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Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors

Abstract

An association between inflammation and cancer has long been recognized, but the cause and effect relationship linking the two remains unclear. Myc is a pleiotropic transcription factor that is overexpressed in many human cancers and instructs many extracellular aspects of the tumor tissue phenotype, including remodeling of tumor stroma and angiogenesis. Here we show in a β-cell tumor model that activation of Myc in vivo triggers rapid recruitment of mast cells to the tumor site—a recruitment that is absolutely required for macroscopic tumor expansion. In addition, treatment of established β-cell tumors with a mast cell inhibitor rapidly triggers hypoxia and cell death of tumor and endothelial cells. Inhibitors of mast cell function may therefore prove therapeutically useful in restraining expansion and survival of pancreatic and other cancers.

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Figure 1: Activation of Myc in β cells triggers rapid recruitment of mast cells to islet-associated stroma.
Figure 2: Myc-driven β-cell tumors do not expand in mice lacking mast cell function.
Figure 3: Myc-induced β-cell proliferation, transformation and de-differentiation are unaffected by mast cell status.
Figure 4: Expansion of Myc-induced tumors in mice lacking mast cell function is restrained by β-cell death, hypoxia and lack of elaborated vasculature.
Figure 5: Lack of mast cells impairs endothelial cell proliferation after sustained Myc activation.
Figure 6: Systemic cromolyn treatment induces hypoxia and apoptosis in established Myc-dependent islet tumors.

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References

  1. Dvorak, H.F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  Google Scholar 

  2. Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

    Article  CAS  Google Scholar 

  3. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).

    Article  CAS  Google Scholar 

  4. Griffioen, A.W. & Molema, G. Angiogenesis: potentials for pharmacologic intervention in the treatment of cancer, cardiovascular diseases, and chronic inflammation. Pharmacol. Rev. 52, 237–268 (2000).

    CAS  PubMed  Google Scholar 

  5. Bernardini, G. et al. Analysis of the role of chemokines in angiogenesis. J. Immunol. Methods 273, 83–101 (2003).

    Article  CAS  Google Scholar 

  6. Vicari, A.P. & Caux, C. Chemokines in cancer. Cytokine Growth Factor Rev. 13, 143–154 (2002).

    Article  CAS  Google Scholar 

  7. Pelengaris, S., Littlewood, T., Khan, M., Elia, G. & Evan, G. Reversible activation of c-Myc in skin: induction of a complex neoplastic phenotype by a single oncogenic lesion. Mol. Cell 3, 565–577 (1999).

    Article  CAS  Google Scholar 

  8. Pelengaris, S., Khan, M. & Evan, G.I. Suppression of Myc-induced apoptosis in beta cells exposes multiple oncogenic properties of Myc and triggers carcinogenic progression. Cell 109, 321–334 (2002).

    Article  CAS  Google Scholar 

  9. Shchors, K. et al. The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β. Genes Dev. 20, 2527–2538 (2006).

    Article  CAS  Google Scholar 

  10. Lawlor, E.R. et al. Reversible kinetic analysis of Myc targets in vivo provides novel insights into Myc-mediated tumorigenesis. Cancer Res. 66, 4591–4601 (2006).

    Article  CAS  Google Scholar 

  11. Scapini, P. et al. CXCL1/macrophage inflammatory protein-2-induced angiogenesis in vivo is mediated by neutrophil-derived vascular endothelial growth factor-A. J. Immunol. 172, 5034–5040 (2004).

    Article  CAS  Google Scholar 

  12. Michalec, L. et al. CCL7 and CXCL10 orchestrate oxidative stress–induced neutrophilic lung inflammation. J. Immunol. 168, 846–852 (2002).

    Article  CAS  Google Scholar 

  13. Belo, A.V. et al. Murine chemokine CXCL2/KC is a surrogate marker for angiogenic activity in the inflammatory granulation tissue. Microcirculation 12, 597–606 (2005).

    Article  CAS  Google Scholar 

  14. Amann, B., Perabo, F.G., Wirger, A., Hugenschmidt, H. & Schultze-Seemann, W. Urinary levels of monocyte chemo-attractant protein-1 correlate with tumour stage and grade in patients with bladder cancer. Br. J. Urol. 82, 118–121 (1998).

    Article  CAS  Google Scholar 

  15. Fischer, M. et al. Expression of CCL5/RANTES by Hodgkin and Reed-Sternberg cells and its possible role in the recruitment of mast cells into lymphomatous tissue. Int. J. Cancer 107, 197–201 (2003).

    Article  CAS  Google Scholar 

  16. Robinson, S.C. & Coussens, L.M. Soluble mediators of inflammation during tumor development. Adv. Cancer Res. 93, 159–187 (2005).

    Article  CAS  Google Scholar 

  17. Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S. & Ruco, L. The origin and function of tumor-associated macrophages. Immunol. Today 13, 265–270 (1992).

    Article  CAS  Google Scholar 

  18. Norrby, K. Mast cells and angiogenesis. APMIS 110, 355–371 (2002).

    Article  CAS  Google Scholar 

  19. Kanbe, N. et al. Human mast cells produce matrix metalloproteinase 9. Eur. J. Immunol. 29, 2645–2649 (1999).

    Article  CAS  Google Scholar 

  20. Toth, T., Toth-Jakatics, R., Jimi, S. & Takebayashi, S. Increased density of interstitial mast cells in amyloid A renal amyloidosis. Mod. Pathol. 13, 1020–1028 (2000).

    Article  CAS  Google Scholar 

  21. Sawatsubashi, M. et al. Association of vascular endothelial growth factor and mast cells with angiogenesis in laryngeal squamous cell carcinoma. Virchows Arch. 436, 243–248 (2000).

    Article  CAS  Google Scholar 

  22. Coussens, L.M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).

    Article  CAS  Google Scholar 

  23. Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).

    Article  CAS  Google Scholar 

  24. Thompson, P.J., Hanson, J.M. & Morley, J. Asthma, mast cells, and sodium cromoglycate. Lancet 2, 848–849 (1983).

    Article  CAS  Google Scholar 

  25. Nagle, D.L., Kozak, C.A., Mano, H., Chapman, V.M. & Bucan, M. Physical mapping of the Tec and Gabrb1 loci reveals that the Wsh mutation on mouse chromosome 5 is associated with an inversion. Hum. Mol. Genet. 4, 2073–2079 (1995).

    Article  CAS  Google Scholar 

  26. Wolters, P.J. et al. Tissue-selective mast cell reconstitution and differential lung gene expression in mast cell–deficient KitW-sh/KitW-sh sash mice. Clin. Exp. Allergy 35, 82–88 (2005).

    Article  CAS  Google Scholar 

  27. Grimbaldeston, M.A. et al. Mast cell–deficient W-sash c-kit mutant KitW-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 167, 835–848 (2005).

    Article  CAS  Google Scholar 

  28. Duttlinger, R. et al. W-sash affects positive and negative elements controlling c-kit expression: ectopic c-kit expression at sites of kit-ligand expression affects melanogenesis. Development 118, 705–717 (1993).

    CAS  PubMed  Google Scholar 

  29. Bonner-Weir, S. Perspective: postnatal pancreatic beta cell growth. Endocrinology 141, 1926–1929 (2000).

    Article  CAS  Google Scholar 

  30. Bonner-Weir, S. Life and death of the pancreatic beta cells. Trends Endocrinol. Metab. 11, 375–378 (2000).

    Article  CAS  Google Scholar 

  31. Laybutt, D.R. et al. Overexpression of c-Myc in β-cells of transgenic mice causes proliferation and apoptosis, downregulation of insulin gene expression, and diabetes. Diabetes 51, 1793–1804 (2002).

    Article  CAS  Google Scholar 

  32. Kaneto, H. et al. Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD/BETA2-mediated transcriptional activation. J. Biol. Chem. 277, 12998–13006 (2002).

    Article  CAS  Google Scholar 

  33. Folkman, J. Angiogenesis. Annu. Rev. Med. 57, 1–18 (2006).

    Article  CAS  Google Scholar 

  34. Bot, I. et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E–deficient mice. Circulation 115, 2516–2525 (2007).

    Article  CAS  Google Scholar 

  35. Kopp, H.G., Ramos, C.A. & Rafii, S. Contribution of endothelial progenitors and proangiogenic hematopoietic cells to vascularization of tumor and ischemic tissue. Curr. Opin. Hematol. 13, 175–181 (2006).

    Article  CAS  Google Scholar 

  36. Rubin, B.P. et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 61, 8118–8121 (2001).

    CAS  PubMed  Google Scholar 

  37. Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).

    Article  CAS  Google Scholar 

  38. Sperling, C., Schwartz, S., Buchner, T., Thiel, E. & Ludwig, W.D. Expression of the stem cell factor receptor C-KIT (CD117) in acute leukemias. Haematologica 82, 617–621 (1997).

    CAS  PubMed  Google Scholar 

  39. Escribano, L., Ocqueteau, M., Almeida, J., Orfao, A. & San Miguel, J.F. Expression of the c-kit (CD117) molecule in normal and malignant hematopoiesis. Leuk. Lymphoma 30, 459–466 (1998).

    Article  CAS  Google Scholar 

  40. Zhang, R. et al. Mob-1, a Ras target gene, is overexpressed in colorectal cancer. Oncogene 14, 1607–1610 (1997).

    Article  CAS  Google Scholar 

  41. Borrello, M.G. et al. Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene. Proc. Natl. Acad. Sci. USA 102, 14825–14830 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank P. Besmer (Memorial Sloan-Kettering Institute) for C57BL/6 KitW-sh;KitW-sh mice; F. Rostker, G. Reyes and N. Sheehy (BMS program, UCSF) for technical assistance; K. De Visser, S. Robinson, L. Coussens and D. Hanahan for advice; G. Spinetti for informed comments; and our colleagues for feedback. This work was supported by grants from the National Institutes of Health (NIH) National Cancer Institute (CA098018) and the Juvenile Diabetes Research Foundation (grant 4-2004-372) and by an NIH Fellowship (F32 CA106039) to K.S.

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Correspondence to Gerard I Evan.

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Soucek, L., Lawlor, E., Soto, D. et al. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13, 1211–1218 (2007). https://doi.org/10.1038/nm1649

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