Cancer and Metastasis Reviews

, Volume 30, Issue 1, pp 45–60 | Cite as

The significant role of mast cells in cancer

  • Khashayarsha Khazaie
  • Nichole R. Blatner
  • Mohammad Wasim Khan
  • Fotini Gounari
  • Elias Gounaris
  • Kristen Dennis
  • Andreas Bonertz
  • Fu-Nien Tsai
  • Matthew J. Strouch
  • Eric Cheon
  • Joseph D. Phillips
  • Philipp Beckhove
  • David J. Bentrem


Mast cells (MC) are a bone marrow-derived, long-lived, heterogeneous cellular population that function both as positive and negative regulators of immune responses. They are arguably the most productive chemical factory in the body and influence other cells through both soluble mediators and cell-to-cell interaction. MC are commonly seen in various tumors and have been attributed alternatively with tumor rejection or tumor promotion. Tumor-infiltrating MC are derived both from sentinel and recruited progenitor cells. MC can directly influence tumor cell proliferation and invasion but also help tumors indirectly by organizing its microenvironment and modulating immune responses to tumor cells. Best known for orchestrating inflammation and angiogenesis, the role of MC in shaping adaptive immune responses has become a focus of recent investigations. MC mobilize T cells and antigen-presenting dendritic cells. They function as intermediaries in regulatory T cells (Treg)-induced tolerance but can also modify or reverse Treg-suppressive properties. The central role of MC in the control of innate and adaptive immunity endows them with the ability to tune the nature of host responses to cancer and ultimately influence the outcome of disease and fate of the cancer patient.


Mast cell Mast cell progenitor Tryptase Chymase Cancer Tumor Colon-cancer Polyposis Regulatory T Cell Immune Surviellance 


  1. 1.
    Chen, C. C., Grimbaldeston, M. A., Tsai, M., Weissman, I. L., & Galli, S. J. (2005). Identification of mast cell progenitors in adult mice. Proceedings of the National Academy of Sciences of the United States of America, 102, 11408–11413.PubMedCrossRefGoogle Scholar
  2. 2.
    Arinobu, Y., Iwasaki, H., & Akashi, K. (2009). Origin of basophils and mast cells. Allergology International, 58, 21–28.PubMedCrossRefGoogle Scholar
  3. 3.
    Enerback, L. (1966). Mast cells in rat gastrointestinal mucosa. 2. Dye-binding and metachromatic properties. Acta Pathologica et Microbiologica Scandinavica, 66, 303–312.PubMedGoogle Scholar
  4. 4.
    Enerbaeck, L. (1986). Mast cell heterogeneity: The evolution of the concept of a specific mucosal mast cell. In A. D. Befus, J. Bienenstock, & J. A. Denburg (Eds.) Mast cell differentiation and heterogeneity (pp. 1–26). Raven Press.Google Scholar
  5. 5.
    Befus, A. D., Pearce, F. L., Gauldie, J., Horsewood, P., & Bienenstock, J. (1982). Mucosal mast cells. I. Isolation and functional characteristics of rat intestinal mast cells. Journal of Immunology, 128, 2475–2480.Google Scholar
  6. 6.
    Metcalfe, D. D., Baram, D., & Mekori, Y. A. (1997). Mast cells. Physiological Reviews, 77, 1033–1079.PubMedGoogle Scholar
  7. 7.
    Irani, A. A., Schechter, N. M., Craig, S. S., DeBlois, G., & Schwartz, L. B. (1986). Two types of human mast cells that have distinct neutral protease compositions. Proceedings of the National Academy of Sciences of the United States of America, 83, 4464–4468.PubMedCrossRefGoogle Scholar
  8. 8.
    Arck, P. C., Handjiski, B., Hagen, E., Joachim, R., Klapp, B. F., & Paus, R. (2001). Indications for a ‘brain-hair follicle axis (BHA)’: Inhibition of keratinocyte proliferation and up-regulation of keratinocyte apoptosis in telogen hair follicles by stress and substance P. The FASEB Journal, 15, 2536–2538.PubMedGoogle Scholar
  9. 9.
    Hallgren, J., & Gurish, M. F. (2007). Pathways of murine mast cell development and trafficking: Tracking the roots and routes of the mast cell. Immunological Reviews, 217, 8–18.PubMedCrossRefGoogle Scholar
  10. 10.
    Gounaris, E., Erdman, S. E., Restaino, C., Gurish, M. F., Friend, D. S., Gounari, F., et al. (2007). Mast cells are an essential hematopoietic component for polyp development. Proceedings of the National Academy of Sciences of the United States of America, 104, 19977–19982.PubMedCrossRefGoogle Scholar
  11. 11.
    Kumamoto, T., Shalhevet, D., Matsue, H., Mummert, M. E., Ward, B. R., Jester, J. V., et al. (2003). Hair follicles serve as local reservoirs of skin mast cell precursors. Blood, 102, 1654–1660.PubMedCrossRefGoogle Scholar
  12. 12.
    Kasugai, T., Tei, H., Okada, M., Hirota, S., Morimoto, M., Yamada, M., et al. (1995). Infection with Nippostrongylus brasiliensis induces invasion of mast cell precursors from peripheral blood to small intestine. Blood, 85, 1334–1340.PubMedGoogle Scholar
  13. 13.
    Rodewald, H. R., Dessing, M., Dvorak, A. M., & Galli, S. J. (1996). Identification of a committed precursor for the mast cell lineage. Science, 271, 818–822.PubMedCrossRefGoogle Scholar
  14. 14.
    Nakano, T., Sonoda, T., Hayashi, C., Yamatodani, A., Kanayama, Y., Yamamura, T., et al. (1985). Fate of bone marrow-derived cultured mast cells after intracutaneous, intraperitoneal, and intravenous transfer into genetically mast cell-deficient W/Wv mice. Evidence that cultured mast cells can give rise to both connective tissue type and mucosal mast cells. The Journal of Experimental Medicine, 162, 1025–1043.PubMedCrossRefGoogle Scholar
  15. 15.
    Gurish, M. F., Pear, W. S., Stevens, R. L., Scott, M. L., Sokol, K., Ghildyal, N., et al. (1995). Tissue-regulated differentiation and maturation of a v-abl-immortalized mast cell-committed progenitor. Immunity, 3, 175–186.PubMedCrossRefGoogle Scholar
  16. 16.
    Lu, L. F., Lind, E. F., Gondek, D. C., Bennett, K. A., Gleeson, M. W., Pino-Lagos, K., et al. (2006). Mast cells are essential intermediaries in regulatory T-cell tolerance. Nature, 442, 997–1002.PubMedCrossRefGoogle Scholar
  17. 17.
    Maltby, S., Khazaie, K., & McNagny, K. M. (2009). Mast cells in tumor growth: Angiogenesis, tissue remodelling and immune-modulation. Biochimica et Biophysica Acta, 1796, 19–26.PubMedGoogle Scholar
  18. 18.
    Galli, S. J. (1990). New insights into “the riddle of the mast cells”: Microenvironmental regulation of mast cell development and phenotypic heterogeneity. Laboratory Investigation, 62, 5–33.PubMedGoogle Scholar
  19. 19.
    Gurish, M. F., & Austen, K. F. (2001). The diverse roles of mast cells. The Journal of Experimental Medicine, 194, F1–F5.PubMedCrossRefGoogle Scholar
  20. 20.
    Grimbaldeston, M. A., Metz, M., Yu, M., Tsai, M., & Galli, S. J. (2006). Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Current Opinion in Immunology, 18, 751–760.PubMedCrossRefGoogle Scholar
  21. 21.
    Kanakura, Y., Thompson, H., Nakano, T., Yamamura, T., Asai, H., Kitamura, Y., et al. (1988). Multiple bidirectional alterations of phenotype and changes in proliferative potential during the in vitro and in vivo passage of clonal mast cell populations derived from mouse peritoneal mast cells. Blood, 72, 877–885.PubMedGoogle Scholar
  22. 22.
    Sonoda, S., Sonoda, T., Nakano, T., Kanayama, Y., Kanakura, Y., Asai, H., et al. (1986). Development of mucosal mast cells after injection of a single connective tissue-type mast cell in the stomach mucosa of genetically mast cell-deficient W/Wv mice. Journal of Immunology, 137, 1319–1322.Google Scholar
  23. 23.
    Boyce, J. A., Mellor, E. A., Perkins, B., Lim, Y. C., & Luscinskas, F. W. (2002). Human mast cell progenitors use alpha4-integrin, VCAM-1, and PSGL-1 E-selectin for adhesive interactions with human vascular endothelium under flow conditions. Blood, 99, 2890–2896.PubMedCrossRefGoogle Scholar
  24. 24.
    Gurish, M. F., Tao, H., Abonia, J. P., Arya, A., Friend, D. S., Parker, C. M., et al. (2001). Intestinal mast cell progenitors require CD49dbeta7 (alpha4beta7 integrin) for tissue-specific homing. The Journal of Experimental Medicine, 194, 1243–1252.PubMedCrossRefGoogle Scholar
  25. 25.
    Abonia, J. P., Austen, K. F., Rollins, B. J., Joshi, S. K., Flavell, R. A., Kuziel, W. A., et al. (2005). Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2. Blood, 105, 4308–4313.PubMedCrossRefGoogle Scholar
  26. 26.
    Abonia, J. P., Hallgren, J., Jones, T., Shi, T., Xu, Y., Koni, P., et al. (2006). Alpha-4 integrins and VCAM-1, but not MAdCAM-1, are essential for recruitment of mast cell progenitors to the inflamed lung. Blood, 108, 1588–1594.PubMedCrossRefGoogle Scholar
  27. 27.
    Hallgren, J., Jones, T. G., Abonia, J. P., Xing, W., Humbles, A., Austen, K. F., et al. (2007). Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors. Proceedings of the National Academy of Sciences of the United States of America, 104, 20478–20483.PubMedCrossRefGoogle Scholar
  28. 28.
    Galli, S. J., Tsai, M., & Wershil, B. K. (1993). The c-kit receptor, stem cell factor, and mast cells. What each is teaching us about the others. The American Journal of Pathology, 142, 965–974.PubMedGoogle Scholar
  29. 29.
    Moller, C., Alfredsson, J., Engstrom, M., Wootz, H., Xiang, Z., Lennartsson, J., et al. (2005). Stem cell factor promotes mast cell survival via inactivation of FOXO3a-mediated transcriptional induction and MEK-regulated phosphorylation of the proapoptotic protein Bim. Blood, 106, 1330–1336.PubMedCrossRefGoogle Scholar
  30. 30.
    Meininger, C. J., Yano, H., Rottapel, R., Bernstein, A., Zsebo, K. M., & Zetter, B. R. (1992). The c-kit receptor ligand functions as a mast cell chemoattractant. Blood, 79, 958–963.PubMedGoogle Scholar
  31. 31.
    Gilfillan, A. M., & Rivera, J. (2009). The tyrosine kinase network regulating mast cell activation. Immunological Reviews, 228, 149–169.PubMedCrossRefGoogle Scholar
  32. 32.
    Okayama, Y., & Kawakami, T. (2006). Development, migration, and survival of mast cells. Immunologic Research, 34, 97–115.PubMedCrossRefGoogle Scholar
  33. 33.
    Taylor, A. M., Galli, S. J., & Coleman, J. W. (1995). Stem-cell factor, the kit ligand, induces direct degranulation of rat peritoneal mast cells in vitro and in vivo: Dependence of the in vitro effect on period of culture and comparisons of stem-cell factor with other mast cell-activating agents. Immunology, 86, 427–433.PubMedGoogle Scholar
  34. 34.
    Galli, S. J., Tsai, M., Gordon, J. R., Geissler, E. N., & Wershil, B. K. (1992). Analyzing mast cell development and function using mice carrying mutations at W/c-kit or Sl/MGF (SCF) loci. Annals of the New York Academy of Sciences, 664, 69–88.PubMedCrossRefGoogle Scholar
  35. 35.
    Nocka, K., Tan, J. C., Chiu, E., Chu, T. Y., Ray, P., Traktman, P., et al. (1990). Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. The EMBO Journal, 9, 1805–1813.PubMedGoogle Scholar
  36. 36.
    Pittoni, P., Piconese, S., Tripodo, C., & Colombo, M. P. (2010). Tumor-intrinsic and -extrinsic roles of c-Kit: Mast cells as the primary off-target of tyrosine kinase inhibitors. Oncogene.Google Scholar
  37. 37.
    Bellone, G., Smirne, C., Carbone, A., Buffolino, A., Scirelli, T., Prati, A., et al. (2006). KIT/stem cell factor expression in premalignant and malignant lesions of the colon mucosa in relationship to disease progression and outcomes. International Journal of Oncology, 29, 851–859.PubMedGoogle Scholar
  38. 38.
    Huang, B., Lei, Z., Zhang, G. M., Li, D., Song, C., Li, B., et al. (2008). SCF-mediated mast cell infiltration and activation exacerbate the inflammation and immunosuppression in tumor microenvironment. Blood, 112, 1269–1279.PubMedCrossRefGoogle Scholar
  39. 39.
    Lu-Kuo, J. M., Fruman, D. A., Joyal, D. M., Cantley, L. C., & Katz, H. R. (2000). Impaired kit- but not FcepsilonRI-initiated mast cell activation in the absence of phosphoinositide 3-kinase p85alpha gene products. The Journal of Biological Chemistry, 275, 6022–6029.PubMedCrossRefGoogle Scholar
  40. 40.
    Samayawardhena, L. A., & Pallen, C. J. (2008). Protein-tyrosine phosphatase alpha regulates stem cell factor-dependent c-Kit activation and migration of mast cells. The Journal of Biological Chemistry, 283, 29175–29185.PubMedCrossRefGoogle Scholar
  41. 41.
    Gounaris, E., Blatner, N. R., Dennis, K., Magnusson, F., Gurish, M. F., Strom, T. B., et al. (2009). T-regulatory cells shift from a protective anti-inflammatory to a cancer-promoting proinflammatory phenotype in polyposis. Cancer Research, 69, 5490–5497.PubMedCrossRefGoogle Scholar
  42. 42.
    Jones, T. G., Hallgren, J., Humbles, A., Burwell, T., Finkelman, F. D., Alcaide, P., et al. (2009). Antigen-induced increases in pulmonary mast cell progenitor numbers depend on IL-9 and CD1d-restricted NKT cells. Journal of Immunology, 183, 5251–5260.CrossRefGoogle Scholar
  43. 43.
    Chen, M. L., Pittet, M. J., Gorelik, L., Flavell, R. A., Weissleder, R., von Boehmer, H., et al. (2005). Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-beta signals in vivo. Proceedings of the National Academy of Sciences of the United States of America, 102, 419–424.PubMedCrossRefGoogle Scholar
  44. 44.
    Mempel, T. R., Pittet, M. J., Khazaie, K., Weninger, W., Weissleder, R., von Boehmer, H., et al. (2006). Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity, 25, 129–141.PubMedCrossRefGoogle Scholar
  45. 45.
    Nummer, D., Suri-Payer, E., Schmitz-Winnenthal, H., Bonertz, A., Galindo, L., Antolovich, D., et al. (2007). Role of tumor endothelium in CD4+ CD25+ regulatory T cell infiltration of human pancreatic carcinoma. Journal of the National Cancer Institute, 99, 1188–1199.PubMedCrossRefGoogle Scholar
  46. 46.
    Wagner, P., Koch, M., Nummer, D., Palm, S., Galindo, L., Autenrieth, D., et al. (2008). Detection and functional analysis of tumor infiltrating T-lymphocytes (TIL) in liver metastases from colorectal cancer. Annals of Surgical Oncology, 15, 2310–2317.PubMedCrossRefGoogle Scholar
  47. 47.
    Bonertz, A., Weitz, J., Pietsch, D. H., Rahbari, N. N., Schlude, C., Ge, Y., et al. (2009). Antigen-specific Treg control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. Journal of Clinical Investigation, 119, 3311–3321.PubMedGoogle Scholar
  48. 48.
    Blatner, N. R., Bonertz, A., Beckhove, P., Cheon, E. C., Krantz, S. B., Strouch, M., et al. (2010). In colorectal cancer mast cells contribute to systemic regulatory T-cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 107, 6430–6435.PubMedCrossRefGoogle Scholar
  49. 49.
    Ruitenberg, E. J., & Elgersma, A. (1976). Absence of intestinal mast cell response in congenitally athymic mice during Trichinella spiralis infection. Nature, 264, 258–260.PubMedCrossRefGoogle Scholar
  50. 50.
    Schmitt, E., Huls, C., Nagel, B., & Rude, E. (1990). Characterization of a T-cell-derived mast cell costimulatory activity (MCA) that acts synergistically with interleukin 3 and interleukin 4 on the growth of murine mast cells. Cytokine, 2, 407–415.PubMedCrossRefGoogle Scholar
  51. 51.
    Alcaide, P., Jones, T. G., Lord, G. M., Glimcher, L. H., Hallgren, J., Arinobu, Y., et al. (2007). Dendritic cell expression of the transcription factor T-bet regulates mast cell progenitor homing to mucosal tissue. The Journal of Experimental Medicine, 204, 431–439.PubMedCrossRefGoogle Scholar
  52. 52.
    Irani, A. M., Craig, S. S., DeBlois, G., Elson, C. O., Schechter, N. M., & Schwartz, L. B. (1987). Deficiency of the tryptase-positive, chymase-negative mast cell type in gastrointestinal mucosa of patients with defective T lymphocyte function. Journal of Immunology, 138, 4381–4386.Google Scholar
  53. 53.
    Jones, T. G., Finkelman, F. D., Austen, K. F., & Gurish, M. F. (2010). T regulatory cells control antigen-induced recruitment of mast cell progenitors to the lungs of C57BL/6 mice. Journal of Immunology, 185, 1804–1811.CrossRefGoogle Scholar
  54. 54.
    Shin, K., Gurish, M. F., Friend, D. S., Pemberton, A. D., Thornton, E. M., Miller, H. R., et al. (2006). Lymphocyte-independent connective tissue mast cells populate murine synovium. Arthritis and Rheumatism, 54, 2863–2871.PubMedCrossRefGoogle Scholar
  55. 55.
    Boesiger, J., Tsai, M., Maurer, M., Yamaguchi, M., Brown, L. F., Claffey, K. P., et al. (1998). Mast cells can secrete vascular permeability factor/vascular endothelial cell growth factor and exhibit enhanced release after immunoglobulin E-dependent upregulation of fc epsilon receptor I expression. The Journal of Experimental Medicine, 188, 1135–1145.PubMedCrossRefGoogle Scholar
  56. 56.
    Blair, R. J., Meng, H., Marchese, M. J., Ren, S., Schwartz, L. B., Tonnesen, M. G., et al. (1997). Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. Journal of Clinical Investigation, 99, 2691–2700.PubMedCrossRefGoogle Scholar
  57. 57.
    Gordon, J. R., & Galli, S. J. (1990). Mast cells as a source of both preformed and immunologically inducible TNF-alpha/cachectin. Nature, 346, 274–276.PubMedCrossRefGoogle Scholar
  58. 58.
    Mannel, D. N., Hultner, L., & Echtenacher, B. (1996). Critical protective role of mast cell-derived tumour necrosis factor in bacterial infection. Research in Immunology, 147, 491–493.PubMedCrossRefGoogle Scholar
  59. 59.
    Echtenacher, B., Mannel, D. N., & Hultner, L. (1996). Critical protective role of mast cells in a model of acute septic peritonitis. Nature, 381, 75–77.PubMedCrossRefGoogle Scholar
  60. 60.
    Malaviya, R., Ikeda, T., Ross, E., & Abraham, S. N. (1996). Mast cell modulation of neutrophil influx and bacterial clearance at sites of infection through TNF-alpha. Nature, 381, 77–80.PubMedCrossRefGoogle Scholar
  61. 61.
    Maurer, M., Echtenacher, B., Hultner, L., Kollias, G., Mannel, D. N., Langley, K. E., et al. (1998). The c-kit ligand, stem cell factor, can enhance innate immunity through effects on mast cells. The Journal of Experimental Medicine, 188, 2343–2348.PubMedCrossRefGoogle Scholar
  62. 62.
    Feger, F., Varadaradjalou, S., Gao, Z., Abraham, S. N., & Arock, M. (2002). The role of mast cells in host defense and their subversion by bacterial pathogens. Trends in Immunology, 23, 151–158.PubMedCrossRefGoogle Scholar
  63. 63.
    Bochner, B. S., Charlesworth, E. N., Lichtenstein, L. M., Derse, C. P., Gillis, S., Dinarello, C. A., et al. (1990). Interleukin-1 is released at sites of human cutaneous allergic reactions. The Journal of Allergy and Clinical Immunology, 86, 830–839.PubMedCrossRefGoogle Scholar
  64. 64.
    Nigrovic, P. A., Binstadt, B. A., Monach, P. A., Johnsen, A., Gurish, M., Iwakura, Y., et al. (2007). Mast cells contribute to initiation of autoantibody-mediated arthritis via IL-1. Proceedings of the National Academy of Sciences of the United States of America, 104, 2325–2330.PubMedCrossRefGoogle Scholar
  65. 65.
    Mantovani, A., Allavena, P., Sica, A., & Balkwill, F. (2008). Cancer-related inflammation. Nature, 454, 436–444.PubMedCrossRefGoogle Scholar
  66. 66.
    Cook, G. P., Savic, S., Wittmann, M., & McDermott, M. F. (2010). The NLRP3 inflammasome, a target for therapy in diverse disease states. European Journal of Immunology, 40, 631–634.PubMedCrossRefGoogle Scholar
  67. 67.
    Kim, G. Y., Lee, J. W., Ryu, H. C., Wei, J. D., Seong, C. M., & Kim, J. H. (2010). Proinflammatory cytokine IL-1beta stimulates IL-8 synthesis in mast cells via a leukotriene B4 receptor 2-linked pathway, contributing to angiogenesis. Journal of Immunology, 184, 3946–3954.CrossRefGoogle Scholar
  68. 68.
    Dostert, C., Petrilli, V., Van Bruggen, R., Steele, C., Mossman, B. T., & Tschopp, J. (2008). Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica. Science, 320, 674–677.PubMedCrossRefGoogle Scholar
  69. 69.
    Depinay, N., Hacini, F., Beghdadi, W., Peronet, R., & Mecheri, S. (2006). Mast cell-dependent down-regulation of antigen-specific immune responses by mosquito bites. Journal of Immunology, 176, 4141–4146.Google Scholar
  70. 70.
    Kennedy Norton, S., Barnstein, B., Brenzovich, J., Bailey, D. P., Kashyap, M., Speiran, K., et al. (2008). IL-10 suppresses mast cell IgE receptor expression and signaling in vitro and in vivo. Journal of Immunology, 180, 2848–2854.Google Scholar
  71. 71.
    Huang, C., Sali, A., & Stevens, R. L. (1998). Regulation and function of mast cell proteases in inflammation. Journal of Clinical Immunology, 18, 169–183.PubMedCrossRefGoogle Scholar
  72. 72.
    Ghildyal, N., Friend, D. S., Freelund, R., Austen, K. F., McNeil, H. P., Schiller, V., et al. (1994). Lack of expression of the tryptase mouse mast cell protease 7 in mast cells of the C57BL/6J mouse. Journal of Immunology, 153, 2624–2630.Google Scholar
  73. 73.
    Stevens, R. L., Friend, D. S., McNeil, H. P., Schiller, V., Ghildyal, N., & Austen, K. F. (1994). Strain-specific and tissue-specific expression of mouse mast cell secretory granule proteases. Proceedings of the National Academy of Sciences of the United States of America, 91, 128–132.PubMedCrossRefGoogle Scholar
  74. 74.
    Miller, H. R., & Pemberton, A. D. (2002). Tissue-specific expression of mast cell granule serine proteinases and their role in inflammation in the lung and gut. Immunology, 105, 375–390.PubMedCrossRefGoogle Scholar
  75. 75.
    Galli, S. J., Kalesnikoff, J., Grimbaldeston, M. A., Piliponsky, A. M., Williams, C. M., & Tsai, M. (2005). Mast cells as “tunable” effector and immunoregulatory cells: Recent advances. Annual Review of Immunology, 23, 749–786.PubMedCrossRefGoogle Scholar
  76. 76.
    Weller, C. L., Collington, S. J., Brown, J. K., Miller, H. R., Al-Kashi, A., Clark, P., et al. (2005). Leukotriene B4, an activation product of mast cells, is a chemoattractant for their progenitors. The Journal of Experimental Medicine, 201, 1961–1971.PubMedCrossRefGoogle Scholar
  77. 77.
    Cheon, E. C., Khazaie, K., Khan, M. W., Strouch, M. J., Krantz, S. B., Phillips, J., et al. (2010). Mast cell 5-Lipoxygenase activity promotes intestinal polyposis in APCΔ468 mice. Cancer Research, (in press).Google Scholar
  78. 78.
    Jain, S., Harris, J., & Ware, J. (2010). Platelets: Linking hemostasis and cancer. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 2362–2367.PubMedCrossRefGoogle Scholar
  79. 79.
    Blank, U., & Rivera, J. (2004). The ins and outs of IgE-dependent mast-cell exocytosis. Trends in Immunology, 25, 266–273.PubMedCrossRefGoogle Scholar
  80. 80.
    Kim, M. S., Radinger, M., & Gilfillan, A. M. (2008). The multiple roles of phosphoinositide 3-kinase in mast cell biology. Trends in Immunology, 29, 493–501.PubMedCrossRefGoogle Scholar
  81. 81.
    Ching, T. T., Hsu, A. L., Johnson, A. J., & Chen, C. S. (2001). Phosphoinositide 3-kinase facilitates antigen-stimulated Ca(2+) influx in RBL-2H3 mast cells via a phosphatidylinositol 3, 4, 5-trisphosphate-sensitive Ca(2+) entry mechanism. The Journal of Biological Chemistry, 276, 14814–14820.PubMedCrossRefGoogle Scholar
  82. 82.
    Nigrovic, P. A., Malbec, O., Lu, B., Markiewski, M. M., Kepley, C., Gerard, N., et al. (2010). C5a receptor enables participation of mast cells in immune complex arthritis independently of Fcgamma receptor modulation. Arthritis and Rheumatism, 62, 3322–3333.PubMedCrossRefGoogle Scholar
  83. 83.
    Gommerman, J. L., Oh, D. Y., Zhou, X., Tedder, T. F., Maurer, M., Galli, S. J., et al. (2000). A role for CD21/CD35 and CD19 in responses to acute septic peritonitis: A potential mechanism for mast cell activation. Journal of Immunology, 165, 6915–6921.Google Scholar
  84. 84.
    Johnson, A. R., Hugli, T. E., & Muller-Eberhard, H. J. (1975). Release of histamine from rat mast cells by the complement peptides C3a and C5a. Immunology, 28, 1067–1080.PubMedGoogle Scholar
  85. 85.
    Marshall, J. S. (2004). Mast-cell responses to pathogens. Nature Reviews Immunology, 4, 787–799.PubMedCrossRefGoogle Scholar
  86. 86.
    Prodeus, A. P., Zhou, X., Maurer, M., Galli, S. J., & Carroll, M. C. (1997). Impaired mast cell-dependent natural immunity in complement C3-deficient mice. Nature, 390, 172–175.PubMedCrossRefGoogle Scholar
  87. 87.
    Wojtecka-Lukasik, E., & Maslinski, S. (1992). Fibronectin and fibrinogen degradation products stimulate PMN-leukocyte and mast cell degranulation. Journal of Physiology and Pharmacology, 43, 173–181.PubMedGoogle Scholar
  88. 88.
    Shefler, I., Salamon, P., Reshef, T., Mor, A., & Mekori, Y. A. (2010). T cell-induced mast cell activation: A role for microparticles released from activated T cells. Journal of Immunology, 185, 4206–4212.CrossRefGoogle Scholar
  89. 89.
    Dvorak, A. M. (2005). Ultrastructural studies of human basophils and mast cells. The Journal of Histochemistry and Cytochemistry, 53, 1043–1070.PubMedCrossRefGoogle Scholar
  90. 90.
    Crivellato, E., Nico, B., Gallo, V. P., & Ribatti, D. (2010). Cell secretion mediated by granule-associated vesicle transport: A glimpse at evolution. Anatomical Record (Hoboken), 293, 1115–1124.CrossRefGoogle Scholar
  91. 91.
    Dvorak, A. M. (1991). Basophil and mast cell degranulation and recovery. In Blood cell biochemistry. Plenum Press, vol 4.Google Scholar
  92. 92.
    Toth-Jakatics, R., Jimi, S., Takebayashi, S., & Kawamoto, N. (2000). Cutaneous malignant melanoma: Correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Human Pathology, 31, 955–960.PubMedCrossRefGoogle Scholar
  93. 93.
    Ribatti, D., Vacca, A., Ria, R., Marzullo, A., Nico, B., Filotico, R., et al. (2003). Neovascularisation, expression of fibroblast growth factor-2, and mast cells with tryptase activity increase simultaneously with pathological progression in human malignant melanoma. European Journal of Cancer, 39, 666–674.PubMedCrossRefGoogle Scholar
  94. 94.
    Ribatti, D., Vacca, A., Marzullo, A., Nico, B., Ria, R., Roncali, L., et al. (2000). Angiogenesis and mast cell density with tryptase activity increase simultaneously with pathological progression in B-cell non-Hodgkin’s lymphomas. International Journal of Cancer, 85, 171–175.Google Scholar
  95. 95.
    Imada, A., Shijubo, N., Kojima, H., & Abe, S. (2000). Mast cells correlate with angiogenesis and poor outcome in stage I lung adenocarcinoma. The European Respiratory Journal, 15, 1087–1093.PubMedCrossRefGoogle Scholar
  96. 96.
    Terada, T., & Matsunaga, Y. (2000). Increased mast cells in hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Journal of Hepatology, 33, 961–966.PubMedCrossRefGoogle Scholar
  97. 97.
    Coussens, L. M., Raymond, W. W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., et al. (1999). Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes & Development, 13, 1382–1397.CrossRefGoogle Scholar
  98. 98.
    Takanami, I., Takeuchi, K., & Naruke, M. (2000). Mast cell density is associated with angiogenesis and poor prognosis in pulmonary adenocarcinoma. Cancer, 88, 2686–2692.PubMedCrossRefGoogle Scholar
  99. 99.
    Nonomura, N., Takayama, H., Nishimura, K., Oka, D., Nakai, Y., Shiba, M., et al. (2007). Decreased number of mast cells infiltrating into needle biopsy specimens leads to a better prognosis of prostate cancer. British Journal of Cancer, 97, 952–956.PubMedGoogle Scholar
  100. 100.
    Johansson, A., Rudolfsson, S., Hammarsten, P., Halin, S., Pietras, K., Jones, J., et al. (2010). Mast cells are novel independent prognostic markers in prostate cancer and represent a target for therapy. The American Journal of Pathology, 177, 1031–1041.PubMedCrossRefGoogle Scholar
  101. 101.
    Tan, P. H., Jayabaskar, T., Yip, G., Tan, Y., Hilmy, M., Selvarajan, S., et al. (2005). p53 and c-kit (CD117) protein expression as prognostic indicators in breast phyllodes tumors: A tissue microarray study. Modern Pathology, 18, 1527–1534.PubMedCrossRefGoogle Scholar
  102. 102.
    Djordjevic, B., & Hanna, W. M. (2008). Expression of c-kit in fibroepithelial lesions of the breast is a mast cell phenomenon. Modern Pathology, 21, 1238–1245.PubMedCrossRefGoogle Scholar
  103. 103.
    Taskinen, M., Karjalainen-Lindsberg, M. L., & Leppa, S. (2008). Prognostic influence of tumor-infiltrating mast cells in patients with follicular lymphoma treated with rituximab and CHOP. Blood, 111, 4664–4667.PubMedCrossRefGoogle Scholar
  104. 104.
    Beer, T. W., Ng, L. B., & Murray, K. (2008). Mast cells have prognostic value in Merkel cell carcinoma. The American Journal of Dermatopathology, 30, 27–30.PubMedCrossRefGoogle Scholar
  105. 105.
    Molin, D., Edstrom, A., Glimelius, I., Glimelius, B., Nilsson, G., Sundstrom, C., et al. (2002). Mast cell infiltration correlates with poor prognosis in Hodgkin’s lymphoma. British Journal Haematology, 119, 122–124.CrossRefGoogle Scholar
  106. 106.
    Glimelius, I., Edstrom, A., Fischer, M., Nilsson, G., Sundstrom, C., Molin, D., et al. (2005). Angiogenesis and mast cells in Hodgkin lymphoma. Leukemia, 19, 2360–2362.PubMedCrossRefGoogle Scholar
  107. 107.
    Yang, F. C., Chen, S., Clegg, T., Li, X., Morgan, T., Estwick, S. A., et al. (2006). Nf1+/- mast cells induce neurofibroma like phenotypes through secreted TGF-beta signaling. Human Molecular Genetics, 15, 2421–2437.PubMedCrossRefGoogle Scholar
  108. 108.
    Crivellato, E., Nico, B., & Ribatti, D. (2008). Mast cells and tumour angiogenesis: New insight from experimental carcinogenesis. Cancer Letters, 269, 1–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Gulubova, M., & Vlaykova, T. (2009). Prognostic significance of mast cell number and microvascular density for the survival of patients with primary colorectal cancer. Journal of Gastroenterology and Hepatology, 24, 1265–1275.PubMedCrossRefGoogle Scholar
  110. 110.
    Yodavudh, S., Tangjitgamol, S., & Puangsa-art, S. (2008). Prognostic significance of microvessel density and mast cell density for the survival of Thai patients with primary colorectal cancer. Journal of the Medical Association of Thailand, 91, 723–732.PubMedGoogle Scholar
  111. 111.
    Acikalin, M. F., Oner, U., Topcu, I., Yasar, B., Kiper, H., & Colak, E. (2005). Tumour angiogenesis and mast cell density in the prognostic assessment of colorectal carcinomas. Digestive and Liver Disease, 37, 162–169.PubMedCrossRefGoogle Scholar
  112. 112.
    Strouch, M. J., Cheon, E. C., Salabat, M. R., Krantz, S. B., Gounaris, E., Melstrom, L. G., et al. (2010). Crosstalk between mast cells and pancreatic cancer cells contributes to pancreatic tumor progression. Clinical Cancer Research, 16, 2257–2265.PubMedCrossRefGoogle Scholar
  113. 113.
    Carlini, M. J., Dalurzo, M. C., Lastiri, J. M., Smith, D. E., Vasallo, B. C., Puricelli, L. I., et al. (2010). Mast cell phenotypes and microvessels in non-small cell lung cancer and its prognostic significance. Human Pathology, 41, 697–705.PubMedCrossRefGoogle Scholar
  114. 114.
    Ibaraki, T., Muramatsu, M., Takai, S., Jin, D., Maruyama, H., Orino, T., et al. (2005). The relationship of tryptase- and chymase-positive mast cells to angiogenesis in stage I non-small cell lung cancer. European Journal of Cardiothoracic Surgery, 28, 617–621.PubMedCrossRefGoogle Scholar
  115. 115.
    Ju, M. J., Qiu, S. J., Gao, Q., Fan, J., Cai, M. Y., Li, Y. W., et al. (2009). Combination of peritumoral mast cells and T-regulatory cells predicts prognosis of hepatocellular carcinoma. Cancer Science, 100, 1267–1274.PubMedCrossRefGoogle Scholar
  116. 116.
    Ju, M. J., Qiu, S. J., Fan, J., Xiao, Y. S., Gao, Q., Zhou, J., et al. (2009). Peritumoral activated hepatic stellate cells predict poor clinical outcome in hepatocellular carcinoma after curative resection. American Journal of Clinical Pathology, 131, 498–510.PubMedCrossRefGoogle Scholar
  117. 117.
    Daniel, D., Meyer-Morse, N., Bergsland, E. K., Dehne, K., Coussens, L. M., & Hanahan, D. (2003). Immune enhancement of skin carcinogenesis by CD4+ T cells. The Journal of Experimental Medicine, 197, 1017–1028.PubMedCrossRefGoogle Scholar
  118. 118.
    de Visser, K. E., Korets, L. V., & Coussens, L. M. (2005). De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell, 7, 411–423.PubMedCrossRefGoogle Scholar
  119. 119.
    Andreu, P., Johansson, M., Affara, N. I., Pucci, F., Tan, T., Junankar, S., et al. (2010). FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell, 17, 121–134.PubMedCrossRefGoogle Scholar
  120. 120.
    DeNardo, D. G., Barreto, J. B., Andreu, P., Vasquez, L., Tawfik, D., Kolhatkar, N., et al. (2009). CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell, 16, 91–102.PubMedCrossRefGoogle Scholar
  121. 121.
    Samoszuk, M., & Corwin, M. A. (2003). Mast cell inhibitor cromolyn increases blood clotting and hypoxia in murine breast cancer. International Journal of Cancer, 107, 159–163.CrossRefGoogle Scholar
  122. 122.
    Soucek, L., Lawlor, E. R., Soto, D., Shchors, K., Swigart, L. B., & Evan, G. I. (2007). Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Natural Medicines, 13, 1211–1218.CrossRefGoogle Scholar
  123. 123.
    Samoszuk, M. K., Su, M. Y., Najafi, A., & Nalcioglu, O. (2001). Selective thrombosis of tumor blood vessels in mammary adenocarcinoma implants in rats. The American Journal of Pathology, 159, 245–251.PubMedCrossRefGoogle Scholar
  124. 124.
    Melillo, R. M., Guarino, V., Avilla, E., Galdiero, M. R., Liotti, F., Prevete, N., et al. (2010). Mast cells have a protumorigenic role in human thyroid cancer. Oncogene, 29, 6203–6215.PubMedCrossRefGoogle Scholar
  125. 125.
    Sinnamon, M. J., Carter, K. J., Sims, L. P., Lafleur, B., Fingleton, B., & Matrisian, L. M. (2008). A protective role of mast cells in intestinal tumorigenesis. Carcinogenesis, 29, 880–886.PubMedCrossRefGoogle Scholar
  126. 126.
    Ribatti, D., & Crivellato, E. (2009). The controversial role of mast cells in tumor growth. International Review of Cell and Molecular Biology, 275, 89–131.PubMedCrossRefGoogle Scholar
  127. 127.
    Nigrovic, P. A., Gray, D. H., Jones, T., Hallgren, J., Kuo, F. C., Chaletzky, B., et al. (2008). Genetic inversion in mast cell-deficient (W(sh)) mice interrupts corin and manifests as hematopoietic and cardiac aberrancy. The American Journal of Pathology, 173, 1693–1701.PubMedCrossRefGoogle Scholar
  128. 128.
    Pulimood, A. B., Mathan, M. M., & Mathan, V. I. (1998). Quantitative and ultrastructural analysis of rectal mucosal mast cells in acute infectious diarrhea. Digestive Diseases and Sciences, 43, 2111–2116.PubMedCrossRefGoogle Scholar
  129. 129.
    Carothers, A. M., Moran, A. E., Cho, N. L., Redston, M., & Bertagnolli, M. M. (2006). Changes in antitumor response in C57BL/6J-Min/+ mice during long-term administration of a selective cyclooxygenase-2 inhibitor. Cancer Research, 66, 6432–6438.PubMedCrossRefGoogle Scholar
  130. 130.
    Bertagnolli, M. M., Eagle, C. J., Zauber, A. G., Redston, M., Solomon, S. D., Kim, K., et al. (2006). Celecoxib for the prevention of sporadic colorectal adenomas. The New England Journal of Medicine, 355, 873–884.PubMedCrossRefGoogle Scholar
  131. 131.
    Masini, E., Bechi, P., Dei, R., Di Bello, M. G., & Sacchi, T. B. (1994). Helicobacter pylori potentiates histamine release from rat serosal mast cells induced by bile acids. Digestive Diseases and Sciences, 39, 1493–1500.PubMedCrossRefGoogle Scholar
  132. 132.
    Nakajima, S., Krishnan, B., Ota, H., Segura, A. M., Hattori, T., Graham, D. Y., et al. (1997). Mast cell involvement in gastritis with or without Helicobacter pylori infection. Gastroenterology, 113, 746–754.PubMedCrossRefGoogle Scholar
  133. 133.
    Plebani, M., Basso, D., Vianello, F., & Di Mario, F. (1994). Helicobacter pylori activates gastric mucosal mast cells. Digestive Diseases and Sciences, 39, 1592–1593.PubMedCrossRefGoogle Scholar
  134. 134.
    Rogers, A. B., & Fox, J. G. (2004). Inflammation and cancer: I. Rodent models of infectious gastrointestinal liver cancer. American Journal of Physiology. Gastrointestinal and Liver Physiology, 286, G361–G366.PubMedCrossRefGoogle Scholar
  135. 135.
    Rao, V. P., Poutahidis, T., Ge, Z., Nambiar, P. R., Boussahmain, C., Wang, Y. Y., et al. (2006). Innate immune inflammatory response against enteric bacteria Helicobacter hepaticus induces mammary adenocarcinoma in mice. Cancer Research, 66, 7395–7400.PubMedCrossRefGoogle Scholar
  136. 136.
    Nielsen, H. J., Hansen, U., Christensen, I. J., Reimert, C. M., Brunner, N., & Moesgaard, F. (1999). Independent prognostic value of eosinophil and mast cell infiltration in colorectal cancer tissue. The Journal of Pathology, 189, 487–495.PubMedCrossRefGoogle Scholar
  137. 137.
    Ogino, S., Shima, K., Baba, Y., Nosho, K., Irahara, N., Kure, S., et al. (2009). Colorectal cancer expression of peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology, 136, 1242–1250.PubMedCrossRefGoogle Scholar
  138. 138.
    Welsh, T. J., Green, R. H., Richardson, D., Waller, D. A., O’Byrne, K. J., & Bradding, P. (2005). Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. Journal of Clinical Oncology, 23, 8959–8967.PubMedCrossRefGoogle Scholar
  139. 139.
    Ali, G., Boldrini, L., Lucchi, M., Picchi, A., Dell’Omodarme, M., Prati, M. C., et al. (2009). Treatment with interleukin-2 in malignant pleural mesothelioma: Immunological and angiogenetic assessment and prognostic impact. British Journal of Cancer, 101, 1869–1875.PubMedCrossRefGoogle Scholar
  140. 140.
    Ali, G., Boldrini, L., Lucchi, M., Mussi, A., Corsi, V., & Fontanini, G. (2009). Tryptase mast cells in malignant pleural mesothelioma as an independent favorable prognostic factor. Journal of Thoracic Oncology, 4, 348–354.PubMedCrossRefGoogle Scholar
  141. 141.
    Hedstrom, G., Berglund, M., Molin, D., Fischer, M., Nilsson, G., Thunberg, U., et al. (2007). Mast cell infiltration is a favourable prognostic factor in diffuse large B-cell lymphoma. British Journal Haematology, 138, 68–71.CrossRefGoogle Scholar
  142. 142.
    Fleischmann, A., Schlomm, T., Kollermann, J., Sekulic, N., Huland, H., Mirlacher, M., et al. (2009). Immunological microenvironment in prostate cancer: High mast cell densities are associated with favorable tumor characteristics and good prognosis. The Prostate, 69, 976–981.PubMedCrossRefGoogle Scholar
  143. 143.
    Kankkunen, J. P., Harvima, I. T., & Naukkarinen, A. (1997). Quantitative analysis of tryptase and chymase containing mast cells in benign and malignant breast lesions. International Journal of Cancer, 72, 385–388.CrossRefGoogle Scholar
  144. 144.
    Dabiri, S., Huntsman, D., Makretsov, N., Cheang, M., Gilks, B., Bajdik, C., et al. (2004). The presence of stromal mast cells identifies a subset of invasive breast cancers with a favorable prognosis. Modern Pathology, 17, 690–695.PubMedCrossRefGoogle Scholar
  145. 145.
    Rajput, A. B., Turbin, D. A., Cheang, M. C., Voduc, D. K., Leung, S., Gelmon, K. A., et al. (2008). Stromal mast cells in invasive breast cancer are a marker of favourable prognosis: A study of 4, 444 cases. Breast Cancer Research and Treatment, 107, 249–257.PubMedCrossRefGoogle Scholar
  146. 146.
    Schechter, N. M., Brass, L. F., Lavker, R. M., & Jensen, P. J. (1998). Reaction of mast cell proteases tryptase and chymase with protease activated receptors (PARs) on keratinocytes and fibroblasts. Journal of Cellular Physiology, 176, 365–373.PubMedCrossRefGoogle Scholar
  147. 147.
    Corvera, C. U., Dery, O., McConalogue, K., Bohm, S. K., Khitin, L. M., Caughey, G. H., et al. (1997). Mast cell tryptase regulates rat colonic myocytes through proteinase-activated receptor 2. Journal of Clinical Investigation, 100, 1383–1393.PubMedCrossRefGoogle Scholar
  148. 148.
    Kawabata, A. (2003). Gastrointestinal functions of proteinase-activated receptors. Life Sciences, 74, 247–254.PubMedCrossRefGoogle Scholar
  149. 149.
    Winter, M. C., Shasby, S. S., Ries, D. R., & Shasby, D. M. (2006). PAR2 activation interrupts E-cadherin adhesion and compromises the airway epithelial barrier: Protective effect of beta-agonists. American Journal of Physiology. Lung Cellular and Molecular Physiology, 291, L628–L635.PubMedCrossRefGoogle Scholar
  150. 150.
    Yoshii, M., Jikuhara, A., Mori, S., Iwagaki, H., Takahashi, H. K., Nishibori, M., et al. (2005). Mast cell tryptase stimulates DLD-1 carcinoma through prostaglandin- and MAP kinase-dependent manners. Journal of Pharmacological Sciences, 98, 450–458.PubMedCrossRefGoogle Scholar
  151. 151.
    MacNaughton, W. K. (2005). Epithelial effects of proteinase-activated receptors in the gastrointestinal tract. Memórias do Instituto Oswaldo Cruz, 100(Suppl 1), 211–215.PubMedGoogle Scholar
  152. 152.
    Morris, D. R., Ding, Y., Ricks, T. K., Gullapalli, A., Wolfe, B. L., & Trejo, J. (2006). Protease-activated receptor-2 is essential for factor VIIa and Xa-induced signaling, migration, and invasion of breast cancer cells. Cancer Research, 66, 307–314.PubMedCrossRefGoogle Scholar
  153. 153.
    Cairns, J. A., & Walls, A. F. (1996). Mast cell tryptase is a mitogen for epithelial cells. Stimulation of IL-8 production and intercellular adhesion molecule-1 expression. Journal of Immunology, 156, 275–283.Google Scholar
  154. 154.
    Berger, P., Perng, D. W., Thabrew, H., Compton, S. J., Cairns, J. A., McEuen, A. R., et al. (2001). Tryptase and agonists of PAR-2 induce the proliferation of human airway smooth muscle cells. Journal of Applied Physiology, 91, 1372–1379.PubMedGoogle Scholar
  155. 155.
    Gruber, B. L., Kew, R. R., Jelaska, A., Marchese, M. J., Garlick, J., Ren, S., et al. (1997). Human mast cells activate fibroblasts: Tryptase is a fibrogenic factor stimulating collagen messenger ribonucleic acid synthesis and fibroblast chemotaxis. Journal of Immunology, 158, 2310–2317.Google Scholar
  156. 156.
    Levi-Schaffer, F., & Piliponsky, A. M. (2003). Tryptase, a novel link between allergic inflammation and fibrosis. Trends in Immunology, 24, 158–161.PubMedCrossRefGoogle Scholar
  157. 157.
    Frungieri, M. B., Weidinger, S., Meineke, V., Kohn, F. M., & Mayerhofer, A. (2002). Proliferative action of mast-cell tryptase is mediated by PAR2, COX2, prostaglandins, and PPARgamma: Possible relevance to human fibrotic disorders. Proceedings of the National Academy of Sciences of the United States of America, 99, 15072–15077.PubMedCrossRefGoogle Scholar
  158. 158.
    Mizutani, H., Schechter, N., Lazarus, G., Black, R. A., & Kupper, T. S. (1991). Rapid and specific conversion of precursor interleukin 1 beta (IL-1 beta) to an active IL-1 species by human mast cell chymase. The Journal of Experimental Medicine, 174, 821–825.PubMedCrossRefGoogle Scholar
  159. 159.
    Groschwitz, K. R., Ahrens, R., Osterfeld, H., Gurish, M. F., Han, X., Abrink, M., et al. (2009). Mast cells regulate homeostatic intestinal epithelial migration and barrier function by a chymase/Mcpt4-dependent mechanism. Proceedings of the National Academy of Sciences of the United States of America, 106, 22381–22386.PubMedCrossRefGoogle Scholar
  160. 160.
    Forbes, E. E., Groschwitz, K., Abonia, J. P., Brandt, E. B., Cohen, E., Blanchard, C., et al. (2008). IL-9- and mast cell-mediated intestinal permeability predisposes to oral antigen hypersensitivity. The Journal of Experimental Medicine, 205, 897–913.PubMedCrossRefGoogle Scholar
  161. 161.
    Flint, N., Cove, F. L., & Evans, G. S. (1994). Heparin stimulates the proliferation of intestinal epithelial cells in primary culture. Journal of Cell Science, 107(Pt 2), 401–411.PubMedGoogle Scholar
  162. 162.
    Szlosarek, P., Charles, K. A., & Balkwill, F. R. (2006). Tumour necrosis factor-alpha as a tumour promoter. European Journal of Cancer, 42, 745–750.PubMedCrossRefGoogle Scholar
  163. 163.
    Stevens, R. L., & Adachi, R. (2007). Protease-proteoglycan complexes of mouse and human mast cells and importance of their beta-tryptase-heparin complexes in inflammation and innate immunity. Immunological Reviews, 217, 155–167.PubMedCrossRefGoogle Scholar
  164. 164.
    McNeil, H. P., Adachi, R., & Stevens, R. L. (2007). Mast cell-restricted tryptases: Structure and function in inflammation and pathogen defense. The Journal of Biological Chemistry, 282, 20785–20789.PubMedCrossRefGoogle Scholar
  165. 165.
    Trivedi, N. N., & Caughey, G. H. (2010). Mast cell peptidases: Chameleons of innate immunity and host defense. American Journal of Respiratory Cell and Molecular Biology, 42, 257–267.PubMedCrossRefGoogle Scholar
  166. 166.
    Dabbous, M. K., Walker, R., Haney, L., Carter, L. M., Nicolson, G. L., & Woolley, D. E. (1986). Mast cells and matrix degradation at sites of tumour invasion in rat mammary adenocarcinoma. British Journal of Cancer, 54, 459–465.PubMedCrossRefGoogle Scholar
  167. 167.
    Vu, T. H., Shipley, J. M., Bergers, G., Berger, J. E., Helms, J. A., Hanahan, D., et al. (1998). MMP-9/gelatinase B is a key regulator of growth plate angiogenesis and apoptosis of hypertrophic chondrocytes. Cell, 93, 411–422.PubMedCrossRefGoogle Scholar
  168. 168.
    Fang, K. C., Wolters, P. J., Steinhoff, M., Bidgol, A., Blount, J. L., & Caughey, G. H. (1999). Mast cell expression of gelatinases A and B is regulated by kit ligand and TGF-beta. Journal of Immunology, 162, 5528–5535.Google Scholar
  169. 169.
    Tanaka, A., Arai, K., Kitamura, Y., & Matsuda, H. (1999). Matrix metalloproteinase-9 production, a newly identified function of mast cell progenitors, is downregulated by c-kit receptor activation. Blood, 94, 2390–2395.PubMedGoogle Scholar
  170. 170.
    Coussens, L. M., Tinkle, C. L., Hanahan, D., & Werb, Z. (2000). MMP-9 supplied by bone marrow-derived cells contributes to skin carcinogenesis. Cell, 103, 481–490.PubMedCrossRefGoogle Scholar
  171. 171.
    McKerrow, J. H., Bhargava, V., Hansell, E., Huling, S., Kuwahara, T., Matley, M., et al. (2000). A functional proteomics screen of proteases in colorectal carcinoma. Molecular Medicine, 6, 450–460.PubMedGoogle Scholar
  172. 172.
    Palermo, C., & Joyce, J. A. (2008). Cysteine cathepsin proteases as pharmacological targets in cancer. Trends in Pharmacological Sciences, 29, 22–28.PubMedCrossRefGoogle Scholar
  173. 173.
    Xiang, M., Gu, Y., Zhao, F., Lu, H., Chen, S., & Yin, L. (2010). Mast cell tryptase promotes breast cancer migration and invasion. Oncology Reports, 23, 615–619.PubMedGoogle Scholar
  174. 174.
    Cairns, J. A., & Walls, A. F. (1997). Mast cell tryptase stimulates the synthesis of type I collagen in human lung fibroblasts. Journal of Clinical Investigation, 99, 1313–1321.PubMedCrossRefGoogle Scholar
  175. 175.
    Hebda, P. A., Collins, M. A., & Tharp, M. D. (1993). Mast cell and myofibroblast in wound healing. Dermatologic Clinics, 11, 685–696.PubMedGoogle Scholar
  176. 176.
    Gailit, J., Marchese, M. J., Kew, R. R., & Gruber, B. L. (2001). The differentiation and function of myofibroblasts is regulated by mast cell mediators. Journal of Investigative Dermatology, 117, 1113–1119.PubMedCrossRefGoogle Scholar
  177. 177.
    Mekori, Y. A., & Metcalfe, D. D. (1999). Mast cell-T cell interactions. The Journal of Allergy and Clinical Immunology, 104, 517–523.PubMedCrossRefGoogle Scholar
  178. 178.
    Baram, D., Vaday, G. G., Salamon, P., Drucker, I., Hershkoviz, R., & Mekori, Y. A. (2001). Human mast cells release metalloproteinase-9 on contact with activated T cells: Juxtacrine regulation by TNF-alpha. Journal of Immunology, 167, 4008–4016.Google Scholar
  179. 179.
    Brill, A., Baram, D., Sela, U., Salamon, P., Mekori, Y. A., & Hershkoviz, R. (2004). Induction of mast cell interactions with blood vessel wall components by direct contact with intact T cells or T cell membranes in vitro. Clinical and Experimental Allergy, 34, 1725–1731.PubMedCrossRefGoogle Scholar
  180. 180.
    Theoharides, T. C., Kempuraj, D., Kourelis, T., & Manola, A. (2008). Human mast cells stimulate activated T cells: Implications for multiple sclerosis. Annals of the New York Academy of Sciences, 1144, 74–82.PubMedCrossRefGoogle Scholar
  181. 181.
    Nakae, S., Ho, L. H., Yu, M., Monteforte, R., Iikura, M., Suto, H., et al. (2007). Mast cell-derived TNF contributes to airway hyperreactivity, inflammation, and TH2 cytokine production in an asthma model in mice. The Journal of Allergy and Clinical Immunology, 120, 48–55.PubMedCrossRefGoogle Scholar
  182. 182.
    Suto, H., Nakae, S., Kakurai, M., Sedgwick, J. D., Tsai, M., & Galli, S. J. (2006). Mast cell-associated TNF promotes dendritic cell migration. Journal of Immunology, 176, 4102–4112.Google Scholar
  183. 183.
    Ren, S. R., Xu, L. B., Wu, Z. Y., Du, J., Gao, M. H., & Qu, C. F. (2010). Exogenous dendritic cell homing to draining lymph nodes can be boosted by mast cell degranulation. Cellular Immunology, 263, 204–211.PubMedCrossRefGoogle Scholar
  184. 184.
    Demeure, C. E., Brahimi, K., Hacini, F., Marchand, F., Peronet, R., Huerre, M., et al. (2005). Anopheles mosquito bites activate cutaneous mast cells leading to a local inflammatory response and lymph node hyperplasia. Journal of Immunology, 174, 3932–3940.Google Scholar
  185. 185.
    Jawdat, D. M., Rowden, G., & Marshall, J. S. (2006). Mast cells have a pivotal role in TNF-independent lymph node hypertrophy and the mobilization of Langerhans cells in response to bacterial peptidoglycan. Journal of Immunology, 177, 1755–1762.Google Scholar
  186. 186.
    Maurer, M., Lopez Kostka, S., Siebenhaar, F., Moelle, K., Metz, M., Knop, J., et al. (2006). Skin mast cells control T cell-dependent host defense in Leishmania major infections. The FASEB Journal, 20, 2460–2467.PubMedCrossRefGoogle Scholar
  187. 187.
    McLachlan, J. B., Hart, J. P., Pizzo, S. V., Shelburne, C. P., Staats, H. F., Gunn, M. D., et al. (2003). Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nature Immunology, 4, 1199–1205.PubMedCrossRefGoogle Scholar
  188. 188.
    Kashyap, M., Thornton, A. M., Norton, S. K., Barnstein, B., Macey, M., Brenzovich, J., et al. (2008). Cutting edge: CD4 T cell-mast cell interactions alter IgE receptor expression and signaling. Journal of Immunology, 180, 2039–2043.Google Scholar
  189. 189.
    Shelburne, C. P., Nakano, H., St John, A. L., Chan, C., McLachlan, J. B., Gunn, M. D., et al. (2009). Mast cells augment adaptive immunity by orchestrating dendritic cell trafficking through infected tissues. Cell Host & Microbe, 6, 331–342.CrossRefGoogle Scholar
  190. 190.
    Kambayashi, T., Baranski, J. D., Baker, R. G., Zou, T., Allenspach, E. J., Shoag, J. E., et al. (2008). Indirect involvement of allergen-captured mast cells in antigen presentation. Blood, 111, 1489–1496.PubMedCrossRefGoogle Scholar
  191. 191.
    Nakae, S., Suto, H., Iikura, M., Kakurai, M., Sedgwick, J. D., Tsai, M., et al. (2006). Mast cells enhance T cell activation: Importance of mast cell costimulatory molecules and secreted TNF. Journal of Immunology, 176, 2238–2248.Google Scholar
  192. 192.
    Christy, A. L., & Brown, M. A. (2007). The multitasking mast cell: Positive and negative roles in the progression of autoimmunity. Journal of Immunology, 179, 2673–2679.Google Scholar
  193. 193.
    Gregory, G. D., Raju, S. S., Winandy, S., & Brown, M. A. (2006). Mast cell IL-4 expression is regulated by Ikaros and influences encephalitogenic Th1 responses in EAE. Journal of Clinical Investigation, 116, 1327–1336.PubMedCrossRefGoogle Scholar
  194. 194.
    Kambayashi, T., Allenspach, E. J., Chang, J. T., Zou, T., Shoag, J. E., Reiner, S. L., et al. (2009). Inducible MHC class II expression by mast cells supports effector and regulatory T cell activation. Journal of Immunology, 182, 4686–4695.CrossRefGoogle Scholar
  195. 195.
    Gri, G., Piconese, S., Frossi, B., Manfroi, V., Merluzzi, S., Tripodo, C., et al. (2008). CD4(+)CD25(+) regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity, 29, 771–781.PubMedCrossRefGoogle Scholar
  196. 196.
    Yan, J., Wang, C., Du, R., Liu, P., & Chen, G. (2009). OX40-OX40 ligand interaction may activate phospholipase C signal transduction pathway in human umbilical vein endothelial cells. Chemistry & Biology Interact.Google Scholar
  197. 197.
    Liopeta, K., Boubali, S., Virgilio, L., Thyphronitis, G., Mavrothalassitis, G., Dimitracopoulos, G., et al. (2009). cAMP regulates IL-10 production by normal human T lymphocytes at multiple levels: A potential role for MEF2. Molecular Immunology, 46, 345–354.PubMedCrossRefGoogle Scholar
  198. 198.
    Forward, N. A., Furlong, S. J., Yang, Y., Lin, T. J., & Hoskin, D. W. (2009). Mast cells down-regulate CD4+CD25+ T regulatory cell suppressor function via histamine H1 receptor interaction. Journal of Immunology, 183, 3014–3022.CrossRefGoogle Scholar
  199. 199.
    Wang, H. C., & Klein, J. R. (2001). Multiple levels of activation of murine CD8(+) intraepithelial lymphocytes defined by OX40 (CD134) expression: Effects on cell-mediated cytotoxicity, IFN-gamma, and IL-10 regulation. Journal of Immunology, 167, 6717–6723.Google Scholar
  200. 200.
    Wang, H. C., Montufar-Solis, D., Teng, B. B., & Klein, J. R. (2004). Maximum immunobioactivity of murine small intestinal intraepithelial lymphocytes resides in a subpopulation of CD43+ T cells. Journal of Immunology, 173, 6294–6302.Google Scholar
  201. 201.
    Vu, M. D., Xiao, X., Gao, W., Degauque, N., Chen, M., Kroemer, A., et al. (2007). OX40 costimulation turns off Foxp3+ Treg. Blood, 110, 2501–2510.PubMedCrossRefGoogle Scholar
  202. 202.
    Colombo, M. P., & Piconese, S. (2009). Polyps wrap mast cells and Treg within tumorigenic tentacles. Cancer Research.Google Scholar
  203. 203.
    de Vries, V. C., Wasiuk, A., Bennett, K. A., Benson, M. J., Elgueta, R., Waldschmidt, T. J., et al. (2009). Mast cell degranulation breaks peripheral tolerance. American Journal of Transplantation, 9, 2270–2280.PubMedCrossRefGoogle Scholar
  204. 204.
    Piconese, S., Gri, G., Tripodo, C., Musio, S., Gorzanelli, A., Frossi, B., et al. (2009). Mast cells counteract regulatory T-cell suppression through interleukin-6 and OX40/OX40L axis toward Th17-cell differentiation. Blood, 114, 2639–2648.PubMedGoogle Scholar
  205. 205.
    Laurence, A., Tato, C. M., Davidson, T. S., Kanno, Y., Chen, Z., Yao, Z., et al. (2007). Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity, 26, 371–381.PubMedCrossRefGoogle Scholar
  206. 206.
    Korn, T., Bettelli, E., Oukka, M., & Kuchroo, V. K. (2009). IL-17 and Th17 Cells. Annual Review of Immunology, 27, 485–517.PubMedCrossRefGoogle Scholar
  207. 207.
    Asseman, C., Mauze, S., Leach, M. W., Coffman, R. L., & Powrie, F. (1999). An essential role for interleukin 10 in the function of regulatory T cells that inhibit intestinal inflammation. The Journal of Experimental Medicine, 190, 995–1004.PubMedCrossRefGoogle Scholar
  208. 208.
    Maloy, K. J., Salaun, L., Cahill, R., Dougan, G., Saunders, N. J., & Powrie, F. (2003). CD4+CD25+ T(R) cells suppress innate immune pathology through cytokine-dependent mechanisms. The Journal of Experimental Medicine, 197, 111–119.PubMedCrossRefGoogle Scholar
  209. 209.
    Erdman, S. E., Rao, V. P., Poutahidis, T., Ihrig, M. M., Ge, Z., Feng, Y., et al. (2003). CD4(+)CD25(+) regulatory lymphocytes require interleukin 10 to interrupt colon carcinogenesis in mice. Cancer Research, 63, 6042–6050.PubMedGoogle Scholar
  210. 210.
    Berg, D. J., Zhang, J., Weinstock, J. V., Ismail, H. F., Earle, K. A., Alila, H., et al. (2002). Rapid development of colitis in NSAID-treated IL-10-deficient mice. Gastroenterology, 123, 1527–1542.PubMedCrossRefGoogle Scholar
  211. 211.
    Brown, J. B., Lee, G., Managlia, E., Grimm, G. R., Dirisina, R., Goretsky, T., et al. (2010). Mesalamine inhibits epithelial beta-catenin activation in chronic ulcerative colitis. Gastroenterology, 138, 595–605, 605 e591–593.Google Scholar
  212. 212.
    Schaefer, J. S., Montufar-Solis, D., Vigneswaran, N., & Klein, J. R. (2010). ICOS promotes IL-17 synthesis in colonic intraepithelial lymphocytes in IL-10-/- mice. Journal of Leukocyte Biology, 87, 301–308.PubMedCrossRefGoogle Scholar
  213. 213.
    Lochner, M., Peduto, L., Cherrier, M., Sawa, S., Langa, F., Varona, R., et al. (2008). In vivo equilibrium of proinflammatory IL-17+ and regulatory IL-10+ Foxp3+ RORgamma t+T cells. The Journal of Experimental Medicine, 205, 1381–1393.PubMedCrossRefGoogle Scholar
  214. 214.
    Beriou, G., Costantino, C. M., Ashley, C. W., Yang, L., Kuchroo, V. K., Baecher-Allan, C., et al. (2009). IL-17-producing human peripheral regulatory T cells retain suppressive function. Blood, 113, 4240–4249.PubMedCrossRefGoogle Scholar
  215. 215.
    Miyara, M., Yoshioka, Y., Kitoh, A., Shima, T., Wing, K., Niwa, A., et al. (2009). Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity, 30, 899–911.PubMedCrossRefGoogle Scholar
  216. 216.
    Zhou, X., Bailey-Bucktrout, S., Jeker, L. T., & Bluestone, J. A. (2009). Plasticity of CD4(+) FoxP3(+) T cells. Current Opinion in Immunology, 21, 281–285.PubMedCrossRefGoogle Scholar
  217. 217.
    Yang, X. O., Nurieva, R., Martinez, G. J., Kang, H. S., Chung, Y., Pappu, B. P., et al. (2008). Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity, 29, 44–56.PubMedCrossRefGoogle Scholar
  218. 218.
    Weaver, C. T., Harrington, L. E., Mangan, P. R., Gavrieli, M., & Murphy, K. M. (2006). Th17: An effector CD4 T cell lineage with regulatory T cell ties. Immunity, 24, 677–688.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Khashayarsha Khazaie
    • 1
    • 2
    • 3
    • 5
  • Nichole R. Blatner
    • 1
    • 5
  • Mohammad Wasim Khan
    • 1
    • 5
  • Fotini Gounari
    • 6
  • Elias Gounaris
    • 1
    • 5
  • Kristen Dennis
    • 1
    • 5
  • Andreas Bonertz
    • 7
  • Fu-Nien Tsai
    • 1
    • 5
  • Matthew J. Strouch
    • 1
    • 4
  • Eric Cheon
    • 1
    • 4
  • Joseph D. Phillips
    • 1
    • 4
  • Philipp Beckhove
    • 8
  • David J. Bentrem
    • 1
    • 2
    • 4
  1. 1.Robert H. Lurie Comprehensive Cancer CenterNorthwestern University, Feinberg School of MedicineChicagoUSA
  2. 2.Jesse Brown Veterans Affairs Medical CenterChicagoUSA
  3. 3.Department of Microbiology-ImmunologyNorthwestern UniversityChicagoUSA
  4. 4.Department of SurgeryNorthwestern UniversityChicagoUSA
  5. 5.Department of Medicine, Division of GastroenterologyNorthwestern University, Feinberg School of MedicineChicagoUSA
  6. 6.Department of Medicine, Section of RheumatologyUniversity of ChicagoChicagoUSA
  7. 7.Division of Translational ImmunologyGerman Cancer Research Center and National Center for Tumor DiseasesHeidelbergGermany
  8. 8.Division of Translational ImmunologyNorthwestern University, Feinberg School of Medicine, German Cancer Research Center and National Center for Tumor DiseasesHeidelbergGermany

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