Article

Soucek L, Lawlor ER, Soto D, Shchors K, Swigart LB, Evan GI.. Mast cells are required for angiogenesis and macroscopic expansion of Myc-induced pancreatic islet tumors. Nat Med 13: 1211-1218

Cancer Research Institute and Department of Pathology, University of California San Francisco, 2340 Sutter Street, San Francisco, California 94143-0875, USA.
Nature Medicine (Impact Factor: 27.36). 11/2007; 13(10):1211-8. DOI: 10.1038/nm1649
Source: PubMed

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 beta-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 beta-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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Available from: Elizabeth R Lawlor, May 12, 2014
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    • "Based on these results, treatment with cromolyn, an inhibitor of MCs degranulation, has been shown to restrain expansion and survival of pancreatic cancer and endothelial cells [15]. Tryptase and chymase are preformed active serine proteases and are stored in large amounts in MCs secretory granules [74], whose angiogenic role has been established [16] [75]. "
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    • "Based on these results, treatment with cromolyn, an inhibitor of MCs degranulation, has been shown to restrain expansion and survival of pancreatic cancer and endothelial cells [15]. Tryptase and chymase are preformed active serine proteases and are stored in large amounts in MCs secretory granules [74], whose angiogenic role has been established [16] [75]. "
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    ABSTRACT: Angiogenesis is a complex process finely regulated by the balance between angiogenesis stimulators and inhibitors. As a result of proangiogenic factors overexpression, it plays a crucial role in cancer development. Although initially mast cells (MCs) role has been defined in hypersensitivity reactions and in immunity, it has been discovered that MCs have a crucial interplay on the regulatory function between inflammatory and tumor cells through the release of classical proangiogenic factors (e.g., vascular endothelial growth factor) and nonclassical proangiogenic mediators granule-associated (mainly tryptase). In fact, in several animal and human malignancies, MCs density is highly correlated with tumor angiogenesis. In particular, tryptase, an agonist of the proteinase-activated receptor-2 (PAR-2), represents one of the most powerful angiogenic mediators released by human MCs after c-Kit receptor activation. This protease, acting on PAR-2 by its proteolytic activity, has angiogenic activity stimulating both human vascular endothelial and tumor cell proliferation in paracrine manner, helping tumor cell invasion and metastasis. Based on literature data it is shown that tryptase may represent a promising target in cancer treatment due to its proangiogenic activity. Here we focused on molecular mechanisms of three tryptase inhibitors (gabexate mesylate, nafamostat mesylate, and tranilast) in order to consider their prospective role in cancer therapy.
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    • "This is potentially governed by the unique genetic and cellular context of each tumor [81,82]. In other mouse models, investigators have noted that innate immune cells such as mast cells [83], macrophages [84], and other antigen-presenting cells (APCs) may function as barriers to tumor growth and facilitators of tumor regression. Thus, it is likely that these other innate and adaptive immune cells contribute to the mechanism of oncogene addiction and tumor regression following oncogene inactivation. "
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