Skip to main content
SpringerLink
Log in
SpringerLink
Log in

Stromal Cells in the Tumor Microenvironment

  • Chapter
  • First Online:
Stromal Immunology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1060))

Abstract

The tumor microenvironment comprises a mass of heterogeneous cell types, including immune cells, endothelial cells, and fibroblasts, alongside cancer cells. It is increasingly becoming clear that the development of this support niche is critical to the continued uncontrolled growth of the cancer. The tumor microenvironment contributes to the maintenance of cancer stemness and also directly promotes angiogenesis, invasion, metastasis, and chronic inflammation. In this chapter, we describe on the role of fibroblasts, specifically termed cancer-associated fibroblasts (CAFs), in the promotion and maintenance of cancers. CAFs have a multitude of effects on the growth and maintenance of cancer, and here we focus on their roles in modulating immune cells and responses; CAFs both inhibit immune cell access to the tumor microenvironment and inhibit their functions within the tumor. Finally, we describe the potential modulation of CAF function as an adjunct to bolster the effectiveness of cancer immunotherapies.

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 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
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. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539–45.

    Article  PubMed  CAS  Google Scholar 

  2. Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.

    PubMed  CAS  Google Scholar 

  3. Busch W. Aus der sitzung der medicinischen section vom 13. Berliner Klin Wochenschrift. 1868;5:137.

    Google Scholar 

  4. Fehleisen F. Ueber die Zuchtung der Erysipelkokken auf kunstlichem Nahrboden und die Ubertragbarkeit auf den Menschen. Dtsch Med Wochenschr. 1882;8:553–4.

    Google Scholar 

  5. Bruns P. Die Heilwirkung des Erysipelas auf Geschwuelste. Beitr Klin Chir. 1888;3:443

    Google Scholar 

  6. Coley WB. A preliminary note on the treatment of inoperable sarcoma by the toxic product of erysipelas. Postgrad Dent. 1893;8:278.

    Google Scholar 

  7. Bissell MJ, Hall HG, Parry G. How does the extracellular matrix direct gene expression? J Theor Biol. 1982;99(1):31–68.

    Article  PubMed  CAS  Google Scholar 

  8. Illmensee K, Mintz B. Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts. Proc Natl Acad Sci U S A. 1976;73(2):549–53.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, 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(1):231–45.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Virchow R. Die Cellularpathologie in Ihrer Begruendung auf Physiologische und Pathologische Gewebelehre. Hirschwald, A, Berlin. 1858.

    Google Scholar 

  11. Tarin D, Croft CB. Ultrastructural features of wound healing in mouse skin. J Anat. 1969;105(Pt 1):189–90.

    PubMed  CAS  Google Scholar 

  12. Bellusci S, Grindley J, Emoto H, Itoh N, Hogan BL. Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development. 1997;124(23):4867–78.

    PubMed  CAS  Google Scholar 

  13. Wahl SM, McCartney-Francis N, Allen JB, Dougherty EB, Dougherty SF. Macrophage production of TGF-beta and regulation by TGF-beta. Ann N Y Acad Sci. 1990;593:188–96.

    Article  PubMed  CAS  Google Scholar 

  14. Bonner JC, Osornio-Vargas AR, Badgett A, Brody AR. Differential proliferation of rat lung fibroblasts induced by the platelet-derived growth factor-AA, -AB, and -BB isoforms secreted by rat alveolar macrophages. Am J Respir Cell Mol Biol. 1991;5(6):539–47.

    Article  PubMed  CAS  Google Scholar 

  15. Skalli O, Ropraz P, Trzeciak A, Benzonana G, Gillessen D, Gabbiani G. A monoclonal antibody against alpha-smooth muscle actin: a new probe for smooth muscle differentiation. J Cell Biol. 1986;103(6 Pt 2):2787–96.

    Article  PubMed  CAS  Google Scholar 

  16. Ryan GB, Cliff WJ, Gabbiani G, Irle C, Montandon D, Statkov PR, et al. Myofibroblasts in human granulation tissue. Hum Pathol. 1974;5(1):55–67.

    Article  PubMed  CAS  Google Scholar 

  17. 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  PubMed  CAS  Google Scholar 

  18. Ronnov-Jessen L, Petersen OW. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Investig. 1993;68(6):696–707.

    PubMed  CAS  Google Scholar 

  19. Le Hir M, Hegyi I, Cueni-Loffing D, Loffing J, Kaissling B. Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys. Histochem Cell Biol. 2005;123(4–5):335–46.

    Article  PubMed  CAS  Google Scholar 

  20. Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, et al. Identification and characterization of a fibroblast marker: FSP1. J Cell Biol. 1995;130(2):393–405.

    Article  PubMed  CAS  Google Scholar 

  21. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002;3(5):349–63.

    Article  PubMed  CAS  Google Scholar 

  22. 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  PubMed  CAS  Google Scholar 

  23. Erez N, Truitt M, Olson P, Arron ST, Hanahan D. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-kappaB-dependent manner. Cancer Cell. 2010;17(2):135–47.

    Article  PubMed  CAS  Google Scholar 

  24. Vinores SA, Henderer JD, Mahlow J, Chiu C, Derevjanik NL, Larochelle W, et al. Isoforms of platelet-derived growth factor and its receptors in epiretinal membranes: immunolocalization to retinal pigmented epithelial cells. Exp Eye Res. 1995;60(6):607–19.

    Article  PubMed  CAS  Google Scholar 

  25. Garin-Chesa P, Old LJ, Rettig WJ. Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers. Proc Natl Acad Sci U S A. 1990;87(18):7235–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Bauer S, Jendro MC, Wadle A, Kleber S, Stenner F, Dinser R, et al. Fibroblast activation protein is expressed by rheumatoid myofibroblast-like synoviocytes. Arthritis Res Ther. 2006;8(6):R171.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Levy MT, McCaughan GW, Abbott CA, Park JE, Cunningham AM, Muller E, et al. Fibroblast activation protein: a cell surface dipeptidyl peptidase and gelatinase expressed by stellate cells at the tissue remodelling interface in human cirrhosis. Hepatology. 1999;29(6):1768–78.

    Article  PubMed  CAS  Google Scholar 

  28. Denton AE, Roberts EW, Linterman MA, Fearon DT. Fibroblastic reticular cells of the lymph node are required for retention of resting but not activated CD8+ T cells. Proc Natl Acad Sci U S A. 2014;111(33):12139–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Roberts EW, Deonarine A, Jones JO, Denton AE, Feig C, Lyons SK, et al. Depletion of stromal cells expressing fibroblast activation protein-alpha from skeletal muscle and bone marrow results in cachexia and anemia. J Exp Med. 2013;210(6):1137–51.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Chang HY, Chi JT, Dudoit S, Bondre C, van de Rijn M, Botstein D, et al. Diversity, topographic differentiation, and positional memory in human fibroblasts. Proc Natl Acad Sci U S A. 2002;99(20):12877–82.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Kidd S, Spaeth E, Watson K, Burks J, Lu H, Klopp A, et al. Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One. 2012;7(2):e30563.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Kojima Y, Acar A, Eaton EN, Mellody KT, Scheel C, Ben-Porath I, et al. Autocrine TGF-beta and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts. Proc Natl Acad Sci U S A. 2010;107(46):20009–14.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19(2):257–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Giannoni E, Bianchini F, Masieri L, Serni S, Torre E, Calorini L, et al. Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial-mesenchymal transition and cancer stemness. Cancer Res. 2010;70(17):6945–56.

    Article  PubMed  CAS  Google Scholar 

  35. Lohr M, Schmidt C, Ringel J, Kluth M, Muller P, Nizze H, et al. Transforming growth factor-beta1 induces desmoplasia in an experimental model of human pancreatic carcinoma. Cancer Res. 2001;61(2):550–5.

    PubMed  CAS  Google Scholar 

  36. Shao ZM, Nguyen M, Barsky SH. Human breast carcinoma desmoplasia is PDGF initiated. Oncogene. 2000;19(38):4337–45.

    Article  PubMed  CAS  Google Scholar 

  37. Yang G, Rosen DG, Zhang Z, Bast RC Jr, Mills GB, Colacino JA, et al. The chemokine growth-regulated oncogene 1 (Gro-1) links RAS signaling to the senescence of stromal fibroblasts and ovarian tumorigenesis. Proc Natl Acad Sci U S A. 2006;103(44):16472–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Lieubeau B, Garrigue L, Barbieux I, Meflah K, Gregoire M. The role of transforming growth factor beta 1 in the fibroblastic reaction associated with rat colorectal tumor development. Cancer Res. 1994;54(24):6526–32.

    PubMed  CAS  Google Scholar 

  39. Bachem MG, Schneider E, Gross H, Weidenbach H, Schmid RM, Menke A, et al. Identification, culture, and characterization of pancreatic stellate cells in rats and humans. Gastroenterology. 1998;115(2):421–32.

    Article  PubMed  CAS  Google Scholar 

  40. Yin C, Evason KJ, Asahina K, Stainier DY. Hepatic stellate cells in liver development, regeneration, and cancer. J Clin Invest. 2013;123(5):1902–10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Ishii G, Sangai T, Oda T, Aoyagi Y, Hasebe T, Kanomata N, et al. Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 2003;309(1):232–40.

    Article  PubMed  CAS  Google Scholar 

  42. Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D, et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 2004;64(23):8492–5.

    Article  PubMed  CAS  Google Scholar 

  43. Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG. Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest. 2002;110(3):341–50.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 2007;67(21):10123–8.

    Article  PubMed  CAS  Google Scholar 

  45. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121(3):335–48.

    Article  PubMed  CAS  Google Scholar 

  46. Yee D, Rosen N, Favoni RE, Cullen KJ. The insulin-like growth factors, their receptors, and their binding proteins in human breast cancer. Cancer Treat Res. 1991;53:93–106.

    Article  PubMed  CAS  Google Scholar 

  47. Frazier KS, Grotendorst GR. Expression of connective tissue growth factor mRNA in the fibrous stroma of mammary tumors. Int J Biochem Cell Biol. 1997;29(1):153–61.

    Article  PubMed  CAS  Google Scholar 

  48. Ponten F, Ren Z, Nister M, Westermark B, Ponten J. Epithelial-stromal interactions in basal cell cancer: the PDGF system. J Invest Dermatol. 1994;102(3):304–9.

    Article  PubMed  CAS  Google Scholar 

  49. Nakamura T, Matsumoto K, Kiritoshi A, Tano Y, Nakamura T. Induction of hepatocyte growth factor in fibroblasts by tumor-derived factors affects invasive growth of tumor cells: in vitro analysis of tumor-stromal interactions. Cancer Res. 1997;57(15):3305–13.

    PubMed  CAS  Google Scholar 

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

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Wang Y, Sudilovsky D, Zhang B, Haughney PC, Rosen MA, Wu DS, et al. A human prostatic epithelial model of hormonal carcinogenesis. Cancer Res. 2001;61(16):6064–72.

    PubMed  CAS  Google Scholar 

  52. Korinek V, Barker N, Moerer P, van Donselaar E, Huls G, Peters PJ, et al. Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4. Nat Genet. 1998;19(4):379–83.

    Article  PubMed  CAS  Google Scholar 

  53. Sato T, Vries RG, Snippert HJ, van de Wetering M, Barker N, Stange DE, et al. Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche. Nature. 2009;459(7244):262–5.

    Article  PubMed  CAS  Google Scholar 

  54. Yen TH, Wright NA. The gastrointestinal tract stem cell niche. Stem Cell Rev. 2006;2(3):203–12.

    Article  PubMed  CAS  Google Scholar 

  55. Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T, et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol. 2010;12(5):468–76.

    Article  PubMed  CAS  Google Scholar 

  56. Yang F, Tuxhorn JA, Ressler SJ, McAlhany SJ, Dang TD, Rowley DR. Stromal expression of connective tissue growth factor promotes angiogenesis and prostate cancer tumorigenesis. Cancer Res. 2005;65(19):8887–95.

    Article  PubMed  CAS  Google Scholar 

  57. Boire A, Covic L, Agarwal A, Jacques S, Sherifi S, Kuliopulos A. PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell. 2005;120(3):303–13.

    Article  PubMed  CAS  Google Scholar 

  58. Vosseler S, Lederle W, Airola K, Obermueller E, Fusenig NE, Mueller MM. Distinct progression-associated expression of tumor and stromal MMPs in HaCaT skin SCCs correlates with onset of invasion. Int J Cancer. 2009;125(10):2296–306.

    Article  PubMed  CAS  Google Scholar 

  59. Bergers G, Brekken R, McMahon G, Vu TH, Itoh T, Tamaki K, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2(10):737–44.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  60. Lederle W, Hartenstein B, Meides A, Kunzelmann H, Werb Z, Angel P, et al. MMP13 as a stromal mediator in controlling persistent angiogenesis in skin carcinoma. Carcinogenesis. 2010;31(7):1175–84.

    Article  PubMed  CAS  Google Scholar 

  61. Pozzi A, Moberg PE, Miles LA, Wagner S, Soloway P, Gardner HA. Elevated matrix metalloprotease and angiostatin levels in integrin alpha 1 knockout mice cause reduced tumor vascularization. Proc Natl Acad Sci U S A. 2000;97(5):2202–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Mantovani A, Schioppa T, Porta C, Allavena P, Sica A. Role of tumor-associated macrophages in tumor progression and invasion. Cancer Metastasis Rev. 2006;25(3):315–22.

    Article  PubMed  Google Scholar 

  63. 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  PubMed  PubMed Central  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  65. Lochter A, Galosy S, Muschler J, Freedman N, Werb Z, Bissell MJ. Matrix metalloproteinase stromelysin-1 triggers a cascade of molecular alterations that leads to stable epithelial-to-mesenchymal conversion and a premalignant phenotype in mammary epithelial cells. J Cell Biol. 1997;139(7):1861–72.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Shimoda M, Principe S, Jackson HW, Luga V, Fang H, Molyneux SD, et al. Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state. Nat Cell Biol. 2014;16

    Google Scholar 

  67. Luga V, Zhang L, Viloria-Petit AM, Ogunjimi AA., Inanlou MR, Chiu E, et al. Exosomes mediate stromal mobilization of autocrine Wnt-PCP signaling in breast cancer cell migration. Cell. Elsevier Inc. 2012;151(7):1542–56.

    Google Scholar 

  68. Zhou W, Fong MY, Min Y, Somlo G, Liu L, Palomares MR, et al. Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell. Elsevier Inc. 2014;25(4):501–15.

    Google Scholar 

  69. Zomer A, Maynard C, Verweij FJ, Kamermans A, Schäfer R, Beerling E, et al. In vivo imaging reveals extracellular vesicle-mediated phenocopying of metastatic behavior. Cell. 2015;161(5):1046–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Duda DG, Duyverman AM, Kohno M, Snuderl M, Steller EJ, Fukumura D, et al. Malignant cells facilitate lung metastasis by bringing their own soil. Proc Natl Acad Sci U S A. 2010;107(50):21677–82.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62(1):112–20.

    Google Scholar 

  72. Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. Elsevier Inc. 2012;21(3):418–29.

    Google Scholar 

  73. Boelens MC, Wu TJ, Nabet BY, Xu B, Qiu Y, Yoon T, et al. Exosome transfer from stromal to breast cancer cells regulates therapy resistance pathways. Cell. Elsevier Inc. 2014;159(3):499–513.

    Google Scholar 

  74. Feig C, Jones JO, Kraman M, Wells RJ, Deonarine A, Chan DS, et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci U S A. 2013;110(50):20212–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med. 2008;14(3):109–19.

    Article  PubMed  CAS  Google Scholar 

  76. Nilsson MB, Langley RR, Fidler IJ. Interleukin-6, secreted by human ovarian carcinoma cells, is a potent proangiogenic cytokine. Cancer Res. 2005;65(23):10794–800.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442(7101):461–5.

    Article  PubMed  CAS  Google Scholar 

  78. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57–70.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  80. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science (80- ). 1996;271(5256):1734–6.

    Google Scholar 

  81. Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010;363(8):711–23.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012;366(26):2455–65.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. 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  PubMed  CAS  Google Scholar 

  85. Herbst RS, Soria JC, Kowanetz M, Fine GD, Hamid O, Gordon MS, et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature. 2014;515(7528):563–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Tumeh PC, Harview CL, Yearley JH, Shintaku IP, Taylor EJ, Robert L, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Sharma P, Allison JP. The future of immune checkpoint therapy. Science (80- ). 2015;348(6230):56–61.

    Google Scholar 

  88. Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science (80- ). 2015;348(6230):62–8.

    Google Scholar 

  89. Naito Y, Saito K, Shiiba K, Ohuchi A, Saigenji K, Nagura H, et al. CD8+ T cells infiltrated within cancer cell nests as a prognostic factor in human colorectal cancer. Cancer Res. 1998;58(16):3491–4.

    PubMed  CAS  Google Scholar 

  90. Zhang L, Conejo-Garcia JR, Katsaros D, Gimotty PA, Massobrio M, Regnani G, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003;348(3):203–13.

    Article  PubMed  CAS  Google Scholar 

  91. Sato E, Olson SH, Ahn J, Bundy B, Nishikawa H, Qian F, et al. Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc Natl Acad Sci U S A. 2005;102(51):18538–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science (80- ). 2006;313(5795):1960–4.

    Google Scholar 

  93. Royal RE, Levy C, Turner K, Mathur A, Hughes M, Kammula US, et al. Phase 2 trial of single agent Ipilimumab (anti-CTLA-4) for locally advanced or metastatic pancreatic adenocarcinoma. J Immunother. 2010;33(8):828–33.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Breart B, Lemaitre F, Celli S, Bousso P. Two-photon imaging of intratumoral CD8+ T cell cytotoxic activity during adoptive T cell therapy in mice. J Clin Invest. 2008;118(4):1390–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Buckanovich RJ, Facciabene A, Kim S, Benencia F, Sasaroli D, Balint K, et al. Endothelin B receptor mediates the endothelial barrier to T cell homing to tumors and disables immune therapy. Nat Med. 2008;14(1):28–36.

    Article  PubMed  CAS  Google Scholar 

  96. Ryschich E, Schmidt J, Hammerling GJ, Klar E, Ganss R. Transformation of the microvascular system during multistage tumorigenesis. Int J Cancer. 2002;97(6):719–25.

    Article  PubMed  CAS  Google Scholar 

  97. Hamzah J, Jugold M, Kiessling F, Rigby P, Manzur M, Marti HH, et al. Vascular normalization in Rgs5-deficient tumours promotes immune destruction. Nature. 2008;453(7193):410–4.

    Article  PubMed  CAS  Google Scholar 

  98. Cardone A, Tolino A, Zarcone R, Borruto Caracciolo G, Tartaglia E. Prognostic value of desmoplastic reaction and lymphocytic infiltration in the management of breast cancer. Panminerva Med. 1997;39(3):174–7.

    PubMed  CAS  Google Scholar 

  99. Maeshima AM, Niki T, Maeshima A, Yamada T, Kondo H, Matsuno Y. Modified scar grade: a prognostic indicator in small peripheral lung adenocarcinoma. Cancer. 2002;95(12):2546–54.

    Article  PubMed  Google Scholar 

  100. Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, et al. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res. 2007;13(7):2082–90.

    Article  PubMed  CAS  Google Scholar 

  101. Kawase A, Ishii G, Nagai K, Ito T, Nagano T, Murata Y, et al. Podoplanin expression by cancer associated fibroblasts predicts poor prognosis of lung adenocarcinoma. Int J Cancer. 2008;123(5):1053–9.

    Article  PubMed  CAS  Google Scholar 

  102. Salmon H, Franciszkiewicz K, Damotte D, Dieu-Nosjean MC, Validire P, Trautmann A, et al. Matrix architecture defines the preferential localization and migration of T cells into the stroma of human lung tumors. J Clin Invest. 2012;122(3):899–910.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Allinen M, Beroukhim R, Cai L, Brennan C, Lahti-Domenici J, Huang H, et al. Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell. 2004;6(1):17–32.

    Article  PubMed  CAS  Google Scholar 

  104. Domanska UM, Timmer-Bosscha H, Nagengast WB, Oude Munnink TH, Kruizinga RC, Ananias HJ, et al. CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy. Neoplasia. 2012;14(8):709–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Li X, Ma Q, Xu Q, Liu H, Lei J, Duan W, et al. SDF-1/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial-mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway. Cancer Lett. 2012;322(2):169–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Wang Z, Ma Q, Liu Q, Yu H, Zhao L, Shen S, et al. Blockade of SDF-1/CXCR4 signalling inhibits pancreatic cancer progression in vitro via inactivation of canonical Wnt pathway. Br J Cancer. 2008;99(10):1695–703.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Hall JM, Korach KS. Stromal cell-derived factor 1, a novel target of estrogen receptor action, mediates the mitogenic effects of estradiol in ovarian and breast cancer cells. Mol Endocrinol. 2003;17(5):792–803.

    Article  PubMed  CAS  Google Scholar 

  108. Muller A, Homey B, Soto H, Ge N, Catron D, Buchanan ME, et al. Involvement of chemokine receptors in breast cancer metastasis. Nature. 2001;410(6824):50–6.

    Article  PubMed  CAS  Google Scholar 

  109. Scotton CJ, Wilson JL, Scott K, Stamp G, Wilbanks GD, Fricker S, et al. Multiple actions of the chemokine CXCL12 on epithelial tumor cells in human ovarian cancer. Cancer Res. 2002;62(20):5930–8.

    PubMed  CAS  Google Scholar 

  110. Kraman M, Bambrough PJ, Arnold JN, Roberts EW, Magiera L, Jones JO, et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein-alpha. Science (80- ). 2010;330(6005):827–30.

    Google Scholar 

  111. Li T, Yang Y, Hua X, Wang G, Liu W, Jia C, et al. Hepatocellular carcinoma-associated fibroblasts trigger NK cell dysfunction via PGE2 and IDO. Cancer Lett. 2012;318(2):154–61.

    Article  PubMed  CAS  Google Scholar 

  112. Uyttenhove C, Pilotte L, Theate I, Stroobant V, Colau D, Parmentier N, et al. Evidence for a tumoral immune resistance mechanism based on tryptophan degradation by indoleamine 2,3-dioxygenase. Nat Med. 2003;9(10):1269–74.

    Article  PubMed  CAS  Google Scholar 

  113. Thomas DA, Massague J. TGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillance. Cancer Cell. 2005;8(5):369–80.

    Article  PubMed  CAS  Google Scholar 

  114. Gorelik L, Flavell RA. Immune-mediated eradication of tumors through the blockade of transforming growth factor-beta signaling in T cells. Nat Med. 2001;7(10):1118–22.

    Article  PubMed  CAS  Google Scholar 

  115. Lee JC, Lee KM, Kim DW, Heo DS. Elevated TGF-beta1 secretion and down-modulation of NKG2D underlies impaired NK cytotoxicity in cancer patients. J Immunol. 2004;172(12):7335–40.

    Article  PubMed  CAS  Google Scholar 

  116. Gidekel Friedlander SY, Chu GC, Snyder EL, Girnius N, Dibelius G, Crowley D, et al. Context-dependent transformation of adult pancreatic cells by oncogenic K-Ras. Cancer Cell. 2009;16(5):379–89.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Tsunawaki S, Sporn M, Ding A, Nathan C. Deactivation of macrophages by transforming growth factor-beta. Nature. 1988;334(6179):260–2.

    Article  PubMed  CAS  Google Scholar 

  118. Allavena P, Sica A, Garlanda C, Mantovani A. The Yin-Yang of tumor-associated macrophages in neoplastic progression and immune surveillance. Immunol Rev. 2008;222:155–61.

    Article  PubMed  CAS  Google Scholar 

  119. Trapani JA. The dual adverse effects of TGF-beta secretion on tumor progression. Cancer Cell. 2005;8(5):349–50.

    Article  PubMed  CAS  Google Scholar 

  120. Ghiringhelli F, Puig PE, Roux S, Parcellier A, Schmitt E, Solary E, et al. Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J Exp Med. 2005;202(7):919–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Mangan PR, Harrington LE, O’Quinn DB, Helms WS, Bullard DC, Elson CO, et al. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441(7090):231–4.

    Article  PubMed  CAS  Google Scholar 

  122. Kim S, Buchlis G, Fridlender ZG, Sun J, Kapoor V, Cheng G, et al. Systemic blockade of transforming growth factor-beta signaling augments the efficacy of immunogene therapy. Cancer Res. 2008;68(24):10247–56.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Terabe M, Ambrosino E, Takaku S, O’Konek JJ, Venzon D, Lonning S, et al. Synergistic enhancement of CD8+ T cell-mediated tumor vaccine efficacy by an anti-transforming growth factor-beta monoclonal antibody. Clin Cancer Res. 2009;15(21):6560–9.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Mace TA, Ameen Z, Collins A, Wojcik S, Mair M, Young GS, et al. Pancreatic cancer-associated stellate cells promote differentiation of myeloid-derived suppressor cells in a STAT3-dependent manner. Cancer Res. 2013;73(10):3007–18.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  125. Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell. 2007;11(6):526–38.

    Article  PubMed  CAS  Google Scholar 

  126. Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Science (80- ). 2010;328(5979):749–52.

    Google Scholar 

  127. Tran E, Chinnasamy D, Yu Z, Morgan RA, Lee CC, Restifo NP, et al. Immune targeting of fibroblast activation protein triggers recognition of multipotent bone marrow stromal cells and cachexia. J Exp Med. 2013;210(6):1125–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lymphocyte Signalling and Development, Babraham Institute, Cambridge, UK

    Alice E. Denton

  2. Department of Pathology, University of California San Francisco, San Francisco, CA, USA

    Edward W. Roberts

  3. Cold Spring Harbor Laboratory, Weill Cornell Medical College, New York, NY, USA

    Douglas T. Fearon

Authors
  1. Alice E. Denton
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Edward W. Roberts
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Douglas T. Fearon
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alice E. Denton .

Editor information

Editors and Affiliations

  1. Somerville College, University of Oxford, Oxford, UK

    Benjamin M.J Owens

  2. F-star Biotechnology Ltd., Cambridge, UK

    Matthew A. Lakins

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer International Publishing AG, part of Springer Nature

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Denton, A.E., Roberts, E.W., Fearon, D.T. (2018). Stromal Cells in the Tumor Microenvironment. In: Owens, B., Lakins, M. (eds) Stromal Immunology. Advances in Experimental Medicine and Biology, vol 1060. Springer, Cham. https://doi.org/10.1007/978-3-319-78127-3_6

Download citation

Publish with us

Policies and ethics

Search

Navigation