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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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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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