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Extracellular Matrix Remodeling and Development of Cancer

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Abstract

The importance of stem cell growth and its fate is highly essential for the use of stem cells in therapy and regeneration. There are conflicting evidences regarding the actual role of stem cells when injected into a patient towards damage recovery and its lifespan inside the body. Tumor microenvironment differs from that of normal cells and may have a role in the growth of stem cells when associated with them. In cancer, the uncontrolled growth of cells remodels the extracellular matrix (ECM). The ECM alteration occurs as the mutated fibroblast cells release growth factors into the ECM which further alters the ECM directly or changes the epithelial cells and then alters the ECM. In this review we will discuss about the components and functions of ECM and how does it differ in cancer cells compared to normal cells. Abnormal dynamics of the ECM and its role in cancer progression will also be discussed.

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References

  1. Michel, G., Tonon, T., Scornet, D., Cock, J. M., & Kloareg, B. (2010). The cell wall polysaccharide metabolism of the brown alga Ectocarpussiliculosus. Insights into the evolution of extracellular matrix polysaccharides in Eukaryotes. New Phytologist, 188(1), 82–97.

    CAS  Google Scholar 

  2. Alberts, B. (2002). Molecular biology of the cell ((4th Eds)). New York: Garland Science.

    Google Scholar 

  3. Abedin, M., & King, N. (2010). Diverse evolutionary paths to cell adhesion. Trends in Cell Biology, 20(12), 734–742.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Kumar, V., Abbas, A. K., & Aster, J. C. (2015). Robbins and cotran pathologic basis of disease. Philadelphia: Elsevier Saunders.

    Google Scholar 

  5. Alberts, B., Bray, D., Hopkin, K., Johnson, A., Lewis, J., Raff, M., et al. (2013). Essential cell biology. New York: Garland Science.

    Google Scholar 

  6. Brownlee, C. (2002). Role of the extracellular matrix in cell–cell signalling: paracrine paradigms. Current Opinion in Plant Biology, 5(5), 396–401.

    CAS  PubMed  Google Scholar 

  7. Kostakioti, M., Hadjifrangiskou, M., & &Hultgren, S. J. (2013). Bacterial biofilms: development, dispersal, and therapeutic strategies in the dawn of the postantibiotic era. Cold Spring Harbor Perspectives in Medicine, 3(4), a010306.

    PubMed  PubMed Central  Google Scholar 

  8. Plopper, G. (2007). ‘The extracellular matrix and cell adhesion’. In: B. Lewin, L. Cassimeris, V. Lingappa & G. Plopper (Eds.) Cells. Sudbury; pp. 645–702.

    Google Scholar 

  9. Di Lullo, G. A., Sweeney, S. M., Körkkö, J., Ala-Kokko, L., & San Antonio, J. D. (2002). Mapping the ligand-binding sites and disease-associated mutations on the most abundant protein in the human, type I collagen. Journal of Biological Chemistry, 277(6), 4223–4231.

    Google Scholar 

  10. Karsenty, G., & Park, R. W. (1995). Regulation of type I collagen genes expression. International Reviews of Immunology, 12(2–4), 177–185.

    CAS  PubMed  Google Scholar 

  11. Kern, B., Shen, J., Starbuck, M., & Karsenty, G. (2001). Cbfa1 contributes to the osteoblast-specific expression of type I collagen genes. Journal of Biological Chemistry, 276(10), 7101–7107.

    CAS  Google Scholar 

  12. Haviv, F., Bradley, M. F., Kalvin, D. M., Schneider, A. J., Davidson, D. J., Majest, S. M., McKay, L. M., Haskell, C. J., Bell, R. L., Nguyen, B., & Marsh, K. C. (2005). Thrombospondin-1 mimetic peptide inhibitors of angiogenesis and tumour growth: design, synthesis, and optimization of pharmacokinetics and biological activities. Journal of Medicinal Chemistry, 48(8), 2838–2846.

    CAS  PubMed  Google Scholar 

  13. Hsia, H. C., & Schwarzbauer, J. E. (2005). Meet the tenascins: multifunctional and mysterious. Journal of Biological Chemistry, 280(29), 26641–26644.

    CAS  Google Scholar 

  14. Carey, D. J. (1997). Syndecans: multifunctional cell-surface co-receptors. The Biochemical Journal, 327, 1–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Miosge, N., Holzhausen, S., Zelent, C., Sprysch, P., & Herken, R. (2001). Nidogen-1 and nidogen-2 are found in basement membranes during human embryonic development. Histochemical Journal, 33(9–10), 523–530.

    CAS  Google Scholar 

  16. Bonnans, C., Chou, J., & Werb, Z. (2014). Remodelling the extracellular matrix in development and disease. Nature Reviews Molecular Cell Biology, 15(12), 786.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Gallagher, J. T., & Lyon, M. (2000). Molecular structure of heparan sulfate and interactions with growth factors and morphogens. In R. V. Iozzo (Ed.), Proteoglycans: structure, biology and molecular interactions (pp. 27–59). New York: Marcel Dekker Inc.

    Google Scholar 

  18. Iozzo, R. V. (1998). Matrix proteoglycans: from molecular design to cellular function. Annual Review of Biochemistry, 67, 609–652.

    CAS  PubMed  Google Scholar 

  19. McCarthy, K. J. (2015). The basement membrane proteoglycans perlecan and agrin: Something old, something new. In Current topics in membranes (Vol. 76, pp. 255–303). Cambridge: Academic.

  20. Baeurle, S. A., Kiselev, M. G., Makarova, E. S., & Nogovitsin, E. A. (2009). Effect of the counterion behavior on the frictional–compressive properties of chondroitin sulfate solutions. Polymer, 50(7), 1805–1813.

    CAS  Google Scholar 

  21. Lodish, H., Berk, A., Matsudaira, P., Kaiser, C. A., Krieger, M., Scott, M. P., Zipursky, S. L., & Darnell, J. Integrating Cells Into Tissues. In Molecular Cell Biology (5th ed., pp. 197–234) . New York: WH Freeman and Company.

  22. Miller, B., Sheppard, A. M., & Pearlman, A. L. (1997). Developmental expression of keratan sulfate-like immunoreactivity distinguishes thalamic nuclei and cortical domains. The Journal of Comparative Neurology, 380(4), 533–552.

    CAS  PubMed  Google Scholar 

  23. Zhang, H., Uchimura, K., & Kadomatsu, K. (2006). Brain keratan sulfate and glial scar formation. Annals of the New York Academy of Sciences, 1086(1), 81–90.

    CAS  PubMed  Google Scholar 

  24. Peach, R. J., Hollenbaugh, D., Stamenkovic, I., & Aruffo, A. (1993). Identification of hyaluronic acid binding sites in the extracellular domain of CD44. Journal of Cell Biology, 122(1), 257–264.

    CAS  Google Scholar 

  25. Huleihel, L., Hussey, G. S., Naranjo, J. D., Zhang, L., Dziki, J. L., Turner, N. J., et al. (2016). Matrix-bound nanovesicles within ECM bioscaffolds. Science Advances, 2(6), e1600502.

    PubMed  PubMed Central  Google Scholar 

  26. Alberts, B., Johnson, A., Lewis, J., et al. (2002). ‘Membrane transport of small molecules and the electrical properties of membranes’ in Molecular biology of the cell (4th ed., pp. 615–657). New York: Garland Science.

    Google Scholar 

  27. Plotnikov, S. V., Pasapera, A. M., Sabass, B., & Waterman, C. M. (2012). Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration. Cell, 151(7), 1513–1527.

    CAS  PubMed  Google Scholar 

  28. Discher, D. E., Janmey, P., & Wang, Y. L. (2005). Tissue cells feel and respond to the stiffness of their substrate. Science, 310(5751), 1139–1143.

    CAS  PubMed  Google Scholar 

  29. Lo, C. M., Wang, H. B., Dembo, M., & Wang, Y. L. (2000). Cell movement is guided by the rigidity of the substrate. Biophysical Journal, 79(1), 144–152.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Hadjipanayi, E., Mudera, V., & Brown, R. A. (2009). Close dependence of fibroblast proliferation on collagen scaffold matrix stiffness. Journal of Tissue Engineering and Regenerative Medicine, 3(2), 77–84.

    CAS  PubMed  Google Scholar 

  31. Engler, A. J., Sen, S., Sweeney, H. L., & Discher, D. E. (2006). Matrix elasticity directs stem cell lineage specification. Cell, 126(4), 677–689.

    CAS  PubMed  Google Scholar 

  32. Wang, H. B., Dembo, M., & Wang, Y. L. (2000). Substrate flexibility regulates growth and apoptosis of normal but not transformed cells. American Journal of Physiology. Cell Physiology, 279(5), C1345–C1350.

    CAS  PubMed  Google Scholar 

  33. Allen, J. L., Cooke, M. E., & Alliston, T. (2012). ECM stiffness primes the TGFβ pathway to promote chondrocyte differentiation. Molecular Biology of the Cell, 23(18), 3731–3742.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Kanchanawong, P., Shtengel, G., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., & Waterman, C. M. (2010). Nanoscale architecture of integrin-based cell adhesions. Nature, 468(7323), 580.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hynes, R. O. (2009). The extracellular matrix: not just pretty fibrils. Science, 326(5957), 1216–1219.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Lu, P., Takai, K., Weaver, V. M., & Werb, Z. (2011). Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor Perspectives in Biology, 3(12), a005058.

    PubMed  PubMed Central  Google Scholar 

  37. Zhen, G., & Cao, X. (2014). Targeting TGFβ signaling in subchondral bone and articular cartilage homeostasis. Trends in Pharmacological Sciences, 35(5), 227–236.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Frantz, C., Stewart, K. M., & Weaver, V. M. (2010). The extracellular matrix at a glance. Journal of Cell Science, 123(24), 4195–4200.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Hay, E. D. (1993). Extracellular matrix alters epithelial differentiation. Current Opinion in Cell Biology, 5(6), 1029–1035.

    CAS  PubMed  Google Scholar 

  40. Oskarsson, T. (2013). Extracellular matrix components in breast cancer progression and metastasis. The Breast, 22, S66–S72.

    PubMed  Google Scholar 

  41. Bussard, K. M., Boulanger, C. A., Booth, B. W., Bruno, R. D., & Smith, G. H. (2010). Reprogramming human cancer cells in the mouse mammary gland. Cancer Research, 70(15), 6336–6343.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Boulanger, C. A., Mack, D. L., Booth, B. W., & Smith, G. H. (2007). Interaction with the mammary microenvironment redirects spermatogenic cell fate in vivo. Proceedings of the National Academy of Sciences of the United States of America, 104 (10), 3871–3876.

  43. Booth, B. W., Mack, D. L., Androutsellis-Theotokis, A., McKay, R. D., Boulanger, C. A., & Smith, G. H. (2008). The mammary microenvironment alters the differentiation repertoire of neural stem cells. Proceedings of the National Academy of Sciences of the United States of America, 105(39), 14891–14896.

  44. Krause, S., Maffini, M. V., Soto, A. M., & Sonnenschein, C. (2010). The microenvironment determines the breast cancer cells’ phenotype: organization of MCF7 cells in 3D cultures. BMC Cancer, 10(1), 263.

    PubMed  PubMed Central  Google Scholar 

  45. Naba, A., Clauser, K. R., Lamar, J. M., Carr, S. A., & Hynes, R. O. (2014). Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. eLife, 3, e01308. https://doi.org/10.7554/eLife.01308.

  46. Nelson, C. M., & Bissell, M. J. (2006). Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annual Review of Cell and Developmental Biology, 22, 287–309.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Gaudet, A. D., & Popovich, P. G. (2014). Extracellular matrix regulation of inflammation in the healthy and injured spinal cord. Experimental Neurology, 258, 24–34.

    CAS  PubMed  Google Scholar 

  48. Bianchi, M. E. (2007). DAMPs, PAMPs and alarmins: all we need to know about danger. Journal of Leukocyte Biology, 81(1), 1–5.

    CAS  PubMed  Google Scholar 

  49. Erridge, C. (2010). Endogenous ligands of TLR2 and TLR4: agonists or assistants? Journal of Leukocyte Biology, 87(6), 989–999.

    CAS  PubMed  Google Scholar 

  50. Kigerl, K. A., de RiveroVaccari, J. P., Dietrich, W. D., Popovich, P. G., & Keane, R. W. (2014). Pattern recognition receptors and central nervous system repair. Experimental Neurology, 258, 5–16.

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Conklin, M. W., Eickhoff, J. C., Riching, K. M., Pehlke, C. A., Eliceiri, K. W., Provenzano, P. P., et al. (2011). Aligned collagen is a prognostic signature for survival in human breast carcinoma. The American Journal of Pathology, 178(3), 1221–1232.

    PubMed  PubMed Central  Google Scholar 

  52. Egeblad, M., Rasch, M. G., & Weaver, V. M. (2010). Dynamic interplay between the collagen scaffold and tumor evolution. Current Opinion in Cell Biology, 22(5), 697–706.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Levental, K. R., Yu, H., Kass, L., Lakins, J. N., Egeblad, M., Erler, J. T., Fong, S. F., Csiszar, K., Giaccia, A., Weninger, W., & Yamauchi, M. (2009). Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell, 139(5), 891–906.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Mouw, J. K., Yui, Y., Damiano, L., Bainer, R. O., Lakins, J. N., Acerbi, I., & Hwang, E. S. (2014). Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nature Medicine, 20(4), 360.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., et al. (2005). Tensional homeostasis and the malignant phenotype. Cancer Cell, 8(3), 241–254.

    CAS  PubMed  Google Scholar 

  56. Provenzano, P. P., Inman, D. R., Eliceiri, K. W., & Keely, P. J. (2009). Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK–ERK linkage. Oncogene, 28(49), 4326.

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Provenzano, P. P., Eliceiri, K. W., Campbell, J. M., Inman, D. R., White, J. G., & Keely, P. J. (2006). Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Medicine, 4(1), 38.

    PubMed  PubMed Central  Google Scholar 

  58. Ilan, N., Elkin, M., & Vlodavsky, I. (2006). Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. International Journal of Biochemistry & Cell Biology, 38(12), 2018–2039.

    CAS  Google Scholar 

  59. Kessenbrock, K., Plaks, V., & Werb, Z. (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 141(1), 52–67.

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Lopez, J. I., Kang, I., You, W. K., McDonald, D. M., & Weaver, V. M. (2011). In situ force mapping of mammary gland transformation. Integrative Biology: Quantitative Biosciences from Nano to Macro, 3(9), 910–921.

    CAS  Google Scholar 

  61. Le, Q. T., Harris, J., Magliocco, A. M., Kong, C. S., Diaz, R., Shin, B., et al. (2009). Validation of lysyl oxidase as a prognostic marker for metastasis and survival in head and neck squamous cell carcinoma: radiation therapy oncology group trial 90 – 03. Journal of Clinical Oncology, 27(26), 4281.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Barker, H. E., Chang, J., Cox, T. R., Lang, G., Bird, D., Nicolau, M., Evans, H. R., Gartland, A., & Erler, J. T. (2011). LOXL2-mediated matrix remodeling in metastasis and mammary gland involution. Cancer Research, 71(5), 1561–1572.

    CAS  PubMed  Google Scholar 

  63. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100(1), 57–70.

    CAS  PubMed  Google Scholar 

  64. Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: the next generation. Cell, 144(5), 646–674.

    CAS  PubMed  Google Scholar 

  65. Feigin, M. E., & Muthuswamy, S. K. (2009). Polarity proteins regulate mammalian cell–cell junctions and cancer pathogenesis. Current Opinion in Cell Biology, 21(5), 694–700.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Luo, J., Solimini, N. L., & Elledge, S. J. (2009). Principles of cancer therapy: oncogene and non-oncogene addiction. Cell, 136(5), 823–837.

    CAS  PubMed  PubMed Central  Google Scholar 

  67. Wozniak, M. A., Desai, R., Solski, P. A., Der, C. J., & Keely, P. J. (2003). ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix. Journal of Cell Biology, 163(3), 583–595.

    CAS  Google Scholar 

  68. Mott, J. D., & Werb, Z. (2004). Regulation of matrix biology by matrix metalloproteinases. Current Opinion in Cell Biology, 16(5), 558–564.

    CAS  PubMed  PubMed Central  Google Scholar 

  69. Rozario, T., & DeSimone, D. W. (2010). The extracellular matrix in development and morphogenesis: a dynamic view. Development Biology, 341(1), 126–140.

    CAS  Google Scholar 

  70. Dalby, M. J., Gadegaard, N., & Oreffo, R. O. (2014). Harnessing nanotopography and integrin–matrix interactions to influence stem cell fate. Nature Materials, 13(6), 558.

    CAS  PubMed  Google Scholar 

  71. Dalby, M. J., Gadegaard, N., Tare, R., Andar, A., Riehle, M. O., Herzyk, P., Wilkinson, C. D., & Oreffo, R. O. (2007). The control of human mesenchymal cell differentiation using nanoscale symmetry and disorder. Nature Materials, 6(12), 997.

    CAS  PubMed  Google Scholar 

  72. McMurray, R. J., Gadegaard, N., Tsimbouri, P. M., Burgess, K. V., McNamara, L. E., Tare, R., Murawski, K., Kingham, E., Oreffo, R., & Dalby, M. J. (2011). Nanoscale surfaces for the long-term maintenance of mesenchymal stem cell phenotype and multipotency. Nature Materials, 10(8), 637.

    CAS  PubMed  Google Scholar 

  73. Kingham, E., White, K., Gadegaard, N., Dalby, M. J., & Oreffo, R. O. (2013). Nanotopographical cues augment mesenchymal differentiation of human embryonic stem cells. Small (Weinheim an der Bergstrasse, Germany), 9(12), 2140–2151.

    CAS  Google Scholar 

  74. Cavo, M., Fato, M., Peñuela, L., Beltrame, F., Raiteri, R., & Scaglione, S. (2016). Microenvironment complexity and matrix stiffness regulate breast cancer cell activity in a 3D in vitro model. Scientific Reports, 6, 35367.

    CAS  PubMed  PubMed Central  Google Scholar 

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The authors are grateful to Chettinad Academy of Research and Education for the infrastructural support.

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Girigoswami, K., Saini, D. & Girigoswami, A. Extracellular Matrix Remodeling and Development of Cancer. Stem Cell Rev and Rep 17, 739–747 (2021). https://doi.org/10.1007/s12015-020-10070-1

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