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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Accession codes
References
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).
Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).
Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86, 353–364 (1996).
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).
Bernardini, G. et al. Analysis of the role of chemokines in angiogenesis. J. Immunol. Methods 273, 83–101 (2003).
Vicari, A.P. & Caux, C. Chemokines in cancer. Cytokine Growth Factor Rev. 13, 143–154 (2002).
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).
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).
Shchors, K. et al. The Myc-dependent angiogenic switch in tumors is mediated by interleukin 1β. Genes Dev. 20, 2527–2538 (2006).
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).
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).
Michalec, L. et al. CCL7 and CXCL10 orchestrate oxidative stress–induced neutrophilic lung inflammation. J. Immunol. 168, 846–852 (2002).
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).
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).
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).
Robinson, S.C. & Coussens, L.M. Soluble mediators of inflammation during tumor development. Adv. Cancer Res. 93, 159–187 (2005).
Mantovani, A., Bottazzi, B., Colotta, F., Sozzani, S. & Ruco, L. The origin and function of tumor-associated macrophages. Immunol. Today 13, 265–270 (1992).
Norrby, K. Mast cells and angiogenesis. APMIS 110, 355–371 (2002).
Kanbe, N. et al. Human mast cells produce matrix metalloproteinase 9. Eur. J. Immunol. 29, 2645–2649 (1999).
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).
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).
Coussens, L.M. et al. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397 (1999).
Bergers, G. et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat. Cell Biol. 2, 737–744 (2000).
Thompson, P.J., Hanson, J.M. & Morley, J. Asthma, mast cells, and sodium cromoglycate. Lancet 2, 848–849 (1983).
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).
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).
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).
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).
Bonner-Weir, S. Perspective: postnatal pancreatic beta cell growth. Endocrinology 141, 1926–1929 (2000).
Bonner-Weir, S. Life and death of the pancreatic beta cells. Trends Endocrinol. Metab. 11, 375–378 (2000).
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).
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).
Folkman, J. Angiogenesis. Annu. Rev. Med. 57, 1–18 (2006).
Bot, I. et al. Perivascular mast cells promote atherogenesis and induce plaque destabilization in apolipoprotein E–deficient mice. Circulation 115, 2516–2525 (2007).
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).
Rubin, B.P. et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 61, 8118–8121 (2001).
Hirota, S. et al. Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. Science 279, 577–580 (1998).
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).
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).
Zhang, R. et al. Mob-1, a Ras target gene, is overexpressed in colorectal cancer. Oncogene 14, 1607–1610 (1997).
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).
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.
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figs. 1–8 (PDF 6909 kb)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nm1649
This article is cited by
-
The effects of MYC on tumor immunity and immunotherapy
Cell Death Discovery (2023)
-
Mechanisms of obesity- and diabetes mellitus-related pancreatic carcinogenesis: a comprehensive and systematic review
Signal Transduction and Targeted Therapy (2023)
-
LncRNA BCAN-AS1 stabilizes c-Myc via N6-methyladenosine-mediated binding with SNIP1 to promote pancreatic cancer
Cell Death & Differentiation (2023)
-
Inflammation and tumor progression: signaling pathways and targeted intervention
Signal Transduction and Targeted Therapy (2021)
-
Effect of chemotherapy on cancer stem cells and tumor-associated macrophages in a prospective study of preoperative chemotherapy in soft tissue sarcoma
Journal of Translational Medicine (2019)