, Jordans S (2008) Cysteine cathepsins: cellular roadmap to different functions. Biochimie 90(2):194–207. https://doi.org/10.1016/j.biochi.2007.07.024

    Article  CAS  PubMed  Google Scholar 

  9. Adair-Kirk TL, Senior RM (2008) Fragments of extracellular matrix as mediators of inflammation. Int J Biochem Cell Biol 40(6–7):1101–1110. https://doi.org/10.1016/j.biocel.2007.12.005

    Article  CAS  PubMed  Google Scholar 

  10. Crawford HC, Dempsey PJ, Brown G, Adam L, Moss ML (2009) ADAM10 as a therapeutic target for cancer and inflammation. Curr Pharm Des 15(20):2288–2299

    Article  CAS  Google Scholar 

  11. Solomonov I, Zehorai E, Talmi-Frank D, Wolf SG, Shainskaya A, Zhuravlev A, Kartvelishvily E, Visse R, Levin Y, Kampf N, Jaitin DA, David E, Amit I, Nagase H, Sagi I (2016) Distinct biological events generated by ECM proteolysis by two homologous collagenases. Proc Natl Acad Sci U S A 113(39):10884–10889. https://doi.org/10.1073/pnas.1519676113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. McGuire JK, Li Q, Parks WC (2003) Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am J Pathol 162(6):1831–1843. https://doi.org/10.1016/S0002-9440(10)64318-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Zhang L, Rice AB, Adler K, Sannes P, Martin L, Gladwell W, Koo JS, Gray TE, Bonner JC (2001) Vanadium stimulates human bronchial epithelial cells to produce heparin-binding epidermal growth factor-like growth factor: a mitogen for lung fibroblasts. Am J Respir Cell Mol Biol 24(2):123–131. https://doi.org/10.1165/ajrcmb.24.2.4096

    Article  CAS  PubMed  Google Scholar 

  14. Garcia-Prieto E, Gonzalez-Lopez A, Cabrera S, Astudillo A, Gutierrez-Fernandez A, Fanjul-Fernandez M, Batalla-Solis E, Puente XS, Fueyo A, Lopez-Otin C, Albaiceta GM (2010) Resistance to bleomycin-induced lung fibrosis in MMP-8 deficient mice is mediated by interleukin-10. PLoS One 5(10):e13242. https://doi.org/10.1371/journal.pone.0013242

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wu B, Crampton SP, Hughes CC (2007) Wnt signaling induces matrix metalloproteinase expression and regulates T cell transmigration. Immunity 26(2):227–239. https://doi.org/10.1016/j.immuni.2006.12.007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Chun TH, Hotary KB, Sabeh F, Saltiel AR, Allen ED, Weiss SJ (2006) A pericellular collagenase directs the 3-dimensional development of white adipose tissue. Cell 125(3):577–591. https://doi.org/10.1016/j.cell.2006.02.050

    Article  CAS  PubMed  Google Scholar 

  17. Wolf K, Alexander S, Schacht V, Coussens LM, von Andrian UH, van Rheenen J, Deryugina E, Friedl P (2009) Collagen-based cell migration models in vitro and in vivo. Semin Cell Dev Biol 20(8):931–941. https://doi.org/10.1016/j.semcdb.2009.08.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Overall CM, Kleifeld O (2006) Tumour microenvironment - opinion: validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6(3):227–239. https://doi.org/10.1038/nrc1821

    Article  CAS  PubMed  Google Scholar 

  19. Kruger A, Kates RE, Edwards DR (2010) Avoiding spam in the proteolytic internet: future strategies for anti-metastatic MMP inhibition. Biochim Biophys Acta 1803(1):95–102. https://doi.org/10.1016/j.bbamcr.2009.09.016

    Article  CAS  PubMed  Google Scholar 

  20. Hu J, Van den Steen PE, Sang QX, Opdenakker G (2007) Matrix metalloproteinase inhibitors as therapy for inflammatory and vascular diseases. Nat Rev Drug Discov 6(6):480–498. https://doi.org/10.1038/nrd2308

    Article  CAS  PubMed  Google Scholar 

  21. Sela-Passwell N, Trahtenherts A, Kruger A, Sagi I (2011) New opportunities in drug design of metalloproteinase inhibitors: combination between structure-function experimental approaches and systems biology. Expert Opin Drug Discovery 6(5):527–542. https://doi.org/10.1517/17460441.2011.560936

    Article  CAS  Google Scholar 

  22. Johnston KA, Lopez KM (2018) Lysyl oxidase in cancer inhibition and metastasis. Cancer Lett 417:174–181. https://doi.org/10.1016/j.canlet.2018.01.006

    Article  CAS  PubMed  Google Scholar 

  23. Li T, Wu C, Gao L, Qin F, Wei Q, Yuan J (2018) Lysyl oxidase family members in urological tumorigenesis and fibrosis. Oncotarget 9(28):20156–20164. https://doi.org/10.18632/oncotarget.24948

    Article  PubMed  PubMed Central  Google Scholar 

  24. Cox TR, Gartland A, Erler JT (2016) Lysyl oxidase, a targetable secreted molecule involved in cancer metastasis. Cancer Res 76(2):188–192. https://doi.org/10.1158/0008-5472.CAN-15-2306

    Article  CAS  PubMed  Google Scholar 

  25. Wu L, Zhu Y (2015) The function and mechanisms of action of LOXL2 in cancer (Review). Int J Mol Med 36(5):1200–1204. https://doi.org/10.3892/ijmm.2015.2337

    Article  CAS  PubMed  Google Scholar 

  26. Contente S, Kenyon K, Rimoldi D, Friedman RM (1990) Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science 249(4970):796–798

    Article  CAS  Google Scholar 

  27. Cox TR, Erler JT (2013) Lysyl oxidase in colorectal cancer. Am J Physiol Gastrointest Liver Physiol 305(10):G659–G666. https://doi.org/10.1152/ajpgi.00425.2012

    Article  CAS  PubMed  Google Scholar 

  28. Erler JT, Giaccia AJ (2006) Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res 66(21):10238–10241. https://doi.org/10.1158/0008-5472.CAN-06-3197

    Article  CAS  PubMed  Google Scholar 

  29. Liu SB, Ikenaga N, Peng ZW, Sverdlov DY, Greenstein A, Smith V, Schuppan D, Popov Y (2016) Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice. FASEB J 30(4):1599–1609. https://doi.org/10.1096/fj.14-268425

    Article  CAS  PubMed  Google Scholar 

  30. Ashley SL, Wilke CA, Kim KK, Moore BB (2017) Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis. Mucosal Immunol 10(2):341–351. https://doi.org/10.1038/mi.2016.61

    Article  CAS  PubMed  Google Scholar 

  31. Zhao W, Yang A, Chen W, Wang P, Liu T, Cong M, Xu A, Yan X, Jia J, You H (2018) Inhibition of lysyl oxidase-like 1 (LOXL1) expression arrests liver fibrosis progression in cirrhosis by reducing elastin crosslinking. Biochim Biophys Acta 1864(4 Pt A):1129–1137. https://doi.org/10.1016/j.bbadis.2018.01.019

    Article  CAS  Google Scholar 

  32. Barker HE, Cox TR, Erler JT (2012) The rationale for targeting the LOX family in cancer. Nat Rev Cancer 12(8):540–552. https://doi.org/10.1038/nrc3319

    Article  CAS  PubMed  Google Scholar 

  33. Barker HE, Chang J, Cox TR, Lang G, Bird D, Nicolau M, Evans HR, Gartland A, Erler JT (2011) LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Res 71(5):1561–1572. https://doi.org/10.1158/0008-5472.CAN-10-2868

    Article  CAS  PubMed  Google Scholar 

  34. Moreno-Bueno G, Salvador F, Martin A, Floristan A, Cuevas EP, Santos V, Montes A, Morales S, Castilla MA, Rojo-Sebastian A, Martinez A, Hardisson D, Csiszar K, Portillo F, Peinado H, Palacios J, Cano A (2011) Lysyl oxidase-like 2 (LOXL2), a new regulator of cell polarity required for metastatic dissemination of basal-like breast carcinomas. EMBO Mol Med 3(9):528–544. https://doi.org/10.1002/emmm.201100156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Ikenaga N, Peng ZW, Vaid KA, Liu SB, Yoshida S, Sverdlov DY, Mikels-Vigdal A, Smith V, Schuppan D, Popov YV (2017) Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal. Gut 66(9):1697–1708. https://doi.org/10.1136/gutjnl-2016-312473

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kraft-Sheleg O, Zaffryar-Eilot S, Genin O, Yaseen W, Soueid-Baumgarten S, Kessler O, Smolkin T, Akiri G, Neufeld G, Cinnamon Y, Hasson P (2016) Localized LoxL3-dependent fibronectin oxidation regulates myofiber stretch and integrin-mediated adhesion. Dev Cell 36(5):550–561. https://doi.org/10.1016/j.devcel.2016.02.009

    Article  CAS  PubMed  Google Scholar 

  37. Gorogh T, Holtmeier C, Weise JB, Hoffmann M, Ambrosch P, Laudien M, Csiszar K (2008) Functional analysis of the 5′ flanking domain of the LOXL4 gene in head and neck squamous cell carcinoma cells. Int J Oncol 33(5):1091–1098

    PubMed  Google Scholar 

  38. Afratis NA, Selman M, Pardo A, Sagi I (2018) Emerging insights into the role of matrix metalloproteases as therapeutic targets in fibrosis. Matrix Biol 68–69:167–179. https://doi.org/10.1016/j.matbio.2018.02.007

    Article  CAS  PubMed  Google Scholar 

  39. Afratis NA, Klepfish M, Karamanos NK, Sagi I (2018) The apparent competitive action of ECM proteases and cross-linking enzymes during fibrosis: applications to drug discovery. Adv Drug Deliv Rev. https://doi.org/10.1016/j.addr.2018.03.004

  40. Levin M, Udi Y, Solomonov I, Sagi I (2017) Next generation matrix metalloproteinase inhibitors - novel strategies bring new prospects. Biochim Biophys Acta 1864(11 Pt A):1927–1939. https://doi.org/10.1016/j.bbamcr.2017.06.009

    Article  CAS  Google Scholar 

  41. Devel L, Czarny B, Beau F, Georgiadis D, Stura E, Dive V (2010) Third generation of matrix metalloprotease inhibitors: gain in selectivity by targeting the depth of the S1' cavity. Biochimie 92(11):1501–1508. https://doi.org/10.1016/j.biochi.2010.07.017

    Article  CAS  PubMed  Google Scholar 

  42. Glomski K, Monette S, Manova K, De Strooper B, Saftig P, Blobel CP (2011) Deletion of Adam10 in endothelial cells leads to defects in organ-specific vascular structures. Blood 118(4):1163–1174. https://doi.org/10.1182/blood-2011-04-348557

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Nagase H, Visse R, Murphy G (2006) Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res 69(3):562–573. https://doi.org/10.1016/j.cardiores.2005.12.002

    Article  CAS  PubMed  Google Scholar 

  44. Lopez-Otin C, Palavalli LH, Samuels Y (2009) Protective roles of matrix metalloproteinases: from mouse models to human cancer. Cell Cycle 8(22):3657–3662. https://doi.org/10.4161/cc.8.22.9956

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Doucet A, Overall CM (2008) Protease proteomics: revealing protease in vivo functions using systems biology approaches. Mol Asp Med 29(5):339–358. https://doi.org/10.1016/j.mam.2008.04.003

    Article  CAS  Google Scholar 

  46. Aiken A, Khokha R (2010) Unraveling metalloproteinase function in skeletal biology and disease using genetically altered mice. Biochim Biophys Acta 1803(1):121–132. https://doi.org/10.1016/j.bbamcr.2009.07.002

    Article  CAS  PubMed  Google Scholar 

  47. Talley NJ, Abreu MT, Achkar JP, Bernstein CN, Dubinsky MC, Hanauer SB, Kane SV, Sandborn WJ, Ullman TA, Moayyedi P, American College of Gastroenterology IBDTF (2011) An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol 106(Suppl 1):S2–S25; . quiz S26. https://doi.org/10.1038/ajg.2011.58

    Article  CAS  PubMed  Google Scholar 

  48. Jacobsen JA, Major Jourden JL, Miller MT, Cohen SM (2010) To bind zinc or not to bind zinc: an examination of innovative approaches to improved metalloproteinase inhibition. Biochim Biophys Acta 1803(1):72–94. https://doi.org/10.1016/j.bbamcr.2009.08.006

    Article  CAS  PubMed  Google Scholar 

  49. Sela-Passwell N, Kikkeri R, Dym O, Rozenberg H, Margalit R, Arad-Yellin R, Eisenstein M, Brenner O, Shoham T, Danon T, Shanzer A, Sagi I (2011) Antibodies targeting the catalytic zinc complex of activated matrix metalloproteinases show therapeutic potential. Nat Med 18(1):143–147. https://doi.org/10.1038/nm.2582

    Article  CAS  PubMed  Google Scholar 

  50. Marshall DC, Lyman SK, McCauley S, Kovalenko M, Spangler R, Liu C, Lee M, O'Sullivan C, Barry-Hamilton V, Ghermazien H, Mikels-Vigdal A, Garcia CA, Jorgensen B, Velayo AC, Wang R, Adamkewicz JI, Smith V (2015) Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer. PLoS One 10(5):e0127063. https://doi.org/10.1371/journal.pone.0127063

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Wong E, Cohen T, Romi E, Levin M, Peleg Y, Arad U, Yaron A, Milla ME, Sagi I (2016) Harnessing the natural inhibitory domain to control TNFalpha converting enzyme (TACE) activity in vivo. Sci Rep 6:35598. https://doi.org/10.1038/srep35598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Kefaloyianni E, Muthu ML, Kaeppler J, Sun X, Sabbisetti V, Chalaris A, Rose-John S, Wong E, Sagi I, Waikar SS, Rennke H, Humphreys BD, Bonventre JV, Herrlich A (2016) ADAM17 substrate release in proximal tubule drives kidney fibrosis. JCI Insight 1(13). https://doi.org/10.1172/jci.insight.87023

  53. Zhang X, Wang Q, Wu J, Wang J, Shi Y, Liu M (2018) Crystal structure of human lysyl oxidase-like 2 (hLOXL2) in a precursor state. Proc Natl Acad Sci U S A 115(15):3828–3833. https://doi.org/10.1073/pnas.1720859115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Elbaum R, Tal E, Perets AI, Oron D, Ziskind D, Silberberg Y, Wagner HD (2007) Dentin micro-architecture using harmonic generation microscopy. J Dent 35(2):150–155. https://doi.org/10.1016/j.jdent.2006.07.007

    Article  CAS  PubMed  Google Scholar 

  55. Friedl P, Wolf K (2003) Proteolytic and non-proteolytic migration of tumour cells and leucocytes. Biochem Soc Symp 70:277–285

    Article  CAS  Google Scholar 

  56. Gritsenko P, Leenders W, Friedl P (2017) Recapitulating in vivo-like plasticity of glioma cell invasion along blood vessels and in astrocyte-rich stroma. Histochem Cell Biol 148(4):395–406. https://doi.org/10.1007/s00418-017-1604-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Friedl P, Brocker EB (2004) Reconstructing leukocyte migration in 3D extracellular matrix by time-lapse videomicroscopy and computer-assisted tracking. Methods Mol Biol 239:77–90

    PubMed  Google Scholar 

  58. Dondossola E, Holzapfel BM, Alexander S, Filippini S, Hutmacher DW, Friedl P (2016) Examination of the foreign body response to biomaterials by nonlinear intravital microscopy. Nat Biomed Eng 1. https://doi.org/10.1038/s41551-016-0007

  59. Frantz C, Stewart KM, Weaver VM (2010) The extracellular matrix at a glance. J Cell Sci 123(Pt 24):4195–4200. https://doi.org/10.1242/jcs.023820

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Yu H, Mouw JK, Weaver VM (2011) Forcing form and function: biomechanical regulation of tumor evolution. Trends Cell Biol 21(1):47–56. https://doi.org/10.1016/j.tcb.2010.08.015

    Article  PubMed  Google Scholar 

  61. Grossman M, Born B, Heyden M, Tworowski D, Fields GB, Sagi I, Havenith M (2011) Correlated structural kinetics and retarded solvent dynamics at the metalloprotease active site. Nat Struct Mol Biol 18(10):1102–1108. https://doi.org/10.1038/nsmb.2120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Rosenblum G, Van den Steen PE, Cohen SR, Grossmann JG, Frenkel J, Sertchook R, Slack N, Strange RW, Opdenakker G, Sagi I (2007) Insights into the structure and domain flexibility of full-length pro-matrix metalloproteinase-9/gelatinase B. Structure 15(10):1227–1236. https://doi.org/10.1016/j.str.2007.07.019

    Article  CAS  PubMed  Google Scholar 

  63. Rosenblum G, Meroueh S, Toth M, Fisher JF, Fridman R, Mobashery S, Sagi I (2007) Molecular structures and dynamics of the stepwise activation mechanism of a matrix metalloproteinase zymogen: challenging the cysteine switch dogma. J Am Chem Soc 129(44):13566–13574. https://doi.org/10.1021/ja073941l

    Article  CAS  PubMed  Google Scholar 

  64. Solomonov I, Talmi-Frank D, Milstein Y, Addadi S, Aloshin A, Sagi I (2014) Introduction of correlative light and air SEM microscopy imaging for tissue research under ambient conditions. Sci Rep 4:5987. https://doi.org/10.1038/srep05987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Porshinsky BS, Saha S, Grossman MD, Beery Ii PR, Stawicki SP (2011) Clinical uses of the medicinal leech: a practical review. J Postgrad Med 57(1):65–71. https://doi.org/10.4103/0022-3859.74297

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Irit Sagi .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Science+Business Media, LLC, part of Springer Nature

About this protocol

Cite this protocol

Afratis, N.A., Sagi, I. (2019). Novel Approaches for Extracellular Matrix Targeting in Disease Treatment. In: Vigetti, D., Theocharis, A.D. (eds) The Extracellular Matrix. Methods in Molecular Biology, vol 1952. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-9133-4_21

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-9133-4_21

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-9132-7

  • Online ISBN: 978-1-4939-9133-4

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics