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Tissue Architecture in Cancer Initiation and Progression

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Biomarkers of the Tumor Microenvironment

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Abstract

Tumors that originate from epithelial cells are referred to as carcinomas and represent the most frequently diagnosed cancers. Epithelial tissue is abundant throughout the body, where it lines organs to serve as a protective barrier against biological, chemical, and physical insults. As such, the maintenance of epithelial tissue architecture is critical for tissue homeostasis and healthy tissue functioning. The structure and function of epithelial tissues are largely influenced by the surrounding microenvironment, which is comprised of an acellular interstitial matrix and stromal cells. The makeup and architecture of this surrounding microenvironment are thus key players in cancer suppression, initiation, progression, and metastasis. Over the course of disease progression, the tumor microenvironment undergoes extensive extracellular matrix remodeling, while stromal cells infiltrate and undergo phenotypic switches to mediate tumor-suppressive and tumor-promoting roles. The detection of aberrant extracellular matrix and stromal cell infiltration and activation thus serve as important biomarkers of patient disease and may provide diagnostic and prognostic value. Consequently, a promising avenue for the future of personalized medicine is the development of targeted therapeutics aimed at normalizing the tumor microenvironment.

Carcinomas are malignant tumors that originate from cells in epithelial tissue. There, abnormal epithelial cells grow uncontrollably, breach the basement membrane, undergo cell-state transitions, invade into the underlying interstitial matrix, and subsequently disseminate to form distant metastases. Concomitantly, dramatic alterations of the tissue stroma contribute to the generation of a tumor-promoting microenvironment. Solid stress and interstitial fluid pressure are elevated in tumors, and the interstitial matrix becomes increasingly stiffened and aligned compared to that of healthy tissues. These physical changes are facilitated by dynamic processes, such as angiogenesis and the recruitment and activation of stromal cells. Further, tumor cells, cancer-associated fibroblasts, and tumor-associated macrophages drive matrix remodeling, which aids in the escape of tumor cells from the primary site. Overall, the tumor microenvironment plays a critical role in cancer initiation and progression. Thus, the tumor microenvironment may be viewed as a complex ecosystem that could be exploited to generate unconventional therapeutics for cancer treatment in the future.

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Abbreviations

CAF:

cancer-associated fibroblast

ECM:

extracellular matrix

EMT:

epithelial-mesenchymal transition

FAP:

fibroblast activation protein

GAG:

glycosaminoglycan

GF:

growth factor

HLA:

hyaluronic acid

IFP:

interstitial fluid pressure

LOX:

lysyl oxidase

MMP:

matrix metalloproteinase

MET:

mesenchymal-epithelial transition

3D:

three-dimensional

TAM:

tumor-associated macrophage

TME:

tumor microenvironment

TGF-β:

transforming growth factor-beta

VEGF:

vascular endothelial growth factor

References

  1. The global challenge of cancer. Nat Can. 2020; 1:1–2.

    Google Scholar 

  2. Faguet GB. A brief history of cancer: age-old milestones underlying our current knowledge database. Int J Cancer. 2015;136:2022–36.

    Article  CAS  PubMed  Google Scholar 

  3. Cagan R, Meyer P. Rethinking cancer: current challenges and opportunities in cancer research. Dis Model Mech. 2017;10:349–52.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Hanahan D, Weinberg RA. The Hallmarks of Cancer. Cell. 2000;100:57–70.

    Article  CAS  PubMed  Google Scholar 

  5. Hanahan D, Weinberg A. Robert, hallmarks of cancer: the next generation. Cell. 2011;144:646–74.

    Article  CAS  PubMed  Google Scholar 

  6. Farquhar MG, Palade GE. Junctional complexes in various epithelia. J Cell Biol. 1963;17:375–412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Balda MS, Matter K. Tight junctions at a glance. J Cell Sci. 2008;121:3677–82.

    Article  CAS  PubMed  Google Scholar 

  8. Harris TJC, Tepass U. Adherens junctions: from molecules to morphogenesis. Nat Rev Mol Cell Biol. 2010;11:502–14.

    Article  CAS  PubMed  Google Scholar 

  9. Hatzfeld M, Keil R, Magin TM. Desmosomes and intermediate filaments: their consequences for tissue mechanics. Cold Spring Harb Perspect Biol. 2017;9:a029157.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Angulo-Urarte A, Van Der Wal T, Huveneers S. Cell-cell junctions as sensors and transducers of mechanical forces. Biochim Biophys Acta Biomembr. 2020;1862:183316.

    Article  CAS  PubMed  Google Scholar 

  11. Kumar NM, Gilula NB. The gap junction communication channel. Cell. 1996;84:381–8.

    Article  CAS  PubMed  Google Scholar 

  12. Guillot C, Lecuit T. Mechanics of epithelial tissue homeostasis and morphogenesis. Science. 2013;340:1185–9.

    Article  CAS  PubMed  Google Scholar 

  13. Frantz C, Stewart KM, Weaver VM. The extracellular matrix at a glance. J Cell Sci. 2010;123:4195–200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Özbek S, Balasubramanian PG, Chiquet-Ehrismann R, Tucker RP, Adams JC. The evolution of extracellular matrix. Mol Biol Cell. 2010;21:4300–5.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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 

  16. Yurchenco PD, Schittny JC. Molecular architecture of basement membranes. FASEB J. 1990;4:1577–90.

    Article  CAS  PubMed  Google Scholar 

  17. LeBleu VS, Macdonald B, Kalluri R. Structure and function of basement membranes. Exp Biol Med (Maywood). 2007;232:1121–9.

    Article  CAS  Google Scholar 

  18. Jayadev R, Sherwood DR. Basement membranes. Curr Biol. 2017;27:R207–11.

    Article  CAS  PubMed  Google Scholar 

  19. Rozario T, Desimone DW. The extracellular matrix in development and morphogenesis: a dynamic view. Dev Biol. 2010;341:126–40.

    Article  CAS  PubMed  Google Scholar 

  20. Schnaper HW, Kleinman HK. Regulation of cell function by extracellular matrix. Pediatr Nephrol. 1993;7:96–104.

    Article  CAS  PubMed  Google Scholar 

  21. Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3:a004978.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Kadler KE, Holmes DF, Trotter JA, Chapman JA. Collagen fibril formation. Biochem J. 1996;316:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Debelle L, Tamburro AM. Elastin: molecular description and function. Int J Biochem Cell Biol. 1999;31:261–72.

    Article  CAS  PubMed  Google Scholar 

  24. Mithieux SM, Weiss AS. Fibrous proteins: coiled-coils, collagen and elastomers. San Diego: Elsevier; 2005. p. 437–61.

    Book  Google Scholar 

  25. Brassart B, et al. Conformational dependence of collagenase (matrix metalloproteinase-1) up-regulation by elastin peptides in cultured fibroblasts. J Biol Chem. 2001;276:5222–7.

    Article  CAS  PubMed  Google Scholar 

  26. Rodgers UR, Weiss AS. Integrin αvβ3 binds a unique non-RGD site near the C-terminus of human tropoelastin. Biochimie. 2004;86:173–8.

    Article  CAS  PubMed  Google Scholar 

  27. Almine JF, Wise SG, Weiss AS. Elastin signaling in wound repair. Birth Defects Research Part C: Embryo Today: Reviews. 2012;96:248–57.

    Article  CAS  Google Scholar 

  28. Potts JR, Campbell ID. Fibronectin structure and assembly. Curr Opin Cell Biol. 1994;6:648–55.

    Article  CAS  PubMed  Google Scholar 

  29. Singh P, Carraher C, Schwarzbauer JE. Assembly of fibronectin extracellular matrix. Annu Rev Cell Dev Biol. 2010;26:397–419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. To WS, Midwood KS. Plasma and cellular fibronectin: distinct and independent functions during tissue repair. Fibrogenesis Tissue Repair. 2011;4:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Durbeej M. Laminins. Cell Tissue Res. 2010;339:259–68.

    Article  CAS  PubMed  Google Scholar 

  32. Hamill KJ, Kligys K, Hopkinson SB, Jones JCR. Laminin deposition in the extracellular matrix: a complex picture emerges. J Cell Sci. 2009;122:4409–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Zwick RK, Guerrero-Juarez CF, Horsley V, Plikus MV. Anatomical, physiological, and functional diversity of adipose tissue. Cell Metab. 2018;27:68–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Virchow R. Die cellularpathologie in ihrer begründung auf physiologische und pathologische gewebelehre. Berlin: A. Hirschwald; 1858.

    Google Scholar 

  35. Burrows MT. Studies on wound healing: I. “first intention” healing of open wounds and the nature of the growth stimulus in the wound and cancer. J Med Res. 1924;44:615-644.611.

    Google Scholar 

  36. Haddow A. Advances in cancer research. Amsterdam: Elsevier; 1973. p. 181–234.

    Google Scholar 

  37. Haddow A. Advances in cancer research. Amsterdam: Elsevier; 1974. p. 343–66.

    Google Scholar 

  38. Flier JS, Underhill LH, Dvorak HF. Tumors: wounds that do not heal. N Engl J Med. 1986;315:1650–9.

    Article  Google Scholar 

  39. Dvorak HF. Tumors: wounds that do not heal—redux. Cancer Immunol Res. 2015;3:1–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Foster DS, Jones RE, Ransom RC, Longaker MT, Norton JA. The evolving relationship of wound healing and tumor stroma. JCI Insight. 2018;3:99911.

    Article  PubMed  Google Scholar 

  41. Amend SR, Pienta KJ. Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget. 2015;6:9669–78.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Valkenburg KC, De Groot AE, Pienta KJ. Targeting the tumour stroma to improve cancer therapy. Nat Rev Clin Oncol. 2018;15:366–81.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Santi A, Kugeratski FG, Zanivan S. Cancer associated fibroblasts: the architects of stroma remodeling. Proteomics. 2018;18:1700167.

    Article  PubMed Central  CAS  Google Scholar 

  44. Sahai E, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20:174–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Nissen NI, Karsdal M, Willumsen N. Collagens and cancer associated fibroblasts in the reactive stroma and its relation to Cancer biology. J Exp Clin Cancer Res. 2019;38(1):115.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science. 2013;342:1234850.

    Article  PubMed  CAS  Google Scholar 

  47. Leggett SE, Hruska AM, Guo M, Wong IY. The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems. Cell Commun Signal. 2021;19:32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Leggett SE, Khoo AS, Wong IY. Multicellular tumor invasion and plasticity in biomimetic materials. Biomater Sci. 2017;5:1460–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Yang J, et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat Rev Mol Cell Biol. 2020;21:341–52.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Lin Y, Xu J, Lan H. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. J Hematol Oncol. 2019;12:76.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–57.

    Article  CAS  PubMed  Google Scholar 

  52. Stacker SA, Achen MG, Jussila L, Baldwin ME, Alitalo K. Lymphangiogenesis and cancer metastasis. Nat Rev Cancer. 2002;2:573–83.

    Article  CAS  PubMed  Google Scholar 

  53. Henke E, Nandigama R, Ergün S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front Mol Biosci. 2020;6:160.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Friedl P, Alexander S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell. 2011;147:992–1009.

    Article  CAS  PubMed  Google Scholar 

  55. Walker C, Mojares E, A. Del Río Hernández, role of extracellular matrix in development and cancer progression. Int J Mol Sci. 2018;19:3028.

    Article  PubMed Central  CAS  Google Scholar 

  56. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev Cancer. 2013;13:246–57.

    Article  CAS  PubMed  Google Scholar 

  57. Leight JL, Wozniak MA, Chen S, Lynch ML, Chen CS. Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition. Mol Biol Cell. 2012;23:781–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kilinc AN, Han S, Barrett LA, Anandasivam N, Nelson CM. Integrin-linked kinase tunes cell–cell and cell-matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGFβ1. Mol Biol Cell. 2021;32:402–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Lee K, et al. Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial–mesenchymal transition. Mol Biol Cell. 2012;23:4097–108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Simi AK, Pang M-F, Nelson CM. Advances in Experimental Medicine and Biology. (Springer International Publishing; 2018. p. 57–67.

    Google Scholar 

  61. Rianna C, Radmacher M, Kumar S. Direct evidence that tumor cells soften when navigating confined spaces. Mol Biol Cell. 2020;31:1726–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Aktas B, et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 2009;11:R46.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Pasquier J, Abu-Kaoud N, Al Thani H, Rafii A. Epithelial to mesenchymal transition in a clinical perspective. J Oncol. 2015;2015:1–10.

    Article  Google Scholar 

  64. Mcatee CO, Barycki JJ, Simpson MA. Advances in cancer research. Amsterdam: Elsevier; 2014. p. 1–34.

    Google Scholar 

  65. Nelson CM, Bissell MJ. Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2006;22:287–309.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Weaver VM, et al. Reversion of the Malignant Phenotype of Human Breast Cells in Three-Dimensional Culture and In Vivo by Integrin Blocking Antibodies. J Cell Biol. 1997;137:231–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Mintz B, Illmensee K. Normal genetically mosaic mice produced from malignant teratocarcinoma cells. Proc Natl Acad Sci. 1975;72:3585–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 2016;30:1002–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Teleanu RI, Chircov C, Grumezescu AM, Teleanu DM. Tumor angiogenesis and anti-angiogenic strategies for cancer treatment. J Clin Med. 2019;9:84.

    Article  PubMed Central  CAS  Google Scholar 

  70. Yamakawa M, et al. Potential lymphangiogenesis therapies: Learning from current antiangiogenesis therapies-A review. Med Res Rev. 2018;38:1769–98.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Fields GB. The rebirth of matrix metalloproteinase inhibitors: moving beyond the dogma. Cell. 2019;8:984.

    Article  CAS  Google Scholar 

  72. Wu L, Yang X. Targeting the hippo pathway for breast cancer therapy. Cancer. 2018;10:422.

    Article  CAS  Google Scholar 

  73. Bissell MJ, Aggeler J. Dynamic reciprocity: how do extracellular matrix and hormones direct gene expression? Prog Clin Biol Res. 1987;249:251–62.

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Chemical & Biological Engineering, Princeton University, Princeton, NJ, USA

    Susan E. Leggett & Celeste M. Nelson

  2. Department of Molecular Biology, Princeton University, Princeton, NJ, USA

    Celeste M. Nelson

Authors
  1. Susan E. Leggett
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  2. Celeste M. Nelson
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Correspondence to Celeste M. Nelson .

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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

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Leggett, S.E., Nelson, C.M. (2022). Tissue Architecture in Cancer Initiation and Progression. 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_6

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  • DOI: https://doi.org/10.1007/978-3-030-98950-7_6

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