SpringerLink
Log in

Stromal Contributions to Tumor Progression in Urothelial Carcinoma of the Bladder

  • Chapter
  • First Online:
Precision Molecular Pathology of Bladder Cancer

Part of the book series: Molecular Pathology Library ((MPLB))

  • 937 Accesses

Abstract

Urothelial carcinomas develop and progress in the context of the supporting cast of the underlying stroma. This stromal cast includes structural cells such as fibroblasts/myofibroblasts, the cells that generate the lymphovasculature, along with the cells of the immune system and the acellular but dynamic protein matrix between all of these elements. Until recently, the characterization of the propensity of urothelial carcinomas to exhibit aggressive behavior has focused primarily on the molecular alterations intrinsic to the tumor cells. Deeper investigations continue to reveal that tumor invasion involves key interactions with the underlying stroma in which there are key differences in the stroma of invasive versus non-invasive tumors. Immune cells responding to a tumor are part of the surrounding stroma, and tumors use several different mechanisms to avoid immune-mediated destruction. Furthermore, the nature of the immune response and types of cells involved can predict patient outcomes. Tumors, with their rapid growth and high turnover, require a ready blood supply and meet such needs by altering the stroma by inducing growth of blood vessels. Tumors also interact in complex ways with the acellular protein scaffolding of the stroma. Invasive urothelial carcinoma intimately interacts with the surrounding stroma in many ways, and ultimately may even require a stromal makeover for continued tumor growth and progression to invasive disease, thereby increasing the potential for metastatic disease.

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

Access this chapter

Log in via an institution

Institutional subscriptions

Similar content being viewed by others

References

  1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55(2):74–108.

    Article  PubMed  Google Scholar 

  2. Choi W, Porten S, Kim S, Willis D, Plimack ER, Hoffman-Censits J, et al. Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy. Cancer Cell. 2014;25(2):152–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Lindgren D, Frigyesi A, Gudjonsson S, Sjodahl G, Hallden C, Chebil G, et al. Combined gene expression and genomic profiling define two intrinsic molecular subtypes of urothelial carcinoma and gene signatures for molecular grading and outcome. Cancer Res. 2010;70(9):3463–72.

    Article  CAS  PubMed  Google Scholar 

  4. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–52.

    Article  CAS  PubMed  Google Scholar 

  5. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial bladder carcinoma. Nature. 2014;507(7492):315–22.

    Article  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Hu M, Polyak K. Microenvironmental regulation of cancer development. Curr Opin Genet Dev. 2008;18(1):27–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Hu M, Yao J, Cai L, Bachman KE, van den Brule F, Velculescu V, et al. Distinct epigenetic changes in the stromal cells of breast cancers. Nat Genet. 2005;37(8):899–905.

    Article  CAS  PubMed  Google Scholar 

  9. Peek EM, Li DR, Zhang H, Kim HP, Zhang B, Garraway IP, et al. Stromal modulation of bladder cancer-initiating cells in a subcutaneous tumor model. Am J Cancer Res. 2012;2(6):745–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Shimoda M, Mellody KT, Orimo A. Carcinoma-associated fibroblasts are a rate-limiting determinant for tumour progression. Semin Cell Dev Biol. 2010;21(1):19–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Alspach E, Fu Y, Stewart SA. Senescence and the pro-tumorigenic stroma. Crit Rev Oncog. 2013;18(6):549–58.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lasry A, Ben-Neriah Y. Senescence-associated inflammatory responses: aging and cancer perspectives. Trends Immunol. 2015;36(4):217–28.

    Article  CAS  PubMed  Google Scholar 

  13. Kosinski C, Li VS, Chan AS, Zhang J, Ho C, Tsui WY, et al. Gene expression patterns of human colon tops and basal crypts and BMP antagonists as intestinal stem cell niche factors. Proc Natl Acad Sci U S A. 2007;104(39):15418–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Kuijpers KA, Heesakkers JP, Jansen CF, Schalken JA. Cadherin-11 is expressed in detrusor smooth muscle cells and myofibroblasts of normal human bladder. Eur Urol. 2007;52(4):1213–21.

    Article  PubMed  Google Scholar 

  15. Karagiannis GS, Poutahidis T, Erdman SE, Kirsch R, Riddell RH, Diamandis EP. Cancer-associated fibroblasts drive the progression of metastasis through both paracrine and mechanical pressure on cancer tissue. Mol Cancer Res. 2012;10(11):1403–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Alexa A, Baderca F, Lighezan R, Izvernariu D. Myofibroblasts reaction in urothelial carcinomas. Romanian J Morphol Embryol. 2009;50(4):639–43.

    Google Scholar 

  17. Luo X, Fu Y, Loza AJ, Murali B, Leahy KM, Ruhland MK, et al. Stromal-initiated changes in the bone promote metastatic niche development. Cell Rep. 2016;14(1):82–92.

    Article  CAS  PubMed  Google Scholar 

  18. Ruhland MK, Loza AJ, Capietto AH, Luo X, Knolhoff BL, Flanagan KC, et al. Stromal senescence establishes an immunosuppressive microenvironment that drives tumorigenesis. Nat Commun. 2016;7:11762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ikemoto S, Kishimoto T, Wada S, Nishio S, Maekawa M. Clinical studies on cell-mediated immunity in patients with urinary bladder carcinoma: blastogenic response, interleukin-2 production and interferon-gamma production of lymphocytes. Br J Urol. 1990;65(4):333–8.

    Article  CAS  PubMed  Google Scholar 

  20. Sharma P, Shen Y, Wen S, Yamada S, Jungbluth AA, Gnjatic S, et al. CD8 Tumor-infiltrating lymphocytes are predictive of survival in muscle-invasive urothelial carcinoma. Proc Natl Acad Sci U S A. 2007;104(10):3967–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Morita T, Tokue A, Minato N. Analysis of natural killer activity and natural killer cell subsets in patients with bladder cancer. Cancer Immunol Immunother. 1990;32(3):191–4.

    Article  CAS  PubMed  Google Scholar 

  22. Lipponen PK, Eskelinen MJ, Jauhiainen K, Harju E, Terho R. Tumour infiltrating lymphocytes as an independent prognostic factor in transitional cell bladder cancer. Eur J Cancer. 1992;29A(1):69–75.

    CAS  PubMed  Google Scholar 

  23. Housseau F, Zeliszewski D, Roy M, Paradis V, Richon S, Ricour A, et al. MHC-dependent cytolysis of autologous tumor cells by lymphocytes infiltrating urothelial carcinomas. Int J Cancer. 1997;71(4):585–94.

    Article  CAS  PubMed  Google Scholar 

  24. Alfano M, Canducci F, Nebuloni M, Clementi M, Montorsi F, Salonia A. The interplay of extracellular matrix and microbiome in urothelial bladder cancer. Nat Rev Urol. 2016;13(2):77–90.

    Article  CAS  PubMed  Google Scholar 

  25. Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (Anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515(7528):558–62.

    Article  CAS  PubMed  Google Scholar 

  26. Rosenberg JE, Hoffman-Censits J, Powles T, van der Heijden MS, Balar AV, Necchi A, et al. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: a single-arm, multicentre, phase 2 trial. Lancet. 2016;387(10031):1909–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Faraj SF, Munari E, Guner G, Taube J, Anders R, Hicks J, et al. Assessment of tumoral PD-L1 expression and intratumoral CD8+ T cells in urothelial carcinoma. Urology. 2015;85(3):703.e1–6.

    Article  Google Scholar 

  28. Jozwicki W, Brozyna AA, Siekiera J, Slominski AT. Changes in immunogenicity during the development of urinary bladder cancer: a preliminary study. Int J Mol Sci. 2016;17(3):285.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Baras AS, Drake C, Liu JJ, Gandhi N, Kates M, Hoque MO, et al. The ratio of CD8 to treg tumor-infiltrating lymphocytes is associated with response to cisplatin-based neoadjuvant chemotherapy in patients with muscle invasive urothelial carcinoma of the bladder. Oncoimmunology. 2016;5(5):e1134412.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Maruf M, Brancato SJ, Agarwal PK. Nonmuscle invasive bladder cancer: a primer on immunotherapy. Cancer Biol Med. 2016;13(2):194–205.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407(6801):249–57.

    Article  CAS  PubMed  Google Scholar 

  32. Kassouf W, Spiess PE, Brown GA, Munsell MF, Grossman HB, Siefker-Radtke A, et al. P0 Stage at radical cystectomy for bladder cancer is associated with improved outcome independent of traditional clinical risk factors. Eur Urol. 2007;52(3):769–74.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Fernandez MI, Bolenz C, Trojan L, Steidler A, Weiss C, Alken P, et al. Prognostic implications of lymphangiogenesis in muscle-invasive transitional cell carcinoma of the bladder. Eur Urol. 2008;53(3):571–8.

    Article  PubMed  Google Scholar 

  34. Bolenz C, Auer M, Strobel P, Heinzelbecker J, Schubert C, Trojan L. The lymphatic system in clinically localized urothelial carcinoma of the bladder: morphologic characteristics and predictive value. Urol Oncol. 2013;31(8):1606–14.

    Article  PubMed  Google Scholar 

  35. Hynes RO. The extracellular matrix: not just pretty fibrils. Science. 2009;326(5957):1216–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Genovese L, Zawada L, Tosoni A, Ferri A, Zerbi P, Allevi R, et al. Cellular localization, invasion, and turnover are differently influenced by healthy and tumor-derived extracellular matrix. Tissue Eng Part A. 2014;20(13-14):2005–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Charras G, Sahai E. Physical influences of the extracellular environment on cell migration. Nat Rev Mol Cell Biol. 2014;15(12):813–24.

    Article  CAS  PubMed  Google Scholar 

  38. Iskratsch T, Wolfenson H, Sheetz MP. Appreciating force and shape-the rise of mechanotransduction in cell biology. Nat Rev Mol Cell Biol. 2014;15(12):825–33.

    Article  CAS  PubMed  Google Scholar 

  39. Enkelmann A, Heinzelmann J, von Eggeling F, Walter M, Berndt A, Wunderlich H, et al. Specific protein and miRNA patterns characterise tumour-associated fibroblasts in bladder cancer. J Cancer Res Clin Oncol. 2011;137(5):751–9.

    Article  CAS  PubMed  Google Scholar 

  40. Liotta LA, Kohn EC. The microenvironment of the tumour-host interface. Nature. 2001;411(6835):375–9.

    Article  CAS  PubMed  Google Scholar 

  41. Iozzo RV, Buraschi S, Genua M, SQ X, Solomides CC, Peiper SC, et al. Decorin antagonizes IGF receptor I (IGF-IR) function by interfering with IGF-IR activity and attenuating downstream signaling. J Biol Chem. 2011;286(40):34712–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bozoky B, Savchenko A, Guven H, Ponten F, Klein G, Szekely L. Decreased decorin expression in the tumor microenvironment. Cancer Med. 2014;3(3):485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. El Behi M, Krumeich S, Lodillinsky C, Kamoun A, Tibaldi L, Sugano G, et al. An essential role for decorin in bladder cancer invasiveness. EMBO Mol Med. 2013;5(12):1835–51.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Dohn LH, Illemann M, Hoyer-Hansen G, Christensen IJ, Hostmark J, Litlekalsoy J, et al. Urokinase-type plasminogen activator receptor (uPAR) expression is associated with T-stage and survival in urothelial carcinoma of the bladder. Urol Oncol. 2015;33(4):165.e15–24.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Johns Hopkins Department of Pathology, Baltimore, MD, USA

    Morgan Cowan, Daniel Miller & Alexander S. Baras

Authors
  1. Morgan Cowan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Alexander S. Baras
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alexander S. Baras .

Editor information

Editors and Affiliations

  1. Department of Pathology, University of California San Diego, San Diego, California, USA

    Donna E. Hansel

  2. Scott Department of Urology, Baylor College of Medicine, Houston, Texas, USA

    Seth P. Lerner

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG

About this chapter

Cite this chapter

Cowan, M., Miller, D., Baras, A.S. (2018). Stromal Contributions to Tumor Progression in Urothelial Carcinoma of the Bladder. In: Hansel, D., Lerner, S. (eds) Precision Molecular Pathology of Bladder Cancer. Molecular Pathology Library. Springer, Cham. https://doi.org/10.1007/978-3-319-64769-2_12

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-64769-2_12

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-64767-8

  • Online ISBN: 978-3-319-64769-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation