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The Role of Mast Cells in Molding the Tumor Microenvironment

  • Original Paper
  • Published:
Cancer Microenvironment

Abstract

Mast cells (MCs) are granulocytic immune cells that reside in tissues exposed to the external environment. MCs are best known for their activity in allergic reactions, but they have been involved in different physiological and pathological conditions. In particular, MC infiltration has been shown in several types of human tumors and in animal cancer models. Nevertheless, the role of MCs in the tumor microenvironment is still debated because they have been associated either to good or poor prognosis depending on tumor type and tissue localization. This dichotomous role relies on MC capacity to secrete a broad spectrum of molecules with modulatory functions, which may condition the final tumor outcome also promoting angiogenesis and tissue remodeling. In this review, we analyze the multifaceted role of mast cell in tumor progression and inhibition considering their ability to interact with: i) immune cells, ii) tumor cells and iii) the extracellular matrix. Eventually, the current MC targeting strategies to treat cancer patients are discussed. Deciphering the actual role of MCs in tumor onset and progression is crucial to identify MC-targeted treatments aimed at killing cancer cells or at making the tumor vulnerable to selected anti-cancer drugs.

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References

  1. Erlich P (1878) Beiträge zur Theorie und Praxis der histologischen Färbung. Dissertation, Leipzig University.

  2. Westphal E (1891) Uber mastzellen. Hirschwald Press, Berlin

    Google Scholar 

  3. Lachter J, Stein M, Lichtig C, Eidelman S, Munichor M (1995) Mast cells in colorectal neoplasias and premalignant disorders. Dis Colon Rectum 38(3):290–293

    Article  PubMed  CAS  Google Scholar 

  4. Ch’ng S, Sullivan M, Yuan L, Davis P, Tan ST (2006) Mast cells dysregulate apoptotic and cell cycle genes in mucosal squamous cell carcinoma. Cancer Cell Int 6:28. doi:10.1186/1475-2867-6-28

    Article  PubMed  PubMed Central  Google Scholar 

  5. Amini RM, Aaltonen K, Nevanlinna H, Carvalho R, Salonen L, Heikkila P, Blomqvist C (2007) Mast cells and eosinophils in invasive breast carcinoma. BMC Cancer 7:165. doi:10.1186/1471-2407-7-165

    Article  PubMed  PubMed Central  Google Scholar 

  6. Blank U, Falcone FH, Nilsson G (2013) The history of mast cell and basophil research—some lessons learnt from the last century. Allergy 68(9):1093–1101. doi:10.1111/all.12197

    PubMed  CAS  Google Scholar 

  7. Tsai M, Grimbaldeston M, Galli SJ (2011) Mast cells and immunoregulation/immunomodulation. Adv Exp Med Biol 716:186–211. doi:10.1007/978-1-4419-9533-9_11

    Article  PubMed  CAS  Google Scholar 

  8. Metz M, Grimbaldeston MA, Nakae S, Piliponsky AM, Tsai M, Galli SJ (2007) Mast cells in the promotion and limitation of chronic inflammation. Immunol Rev 217:304–328. doi:10.1111/j.1600-065X.2007.00520.x

    Article  PubMed  CAS  Google Scholar 

  9. Kalesnikoff J, Galli SJ (2008) New developments in mast cell biology. Nat Immunol 9(11):1215–1223. doi:10.1038/ni.f.216

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Gurish MF, Austen KF (2012) Developmental origin and functional specialization of mast cell subsets. Immunity 37(1):25–33. doi:10.1016/j.immuni.2012.07.003

    Article  PubMed  CAS  Google Scholar 

  11. Anderson DM, Lyman SD, Baird A, Wignall JM, Eisenman J, Rauch C, March CJ, Boswell HS, Gimpel SD, Cosman D et al (1990) Molecular cloning of mast cell growth factor, a hematopoietin that is active in both membrane bound and soluble forms. Cell 63(1):235–243

    Article  PubMed  CAS  Google Scholar 

  12. Meininger CJ, Yano H, Rottapel R, Bernstein A, Zsebo KM, Zetter BR (1992) The c-kit receptor ligand functions as a mast cell chemoattractant. Blood 79(4):958–963

    PubMed  CAS  Google Scholar 

  13. Ulivi P, Zoli W, Medri L, Amadori D, Saragoni L, Barbanti F, Calistri D, Silvestrini R (2004) c-kit and SCF expression in normal and tumor breast tissue. Breast Cancer Res Treat 83(1):33–42. doi:10.1023/B:BREA.0000010694.35023.9e

    Article  PubMed  CAS  Google Scholar 

  14. Huang B, Lei Z, Zhang GM, Li D, Song C, Li B, Liu Y, Yuan Y, Unkeless J, Xiong H, Feng ZH (2008) SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood 112(4):1269–1279. doi:10.1182/blood-2008-03-147033

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  15. Pittoni P, Tripodo C, Piconese S, Mauri G, Parenza M, Rigoni A, Sangaletti S, Colombo MP (2011) Mast cell targeting hampers prostate adenocarcinoma development but promotes the occurrence of highly malignant neuroendocrine cancers. Cancer Res 71(18):5987–5997. doi:10.1158/0008-5472.CAN-11-1637

    Article  PubMed  CAS  Google Scholar 

  16. Greenberg NM, DeMayo F, Finegold MJ, Medina D, Tilley WD, Aspinall JO, Cunha GR, Donjacour AA, Matusik RJ, Rosen JM (1995) Prostate cancer in a transgenic mouse. Proc Natl Acad Sci U S A 92(8):3439–3443

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  17. Pittoni P, Colombo MP (2012) The dark side of mast cell-targeted therapy in prostate cancer. Cancer Res 72(4):831–835. doi:10.1158/0008-5472.CAN-11-3110

    Article  PubMed  CAS  Google Scholar 

  18. Irani AA, Schechter NM, Craig SS, DeBlois G, Schwartz LB (1986) Two types of human mast cells that have distinct neutral protease compositions. Proc Natl Acad Sci U S A 83(12):4464–4468

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Stone KD, Prussin C, Metcalfe DD (2010) IgE, mast cells, basophils, and eosinophils. J Allergy Clin Immunol 125(2 Suppl 2):S73–S80. doi:10.1016/j.jaci.2009.11.017

    Article  PubMed  PubMed Central  Google Scholar 

  20. Theoharides TC, Conti P (2004) Mast cells: the Jekyll and Hyde of tumor growth. Trends Immunol 25(5):235–241. doi:10.1016/j.it.2004.02.013

    Article  PubMed  CAS  Google Scholar 

  21. Mori A, Zhai YL, Toki T, Nikaido T, Fujii S (1997) Distribution and heterogeneity of mast cells in the human uterus. Hum Reprod 12(2):368–372

    Article  PubMed  CAS  Google Scholar 

  22. Gelfand EW (2004) Inflammatory mediators in allergic rhinitis. J Allergy Clin Immunol 114(5 Suppl):S135–S138. doi:10.1016/j.jaci.2004.08.043

    Article  PubMed  Google Scholar 

  23. Bischoff SC (2009) Physiological and pathophysiological functions of intestinal mast cells. Semin Immunopathol 31(2):185–205. doi:10.1007/s00281-009-0165-4

    Article  PubMed  CAS  Google Scholar 

  24. Rivera J, Gilfillan AM (2006) Molecular regulation of mast cell activation. J Allergy Clin Immunol 117(6):1214–1225. doi:10.1016/j.jaci.2006.04.015, quiz 1226

    Article  PubMed  CAS  Google Scholar 

  25. Migalovich-Sheikhet H, Friedman S, Mankuta D, Levi-Schaffer F (2012) Novel identified receptors on mast cells. Front Immunol 3:238. doi:10.3389/fimmu.2012.00238

    Article  PubMed  PubMed Central  Google Scholar 

  26. Karra L, Levi-Schaffer F (2011) Down-regulation of mast cell responses through ITIM containing inhibitory receptors. Adv Exp Med Biol 716:143–159. doi:10.1007/978-1-4419-9533-9_9

    Article  PubMed  CAS  Google Scholar 

  27. Gu YZ, Hogenesch JB, Bradfield CA (2000) The PAS superfamily: sensors of environmental and developmental signals. Annu Rev Pharmacol Toxicol 40:519–561. doi:10.1146/annurev.pharmtox.40.1.519

    Article  PubMed  CAS  Google Scholar 

  28. Matsumoto Y, Ide F, Kishi R, Akutagawa T, Sakai S, Nakamura M, Ishikawa T, Fujii-Kuriyama Y, Nakatsuru Y (2007) Aryl hydrocarbon receptor plays a significant role in mediating airborne particulate-induced carcinogenesis in mice. Environ Sci Technol 41(10):3775–3780

    Article  PubMed  CAS  Google Scholar 

  29. Lin P, Chang H, Ho WL, Wu MH, Su JM (2003) Association of aryl hydrocarbon receptor and cytochrome P4501B1 expressions in human non-small cell lung cancers. Lung Cancer 42(3):255–261

    Article  PubMed  Google Scholar 

  30. Andersson P, McGuire J, Rubio C, Gradin K, Whitelaw ML, Pettersson S, Hanberg A, Poellinger L (2002) A constitutively active dioxin/aryl hydrocarbon receptor induces stomach tumors. Proc Natl Acad Sci U S A 99(15):9990–9995. doi:10.1073/pnas.152706299

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  31. Moennikes O, Loeppen S, Buchmann A, Andersson P, Ittrich C, Poellinger L, Schwarz M (2004) A constitutively active dioxin/aryl hydrocarbon receptor promotes hepatocarcinogenesis in mice. Cancer Res 64(14):4707–4710. doi:10.1158/0008-5472.CAN-03-0875

    Article  PubMed  CAS  Google Scholar 

  32. Monteleone I, Rizzo A, Sarra M, Sica G, Sileri P, Biancone L, MacDonald TT, Pallone F, Monteleone G (2011) Aryl hydrocarbon receptor-induced signals up-regulate IL-22 production and inhibit inflammation in the gastrointestinal tract. Gastroenterology 141(1):237–248, 248 e231. doi:10.1053/j.gastro.2011.04.007

    Article  PubMed  CAS  Google Scholar 

  33. Monteleone I, Pallone F, Monteleone G (2013) Aryl hydrocarbon receptor and colitis. Semin Immunopathol 35(6):671–675. doi:10.1007/s00281-013-0396-2

    Article  PubMed  CAS  Google Scholar 

  34. Sibilano R, Frossi B, Calvaruso M, Danelli L, Betto E, Dall’Agnese A, Tripodo C, Colombo MP, Pucillo CE, Gri G (2012) The aryl hydrocarbon receptor modulates acute and late mast cell responses. J Immunol 189(1):120–127. doi:10.4049/jimmunol.1200009

    Article  PubMed  CAS  Google Scholar 

  35. Theoharides TC, Kempuraj D, Tagen M, Conti P, Kalogeromitros D (2007) Differential release of mast cell mediators and the pathogenesis of inflammation. Immunol Rev 217:65–78. doi:10.1111/j.1600-065X.2007.00519.x

    Article  PubMed  CAS  Google Scholar 

  36. Jutel M, Watanabe T, Klunker S, Akdis M, Thomet OA, Malolepszy J, Zak-Nejmark T, Koga R, Kobayashi T, Blaser K, Akdis CA (2001) Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature 413(6854):420–425. doi:10.1038/35096564

    Article  PubMed  CAS  Google Scholar 

  37. Elenkov IJ, Webster E, Papanicolaou DA, Fleisher TA, Chrousos GP, Wilder RL (1998) Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors. J Immunol 161(5):2586–2593

    PubMed  CAS  Google Scholar 

  38. Morgan RK, McAllister B, Cross L, Green DS, Kornfeld H, Center DM, Cruikshank WW (2007) Histamine 4 receptor activation induces recruitment of FoxP3+ T cells and inhibits allergic asthma in a murine model. J Immunol 178(12):8081–8089

    Article  PubMed  CAS  Google Scholar 

  39. Seifert R, Strasser A, Schneider EH, Neumann D, Dove S, Buschauer A (2013) Molecular and cellular analysis of human histamine receptor subtypes. Trends Pharmacol Sci 34(1):33–58. doi:10.1016/j.tips.2012.11.001

    Article  PubMed  CAS  Google Scholar 

  40. Medina VA, Rivera ES (2010) Histamine receptors and cancer pharmacology. Br J Pharmacol 161(4):755–767. doi:10.1111/j.1476-5381.2010.00961.x

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  41. Gri G, Piconese S, Frossi B, Manfroi V, Merluzzi S, Tripodo C, Viola A, Odom S, Rivera J, Colombo MP, Pucillo CE (2008) CD4 + CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 29(5):771–781. doi:10.1016/j.immuni.2008.08.018

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  42. Piconese S, Gri G, Tripodo C, Musio S, Gorzanelli A, Frossi B, Pedotti R, Pucillo CE, Colombo MP (2009) Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood 114(13):2639–2648. doi:10.1182/blood-2009-05-220004

    Article  PubMed  CAS  Google Scholar 

  43. Souza HS, Elia CC, Spencer J, MacDonald TT (1999) Expression of lymphocyte-endothelial receptor-ligand pairs, alpha4beta7/MAdCAM-1 and OX40/OX40 ligand in the colon and jejunum of patients with inflammatory bowel disease. Gut 45(6):856–863

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  44. Malmstrom V, Shipton D, Singh B, Al-Shamkhani A, Puklavec MJ, Barclay AN, Powrie F (2001) CD134L expression on dendritic cells in the mesenteric lymph nodes drives colitis in T cell-restored SCID mice. J Immunol 166(11):6972–6981

    Article  PubMed  CAS  Google Scholar 

  45. de Vries VC, Wasiuk A, Bennett KA, Benson MJ, Elgueta R, Waldschmidt TJ, Noelle RJ (2009) Mast cell degranulation breaks peripheral tolerance. Am J Transplant 9(10):2270–2280. doi:10.1111/j.1600-6143.2009.02755.x

    Article  PubMed  Google Scholar 

  46. Grimbaldeston MA, Chen CC, Piliponsky AM, Tsai M, Tam SY, Galli SJ (2005) Mast cell-deficient W-sash c-kit mutant Kit W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am J Pathol 167(3):835–848. doi:10.1016/S0002-9440(10)62055-X

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Colombo MP, Piconese S (2009) Polyps wrap mast cells and Treg within tumorigenic tentacles. Cancer Res 69(14):5619–5622. doi:10.1158/0008-5472.CAN-09-1351

    Article  PubMed  CAS  Google Scholar 

  48. Gounaris E, Erdman SE, Restaino C, Gurish MF, Friend DS, Gounari F, Lee DM, Zhang G, Glickman JN, Shin K, Rao VP, Poutahidis T, Weissleder R, McNagny KM, Khazaie K (2007) Mast cells are an essential hematopoietic component for polyp development. Proc Natl Acad Sci U S A 104(50):19977–19982. doi:10.1073/pnas.0704620104

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  49. Gounaris E, Blatner NR, Dennis K, Magnusson F, Gurish MF, Strom TB, Beckhove P, Gounari F, Khazaie K (2009) T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Res 69(13):5490–5497. doi:10.1158/0008-5472.CAN-09-0304

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  50. Dennis KL, Wang Y, Blatner NR, Wang S, Saadalla A, Trudeau E, Roers A, Weaver CT, Lee JJ, Gilbert JA, Chang EB, Khazaie K (2013) Adenomatous polyps are driven by microbe-instigated focal inflammation and are controlled by IL-10-producing T cells. Cancer Res 73(19):5905–5913. doi:10.1158/0008-5472.CAN-13-1511

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  51. Cheon EC, Khazaie K, Khan MW, Strouch MJ, Krantz SB, Phillips J, Blatner NR, Hix LM, Zhang M, Dennis KL, Salabat MR, Heiferman M, Grippo PJ, Munshi HG, Gounaris E, Bentrem DJ (2011) Mast cell 5-lipoxygenase activity promotes intestinal polyposis in APCDelta468 mice. Cancer Res 71(5):1627–1636. doi:10.1158/0008-5472.CAN-10-1923

    Article  PubMed  CAS  Google Scholar 

  52. Saleem SJ, Martin RK, Morales JK, Sturgill JL, Gibb DR, Graham L, Bear HD, Manjili MH, Ryan JJ, Conrad DH (2012) Cutting edge: mast cells critically augment myeloid-derived suppressor cell activity. J Immunol 189(2):511–515. doi:10.4049/jimmunol.1200647

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Mandruzzato S, Solito S, Falisi E, Francescato S, Chiarion-Sileni V, Mocellin S, Zanon A, Rossi CR, Nitti D, Bronte V, Zanovello P (2009) IL4Ralpha + myeloid-derived suppressor cell expansion in cancer patients. J Immunol 182(10):6562–6568. doi:10.4049/jimmunol.0803831

    Article  PubMed  CAS  Google Scholar 

  54. Yang Z, Zhang B, Li D, Lv M, Huang C, Shen GX, Huang B (2010) Mast cells mobilize myeloid-derived suppressor cells and Treg cells in tumor microenvironment via IL-17 pathway in murine hepatocarcinoma model. PLoS One 5(1):e8922. doi:10.1371/journal.pone.0008922

    Article  PubMed  PubMed Central  Google Scholar 

  55. Molin D, Edstrom A, Glimelius I, Glimelius B, Nilsson G, Sundstrom C, Enblad G (2002) Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. Br J Haematol 119(1):122–124

    Article  PubMed  Google Scholar 

  56. Franco G, Guarnotta C, Frossi B, Piccaluga PP, Boveri E, Gulino A, Fuligni F, Rigoni A, Porcasi R, Buffa S, Betto E, Florena AM, Franco V, Iannitto E, Arcaini L, Pileri SA, Pucillo C, Colombo MP, Sangaletti S, Tripodo C (2014) Bone marrow stroma CD40 expression correlates with inflammatory mast cell infiltration and disease progression in splenic marginal zone lymphoma. Blood. doi:10.1182/blood-2013-04-497271

    PubMed  Google Scholar 

  57. Hedstrom G, Berglund M, Molin D, Fischer M, Nilsson G, Thunberg U, Book M, Sundstrom C, Rosenquist R, Roos G, Erlanson M, Amini RM, Enblad G (2007) Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma. Br J Haematol 138(1):68–71. doi:10.1111/j.1365-2141.2007.06612.x

    Article  PubMed  Google Scholar 

  58. Tripodo C, Gri G, Piccaluga PP, Frossi B, Guarnotta C, Piconese S, Franco G, Vetri V, Pucillo CE, Florena AM, Colombo MP, Pileri SA (2010) Mast cells and Th17 cells contribute to the lymphoma-associated pro-inflammatory microenvironment of angioimmunoblastic T-cell lymphoma. Am J Pathol 177(2):792–802. doi:10.2353/ajpath.2010.091286

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  59. Rabenhorst A, Schlaak M, Heukamp LC, Forster A, Theurich S, von Bergwelt-Baildon M, Buttner R, Kurschat P, Mauch C, Roers A, Hartmann K (2012) Mast cells play a protumorigenic role in primary cutaneous lymphoma. Blood 120(10):2042–2054. doi:10.1182/blood-2012-03-415638

    Article  PubMed  CAS  Google Scholar 

  60. Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW (2008) Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell 135(3):437–448. doi:10.1016/j.cell.2008.08.041

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  61. Baratelli F, Le M, Gershman GB, French SW (2014) Do mast cells play a pathogenetic role in neurofibromatosis type 1 and ulcerative colitis? Exp Mol Pathol 96(2):230–234. doi:10.1016/j.yexmp.2014.02.006

    Article  PubMed  CAS  Google Scholar 

  62. Eaden J (2004) Review article: colorectal carcinoma and inflammatory bowel disease. Aliment Pharmacol Ther 20(Suppl 4):24–30. doi:10.1111/j.1365-2036.2004.02046.x

    Article  PubMed  Google Scholar 

  63. Heijmans J, Buller NV, Muncan V, van den Brink GR (2012) Role of mast cells in colorectal cancer development, the jury is still out. Biochim Biophys Acta 1822(1):9–13. doi:10.1016/j.bbadis.2010.12.001

    Article  PubMed  CAS  Google Scholar 

  64. Chichlowski M, Westwood GS, Abraham SN, Hale LP (2010) Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice. PLoS One 5(8):e12220. doi:10.1371/journal.pone.0012220

    Article  PubMed  PubMed Central  Google Scholar 

  65. Khan MW, Keshavarzian A, Gounaris E, Melson JE, Cheon EC, Blatner NR, Chen ZE, Tsai FN, Lee G, Ryu H, Barrett TA, Bentrem DJ, Beckhove P, Khazaie K (2013) PI3K/AKT signaling is essential for communication between tissue-infiltrating mast cells, macrophages, and epithelial cells in colitis-induced cancer. Clin Cancer Res 19(9):2342–2354. doi:10.1158/1078-0432.CCR-12-2623

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  66. Kim YJ, Hong KS, Chung JW, Kim JH, Hahm KB (2010) Prevention of colitis-associated carcinogenesis with infliximab. Cancer Prev Res (Phila) 3(10):1314–1333. doi:10.1158/1940-6207.CAPR-09-0272

    Article  CAS  Google Scholar 

  67. Gulubova M, Vlaykova T (2009) Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. J Gastroenterol Hepatol 24(7):1265–1275. doi:10.1111/j.1440-1746.2007.05009.x

    Article  PubMed  Google Scholar 

  68. Malfettone A, Silvestris N, Saponaro C, Ranieri G, Russo A, Caruso S, Popescu O, Simone G, Paradiso A, Mangia A (2013) High density of tryptase-positive mast cells in human colorectal cancer: a poor prognostic factor related to protease-activated receptor 2 expression. J Cell Mol Med 17(8):1025–1037. doi:10.1111/jcmm.12073

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  69. Frossi B, Gri G, Tripodo C, Pucillo C (2010) Exploring a regulatory role for mast cells: ‘MCregs’? Trends Immunol 31(3):97–102. doi:10.1016/j.it.2009.12.007

    Article  PubMed  CAS  Google Scholar 

  70. Schmidt DR, Kao WJ (2007) The interrelated role of fibronectin and interleukin-1 in biomaterial-modulated macrophage function. Biomaterials 28(3):371–382. doi:10.1016/j.biomaterials.2006.08.041

    Article  PubMed  CAS  Google Scholar 

  71. Junttila MR, de Sauvage FJ (2013) Influence of tumour micro-environment heterogeneity on therapeutic response. Nature 501(7467):346–354. doi:10.1038/nature12626

    Article  PubMed  CAS  Google Scholar 

  72. Lilla JN, Werb Z (2010) Mast cells contribute to the stromal microenvironment in mammary gland branching morphogenesis. Dev Biol 337(1):124–133. doi:10.1016/j.ydbio.2009.10.021

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  73. Yoshii M, Jikuhara A, Mori S, Iwagaki H, Takahashi HK, Nishibori M, Tanaka N (2005) Mast cell tryptase stimulates DLD-1 carcinoma through prostaglandin- and MAP kinase-dependent manners. J Pharmacol Sci 98(4):450–458

    Article  PubMed  CAS  Google Scholar 

  74. Abdel-Majid RM, Marshall JS (2004) Prostaglandin E2 induces degranulation-independent production of vascular endothelial growth factor by human mast cells. J Immunol 172(2):1227–1236

    Article  PubMed  CAS  Google Scholar 

  75. Coussens LM, Raymond WW, Bergers G, Laig-Webster M, Behrendtsen O, Werb Z, Caughey GH, Hanahan D (1999) Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev 13(11):1382–1397

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  76. Harvima IT, Levi-Schaffer F, Draber P, Friedman S, Polakovicova I, Gibbs BF, Blank U, Nilsson G, Maurer M (2014) Molecular targets on mast cells and basophils for novel therapies. J Allergy Clin Immunol. doi:10.1016/j.jaci.2014.03.007

    PubMed  Google Scholar 

  77. Caughey GH (2007) Mast cell tryptases and chymases in inflammation and host defense. Immunol Rev 217:141–154. doi:10.1111/j.1600-065X.2007.00509.x

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  78. Coussens LM, Shapiro SD, Soloway PD, Werb Z (2001) Models for gain-of-function and loss-of-function of MMPs. Transgenic and gene targeted mice. Methods Mol Biol 151:149–179

    PubMed  CAS  Google Scholar 

  79. Shi ZG, Li JP, Shi LL, Li X (2012) An updated patent therapeutic agents targeting MMPs. Recent Pat Anticancer Drug Discov 7(1):74–101

    Article  PubMed  CAS  Google Scholar 

  80. Oka T, Kalesnikoff J, Starkl P, Tsai M, Galli SJ (2012) Evidence questioning cromolyn’s effectiveness and selectivity as a ‘mast cell stabilizer’ in mice. Lab Invest 92(10):1472–1482. doi:10.1038/labinvest.2012.116

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  81. Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI (2007) Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13(10):1211–1218. doi:10.1038/nm1649

    Article  PubMed  CAS  Google Scholar 

  82. Pierotti MA, Tamborini E, Negri T, Pricl S, Pilotti S (2011) Targeted therapy in GIST: in silico modeling for prediction of resistance. Nat Rev Clin Oncol 8(3):161–170. doi:10.1038/nrclinonc.2011.3

    Article  PubMed  CAS  Google Scholar 

  83. Ribatti D, Crivellato E (2011) Mast cells and tumors: from biology to clinic. In: Springer (ed) Mast cells and tumors: from biology to clinic.

  84. Pittoni P, Piconese S, Tripodo C, Colombo MP (2011) Tumor-intrinsic and -extrinsic roles of c-Kit: mast cells as the primary off-target of tyrosine kinase inhibitors. Oncogene 30(7):757–769. doi:10.1038/onc.2010.494

    Article  PubMed  CAS  Google Scholar 

  85. Rajput AB, Turbin DA, Cheang MC, Voduc DK, Leung S, Gelmon KA, Gilks CB, Huntsman DG (2008) Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: a study of 4,444 cases. Breast Cancer Res Treat 107(2):249–257. doi:10.1007/s10549-007-9546-3

    Article  PubMed  PubMed Central  Google Scholar 

  86. Wang B, Li L, Liao Y, Li J, Yu X, Zhang Y, Xu J, Rao H, Chen S, Zhang L, Zheng L (2013) Mast cells expressing interleukin 17 in the muscularis propria predict a favorable prognosis in esophageal squamous cell carcinoma. Cancer Immunol Immunother: CII 62(10):1575–1585. doi:10.1007/s00262-013-1460-4

    Article  PubMed  CAS  Google Scholar 

  87. Fakhrjou A, Niroumand-Oscoei SM, Somi MH, Ghojazadeh M, Naghashi S, Samankan S (2013) Prognostic Value of Tumor-Infiltrating Mast Cells in Outcome of Patients with Esophagus Squamous Cell Carcinoma. J Gastrointest Cancer. doi:10.1007/s12029-013-9550-2

    Google Scholar 

  88. Ammendola M, Sacco R, Donato G, Zuccala V, Russo E, Luposella M, Vescio G, Rizzuto A, Patruno R, De Sarro G, Montemurro S, Sammarco G, Ranieri G (2013) Mast cell positivity to tryptase correlates with metastatic lymph nodes in gastrointestinal cancer patients treated surgically. Oncology 85(2):111–116. doi:10.1159/000351145

    Article  PubMed  CAS  Google Scholar 

  89. Chen L, Zhang Q, Chang W, Du Y, Zhang H, Cao G (2012) Viral and host inflammation-related factors that can predict the prognosis of hepatocellular carcinoma. Eur J Cancer 48(13):1977–1987. doi:10.1016/j.ejca.2012.01.015

    Article  PubMed  CAS  Google Scholar 

  90. Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P (2005) Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 23(35):8959–8967. doi:10.1200/JCO.2005.01.4910

    Article  PubMed  Google Scholar 

  91. Imada A, Shijubo N, Kojima H, Abe S (2000) Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma. Eur Respir J 15(6):1087–1093

    Article  PubMed  CAS  Google Scholar 

  92. Takanami I, Takeuchi K, Naruke M (2000) Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma. Cancer 88(12):2686–2692

    Article  PubMed  CAS  Google Scholar 

  93. Duncan LM, Richards LA, Mihm MC Jr (1998) Increased mast cell density in invasive melanoma. J Cutan Pathol 25(1):11–15

    Article  PubMed  CAS  Google Scholar 

  94. Ribatti D, Ennas MG, Vacca A, Ferreli F, Nico B, Orru S, Sirigu P (2003) Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur J Clin Investig 33(5):420–425

    Article  CAS  Google Scholar 

  95. Esposito I, Menicagli M, Funel N, Bergmann F, Boggi U, Mosca F, Bevilacqua G, Campani D (2004) Inflammatory cells contribute to the generation of an angiogenic phenotype in pancreatic ductal adenocarcinoma. J Clin Pathol 57(6):630–636

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  96. Strouch MJ, Cheon EC, Salabat MR, Krantz SB, Gounaris E, Melstrom LG, Dangi-Garimella S, Wang E, Munshi HG, Khazaie K, Bentrem DJ (2010) Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clin Cancer Res 16(8):2257–2265. doi:10.1158/1078-0432.CCR-09-1230

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  97. Cai SW, Yang SZ, Gao J, Pan K, Chen JY, Wang YL, Wei LX, Dong JH (2011) Prognostic significance of mast cell count following curative resection for pancreatic ductal adenocarcinoma. Surgery 149(4):576–584. doi:10.1016/j.surg.2010.10.009

    Article  PubMed  Google Scholar 

  98. Johansson A, Rudolfsson S, Hammarsten P, Halin S, Pietras K, Jones J, Stattin P, Egevad L, Granfors T, Wikstrom P, Bergh A (2010) Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. Am J Pathol 177(2):1031–1041. doi:10.2353/ajpath.2010.100070

    Article  PubMed  CAS  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by grants from Fondazione Cariplo (number 2010-0790) and Associazione Italiana per la Ricerca sul Cancro (AIRC: Investigator Grant number 14194 to Mario Paolo Colombo). The work of Carlo Pucillo is supported by a grant from Associazione Italiana Mastocitosi (ASIMAS). Alice Rigoni is supported by a triennial fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

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Authors and Affiliations

  1. Molecular Immunology Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, via Amadeo 42, 20133, Milan, Italy

    A. Rigoni & M. P. Colombo

  2. Department of Medical and Biological Sciences, University of Udine, 33100, Udine, Italy

    C. Pucillo

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  1. A. Rigoni
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  2. M. P. Colombo
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  3. C. Pucillo
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Correspondence to M. P. Colombo.

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Rigoni, A., Colombo, M.P. & Pucillo, C. The Role of Mast Cells in Molding the Tumor Microenvironment. Cancer Microenvironment 8, 167–176 (2015). https://doi.org/10.1007/s12307-014-0152-8

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