Editorial Open Access
Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 21, 2024; 30(23): 2927-2930
Published online Jun 21, 2024. doi: 10.3748/wjg.v30.i23.2927
Relationship between mast cell, angiogenesis and pancreatic cancer: Our experience
Francesca Vescio, Giuseppe Currò, Silvia Curcio, Science of Health Department, General Surgery Unit, University “Magna Graecia” Medical School, University Hospital “R. Dulbecco”, Catanzaro 88100, Italy
Michele Ammendola, Science of Health Department, Digestive Surgery Unit, University “Magna Graecia” Medical School, University Hospital “R. Dulbecco”, Catanzaro 88100, Italy
ORCID number: Francesca Vescio (0000-0002-0929-1671); Michele Ammendola (0000-0001-8043-6100); Giuseppe Currò (0000-0001-9566-1378).
Author contributions: Ammendola M initiated the idea of writing up the editorial; Vescio F and Curcio S contributed to the manuscript writing equally and performed the bibliographic search; Currò G revised the final paper; All authors have read and approved the final version of the manuscript.
Conflict-of-interest statement: All the authors report having no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Michele Ammendola, MD, Professor, Science of Health Department, Digestive Surgery Unit, University “Magna Graecia” Medical School, University Hospital “R. Dulbecco”, Viale Europa Loc Germaneto, Catanzaro 88100, Italy. michele.ammendola@unicz.it
Received: January 13, 2024
Revised: May 4, 2024
Accepted: May 27, 2024
Published online: June 21, 2024
Processing time: 159 Days and 5.9 Hours


In this editorial, we focus specifically on the mechanisms by which pancreatic inflammation affects pancreatic cancer. Cancer of the pancreas remains one of the deadliest cancer types. The highest incidence and mortality rates of pancreatic cancer are found in developed countries. Trends of pancreatic cancer incidence and mortality vary considerably worldwide. A better understanding of the etiology and identification of the risk factors is essential for the primary prevention of this disease. Pancreatic tumors are characterized by a complex microenvironment that orchestrates metabolic alterations and supports a milieu of interactions among various cell types within this niche. In this editorial, we highlight the foundational studies that have driven our understanding of these processes. In our experimental center, we have carefully studied the mechanisms of that link pancreatic inflammation and pancreatic cancer. We focused on the role of mast cells (MCs). MCs contain pro-angiogenic factors, including tryptase, that are associated with increased angiogenesis in various tumors. In this editorial, we address the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue. The assessment includes the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and angiogenesis in terms of microvascularization density.

Key Words: Mast cells, C-Kit receptor, Tryptase, Angiogenesis, Microvascular density, Endothelial area, Pancreatic tumor tissue, Adjacent normal tissue

Core Tip: This editorial focuses on the mechanisms that link pancreatic inflammation to pancreatic cancer. Pancreatic cancer remains one of the most aggressive pathologies. A better understanding of its etiology and the identification of risk factors is essential for primary prevention. Mast cells (MCs) contain pro-angiogenic factors, particularly tryptase, that are associated with increased angiogenesis. We evaluated the role of MCs in angiogenesis in both pancreatic ductal adenocarcinoma tissue and adjacent normal tissue by assessing the density of c-Kit receptor-positive MCs, the density of tryptase-positive MCs, the area of tryptase-positive MCs, and microvascularization density.


The pancreas is an organ belonging to the digestive system located in the retroperitoneum. Its location makes it difficult to access both in instrumental diagnostics and in the surgical approach. Pancreatic acinar cells secrete digestive enzymes including amylase, which digests carbohydrates; lipase, which breaks down fats; and trypsin and chymotrypsin, which digest proteins. The endocrine component is made up of islet cells that release insulin and glucagon to maintain glycemic balance[1]. The pancreas has a good reserve capacity, and the loss of its functionality is recognized only when the majority of the gland has been destroyed. The exocrine portion of the gland can suffer from three main diseases, acute pancreatitis (AP), chronic pancreatitis (CP), and pancreatic ductal adenocarcinoma (PDAC)[2]. In this editorial we will review the mechanisms linking CP and pancreatic cancer, outlining the possible causes involved in the transformation from benign to malignant pancreatic disease to achieve an early diagnosis.

PDAC, has a poor prognosis due to late diagnosis, early metastases, and resistance to therapy. Although there have been improvements in both diagnosis and treatment in recent years, the outcomes remain poor, with a 5-year overall survival of only 10.8% Surgery remains the only potential cure for resectable PDAC. Pancreatitis is a fibro-inflammatory disorder of the pancreas that involves the activation of digestive enzymes in the pancreas prior to their release into the small intestine, resulting in parenchymal injury, inflammation, and abdominal pain. AP or CP may be related to autoimmunity or hyperlipidemia. A controlled diet and reduction of alcoholic beverages and cigarette smoking are useful in limiting the progression of pancreatitis from acute to chronic[4]. Repeated episodes of AP lead to CP, in which irregular secretion and premature activation of enzymes result in increased damage to the residual pancreas, resulting in severe maldigestion and diabetes.

Histopathological features of CP include chronic inflammation, acinar atrophy, adipose tissue replacement, fibrosis, and abnormal ducts[5,6]. Pancreatitis has been shown to be a risk factor for pancreatic cancer[7-9]. In the pathophysiology of AP and CP, oxidative stress and the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS) lead to necrosis and fibrosis of acinar cells. ROS and RNS cause DNA fragmentation, membrane disintegration, and protein misfolding. They also activate the immune system. Immune cells and other stromal components produce inflammatory cytokines and chemokines which, together with ROS and RNS, cause epithelial cell damage and increased proliferation[10]. Cytokines operate in cell signaling and are the primary operators in defining the inflammation state of the tumor microenvironment[11,12]. In a recent study, Lanki et al[13] analyzed 231 patients, 186 with stage I-III PDAC and 45 with CP with a serum panel including 48 inflammatory cytokines, carbohydrate antigen 19-9 (CA19-9), and C-reactive protein (CRP) to identify differences the inflammatory cytokines present in the two pathologies. They concluded that the inflammatory cytokines CTACK, GRO-α, and β-NGF together with CA19-9 and CRP may help distinguish PDAC from CP. Other inflammatory mediators, such as cyclooxygenase-2, NF-B, and STAT3, were involved in inflammatory infiltration and damage of acinar cells[14]. Numerous studies have highlighted how inflammatory stimuli in animals carrying an oncogenic Kras mutation activate a positive feedback mechanism that amplifies Ras activity to pathological levels and triggers chronic inflammation and preneoplastic lesions[15]. Ling et al[16] demonstrated that the Kras oncogene induces the constitutive activation of signals necessary for the establishment of PDAC. Finally, another study demonstrated that in the presence of a Kras mutant, TNF-α-induced activation of the NF-B pathway maintained transformed cells in a constant inflammatory state[17]. The immune system has great potential for reducing tumors, but its dysregulation can lead to tumor spread and reduced survival of individuals.


At our research center, we have studied the mechanisms that link pancreatitis and pancreatic cancer in detail. We have focused on the role of mast cells (MCs), which are bone marrow-derived cells found in many human organs and tissues and contain many pre-existing and newly formed secretory granules with specific pleiotropic functions[18].

The function of MC is especially regulated by their membrane receptor tyrosine kinase, the c-Kit receptor (c-Kit-R), which naturally binds stem cell factor. After activation by various stimuli[19], MCs release their secretory granules into the microenvironment. Recently, various research groups have shown that MCs contain several pro-angiogenic factors and synthesize and secrete a potent pro-angiogenic factor called tryptase. Tryptase is the most abundant factor stored in the secretory granules of MCs it can stimulate microvessel formation. Our studies have used immunohistochemistry and image analysis to determine the concentration of MCs positive for c-Kit-R, the number of MCs positive for tryptase, the area of MC-positive tryptase, microvascular density (MVD), and endothelial area in a series of pancreatic cancer patients undergoing radical surgery. The correlation between the parameters studied and the main clinical and pathological characteristics was also investigated[20-22].


Conclusions from these preliminary data suggest that MC granules contain many protease enzymes that, by different mechanisms, induce the formation of new microvessels that supply the tumor load. Numerous studies suggest that MC density growth is associated with MVD growth in several malignancies. A study of survival of patients with resected pancreatic cancer demonstrated that high expression of MVD was closely associated with a worse prognosis[23]. Preliminary in vivo/in vitro results have been obtained by other researchers. Their data suggest that therapeutic targeting of MC degranulation factors could be a novel strategy to inhibit tumor growth and neo-angiogenesis.


Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Surgery

Country of origin: Italy

Peer-review report’s classification

Scientific Quality: Grade B

Novelty: Grade B

Creativity or Innovation: Grade B

Scientific Significance: Grade B

P-Reviewer: Miao ZR, China S-Editor: Chen YL L-Editor: Filipodia P-Editor: Zheng XM

1.  Kandikattu HK, Venkateshaiah SU, Mishra A. Chronic Pancreatitis and the Development of Pancreatic Cancer. Endocr Metab Immune Disord Drug Targets. 2020;20:1182-1210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 5]  [Cited by in F6Publishing: 26]  [Article Influence: 8.7]  [Reference Citation Analysis (0)]
2.  Raimondi S, Lowenfels AB, Morselli-Labate AM, Maisonneuve P, Pezzilli R. Pancreatic cancer in chronic pancreatitis; aetiology, incidence, and early detection. Best Pract Res Clin Gastroenterol. 2010;24:349-358.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 402]  [Cited by in F6Publishing: 408]  [Article Influence: 29.1]  [Reference Citation Analysis (0)]
3.  Jones CE, Sharick JT, Sizemore ST, Cukierman E, Strohecker AM, Leight JL. A miniaturized screening platform to identify novel regulators of extracellular matrix alignment. Cancer Res Commun. 2022;2:1471-1486.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Reference Citation Analysis (0)]
4.  Larusch J, Whitcomb D. Atypical CFTR variants impact pancreatitis and male infertility in the North American pancreatitis study. J Cyst Fibros. 2011;10:S3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
5.  Łukaszewicz-Zając M, Gryko M, Mroczko B. The role of selected chemokines and their specific receptors in pancreatic cancer. Int J Biol Markers. 2018;33:141-147.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 11]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
6.  Szatmary P, Gukovsky I.   The role of cytokines and inflammation in the genesis of experimental pancreatitis. 2016. [cited 1 May 2024]. Available from: https://www.pancreapedia.org/reviews/role-of-cytokines-and-inflammation-in-genesis-of-experimental-pancreatitis.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Finn OJ. Immuno-oncology: understanding the function and dysfunction of the immune system in cancer. Ann Oncol. 2012;23 Suppl 8:viii6-viii9.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 324]  [Cited by in F6Publishing: 379]  [Article Influence: 34.5]  [Reference Citation Analysis (0)]
8.  McKay CJ, Glen P, McMillan DC. Chronic inflammation and pancreatic cancer. Best Pract Res Clin Gastroenterol. 2008;22:65-73.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 83]  [Cited by in F6Publishing: 87]  [Article Influence: 5.4]  [Reference Citation Analysis (0)]
9.  Korpela T, Udd M, Mustonen H, Ristimäki A, Haglund C, Seppänen H, Kylänpää L. Association between chronic pancreatitis and pancreatic cancer: A 10-year retrospective study of endoscopically treated and surgical patients. Int J Cancer. 2020;147:1450-1460.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 14]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
10.  Pinho AV, Chantrill L, Rooman I. Chronic pancreatitis: a path to pancreatic cancer. Cancer Lett. 2014;345:203-209.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 95]  [Cited by in F6Publishing: 103]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
11.  Zeh HJ, Winikoff S, Landsittel DP, Gorelik E, Marrangoni AM, Velikokhatnaya L, Winans MT, Lee K, Moser A, Bartlett D, Lotze MT, Siegfried JM, Whitcomb D, Papacristou G, Slivka A, Bigbee WL, Lokshin AE. Multianalyte profiling of serum cytokines for detection of pancreatic cancer. Cancer Biomark. 2005;1:259-269.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 24]  [Cited by in F6Publishing: 26]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
12.  Mroczko B, Groblewska M, Gryko M, Kedra B, Szmitkowski M. Diagnostic usefulness of serum interleukin 6 (IL-6) and C-reactive protein (CRP) in the differentiation between pancreatic cancer and chronic pancreatitis. J Clin Lab Anal. 2010;24:256-261.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 76]  [Cited by in F6Publishing: 84]  [Article Influence: 6.0]  [Reference Citation Analysis (0)]
13.  Lanki M, Mustonen H, Salmi M, Jalkanen S, Haglund C, Seppänen H. Serum cytokine profiles in patients with pancreatic cancer and chronic pancreatitis. Pancreatology. 2023;23:657-662.  [PubMed]  [DOI]  [Cited in This Article: ]  [Reference Citation Analysis (0)]
14.  Leung PS, Chan YC. Role of oxidative stress in pancreatic inflammation. Antioxid Redox Signal. 2009;11:135-165.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 182]  [Cited by in F6Publishing: 185]  [Article Influence: 12.3]  [Reference Citation Analysis (0)]
15.  Daniluk J, Liu Y, Deng D, Chu J, Huang H, Gaiser S, Cruz-Monserrate Z, Wang H, Ji B, Logsdon CD. An NF-κB pathway-mediated positive feedback loop amplifies Ras activity to pathological levels in mice. J Clin Invest. 2012;122:1519-1528.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 196]  [Cited by in F6Publishing: 212]  [Article Influence: 17.7]  [Reference Citation Analysis (0)]
16.  Ling J, Kang Y, Zhao R, Xia Q, Lee DF, Chang Z, Li J, Peng B, Fleming JB, Wang H, Liu J, Lemischka IR, Hung MC, Chiao PJ. KrasG12D-induced IKK2/β/NF-κB activation by IL-1α and p62 feedforward loops is required for development of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:105-120.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 388]  [Cited by in F6Publishing: 390]  [Article Influence: 32.5]  [Reference Citation Analysis (0)]
17.  Maniati E, Bossard M, Cook N, Candido JB, Emami-Shahri N, Nedospasov SA, Balkwill FR, Tuveson DA, Hagemann T. Crosstalk between the canonical NF-κB and Notch signaling pathways inhibits Pparγ expression and promotes pancreatic cancer progression in mice. J Clin Invest. 2011;121:4685-4699.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 170]  [Cited by in F6Publishing: 190]  [Article Influence: 14.6]  [Reference Citation Analysis (0)]
18.  Marshall JS. Mast-cell responses to pathogens. Nat Rev Immunol. 2004;4:787-799.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 576]  [Cited by in F6Publishing: 586]  [Article Influence: 29.3]  [Reference Citation Analysis (0)]
19.  Ammendola M, Gadaleta CD, Frampton AE, Piardi T, Memeo R, Zuccalà V, Luposella M, Patruno R, Zizzo N, Gadaleta P, Pessaux P, Sacco R, Sammarco G, Ranieri G. The density of mast cells c-Kit(+) and tryptase(+) correlates with each other and with angiogenesis in pancreatic cancer patients. Oncotarget. 2017;8:70463-70471.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 12]  [Cited by in F6Publishing: 13]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
20.  Ntellas P, Dadouli K, Perivoliotis K, Sogka E, Pentheroudakis G, Ioannou M, Hadjichristodoulou C, Tepetes K, Mauri D. Microvessel Density and Impact of Angiogenesis on Survival of Resected Pancreatic Cancer Patients: A Systematic Review and Meta-analysis. Pancreas. 2019;48:233-241.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
21.  Ribatti D, Ranieri G, Basile A, Azzariti A, Paradiso A, Vacca A. Tumor endothelial markers as a target in cancer. Expert Opin Ther Targets. 2012;16:1215-1225.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 2.1]  [Reference Citation Analysis (0)]
22.  Ranieri G. Hot topic: targeting tumor angiogenesis: an update. Curr Med Chem. 2012;19:937.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 14]  [Article Influence: 1.2]  [Reference Citation Analysis (0)]
23.  Ammendola M, Sacco R, Sammarco G, Donato G, Zuccalà V, Luposella M, Patruno R, Marech I, Montemurro S, Zizzo N, Gadaleta CD, Ranieri G. Mast cells density positive to tryptase correlates with angiogenesis in pancreatic ductal adenocarcinoma patients having undergone surgery. Gastroenterol Res Pract. 2014;2014:951957.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 29]  [Cited by in F6Publishing: 36]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]