Mast Cell Tryptase Contributes to Pancreatic Cancer Growth through Promoting Angiogenesis via Activation of Angiopoietin-1

Abstract

Pancreatic cancer is a highly lethal malignancy and one of the leading causes of cancer-related death. During the development and progression of cancer, tumor angiogenesis plays a crucial role. A great deal of evidence has revealed that human mast cells (MCs) contributed to tumor angiogenesis through releasing several pro-angiogenetic factors, among which tryptase is one of the most active. However, the role of mast cell tryptase (MCT) in human pancreatic cancer angiogenesis is still not well documented. In this study, we examined the MCT levels in serum from pancreatic cancer patients and evaluated the correlationship of the MCT level and tumor angiogenesis. In addition, the effect of MCT on endothelial cell proliferation and tube formation was investigated both in vitro and in nude mice bearing pancreatic tumor. It was found that MCT contributes to endothelial cell growth and tube formation via up-regulation of angiopoietin-1 expression. Moreover, using the MCT inhibitor nafamostat, tryptase-induced angiogenesis was obviously suppressed both in vitro and in vivo. Our findings suggest that MCT plays an important role in pancreatic cancer angiogenesis and tumor growth via activating the angiopoietin-1 pathway, and tryptase inhibitors may be evaluated as an effective anti-angiogenetic approach in pancreatic cancer therapy.

Role of Mast Cells in Shaping the Tumor Microenvironment

“…There is a number of angiogenic mediators released by MCs in the tumor microenvironment including IL-8, NGF, TNF-α, TGF-β, and urokinase-type plasminogen activator (PA) [3]. MC tryptase promotes the proliferation of endothelial cells [26], facilitates the in vitro vascular tube formation, and degrades the matrix of connective tissue to create adequate space for neovascular development [3]. Additionally, histamine acting on H1R and H2R stimulates the formation of new vessels [3].…”

Integrative Epigenomic and Transcriptomic Analysis Reveals Robust Metabolic Switching in the Brain During Intermittent Fasting

“…Indeed, global metabolic mapping revealed different metabolic profiles in IF16 and EOD, with asymmetrical trigger of different milieu of carbohydrate, lipid, and protein cellular metabolic pathways, as well as performing varying degrees of anabolism and catabolism of these macromolecules. While most of the signalling pathways have been previously reported to be influenced by fasting (Ahima et al, 2006;Bujak et al, 2015;Choi et al, 2018;Dogan et al, 2011;Goldstein et al, 2016;Guo et al, 2016;Jensen et al, 2019;Kim, 2009;Li et al, 2019;Luo et al, 2018;Mahadik, 2012;Martins et al, 2016;Miyazaki et al, 2004;Morikawa et al, 2004;Nicklin et al, 2013;Pel and Lines, 2015;Rodrı et al, 2012;Tulsian et al, 2018;Wee and Wang, 2017;Wijngaarden et al, 2019;Yoon et al, 2018), our findings suggest a temporal link of the signaling response to the period of energy restriction. This is achieved by manipulating the epigenetic and transcriptomic cascade differently, which in turn results in varied metabolic arms being triggered to respond to energy demand.…”

A qualitative transcriptional prognostic signature for patients with stage I-II pancreatic ductal adenocarcinoma

“…56 Another low expression gene, ANGPT1, interacted with 3 genes in 64-GPS and mutated in 50% of high-risk patients and in only 7.14% of low-risk patients, which may be an important underlying regulator that involved in MCT-induced angiogenesis in pancreatic cancer. 57 These results suggested that mutation-induced disturbances in these genes might lead to poor prognosis for PDAC patients.…”