Polymorphonuclear neutrophils promote dyshesion of tumor cells and elastase‐mediated degradation of E‐cadherin in pancreatic tumors

Abstract

Pancreatic ductal adenocarcinoma (PDAC) presenting with a micropapillary growth pattern is frequently associated with a prominent neutrophil infiltration into the tumor. The relevance of neutrophil infiltrates for tumor progression, however, is still debated. To gain insight into the role of polymorphonuclear neutrophils (PMNs) in PDAC, we assessed their effect on pancreatic tumor cells grown in vitro as monolayers. Time-lapse video microscopy showed a PMN-induced dyshesion of the tumor cells, and subsequent experiments revealed that this dyshesion was due to PMN elastase-mediated degradation of E-cadherin, an adhesion molecule that mediates the intercellular contact of the tumor cells. E-cadherin degradation by elastase or -(for comparison) down-modulation by specific siRNA, significantly increased the migratory capacity of the pancreatic tumor cells, leading to the hypothesis that PMNs could contribute to the invasive tumor growth. To address this issue, biopsies of patients with PDAC (n = 112) were analyzed. We found that E-cadherin expression correlated negatively with PMN infiltration, compatible with the notion that E-cadherin is cleaved by PMN-derived elastase, which in turn could result in the dispersal of the tumor cells, enhanced migratory capacity and thus invasive tumor growth.Keywords: E-cadherin r Invasion r Pancreatic cancer r PMN elastase r Polymorphonuclear neutrophils Supporting Information available online IntroductionPancreatic ductal adenocarcinoma (PDAC) is the fourth most common cancer-related death in Western countries with a devasCorrespondence: Prof. Gertrud M. Hänsch e-mail: Maria.Haensch@urz-uni-heidelberg.de tating prognosis of an overall 5-year survival rate of less than 5% [1]. The dismal prognosis is due to the aggressive and invasive tumor growth, early metastasis, and resistance to radiation and chemotherapy [1,2]. A hallmark of pancreatic cancer is the distinct intratumoral inflammatory reaction, with an infiltration of T lymphocytes, macrophages [3][4][5]. Infiltration of polymorphonuclear neutrophils (PMNs) was described in PDAC and cancers of the periampullary region, where intratumor PMN infiltration was C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 3370 Matthias M. Gaida et al. Eur. J. Immunol. 2012. 42: 3369-3380 associated with a "micropapillary" and "scattered" growth pattern, poor histological differentiation and a poor prognosis [6,7]. The role of the PMNs in the tumor progression is controversially discussed, and not yet conclusively understood [3,8,9]. PMNs have the potential to kill tumor cells, either directly [10] or by Ab-dependent cell-mediated cytotoxicity [11]. However, adverse effects of PMNs such as the promotion of aggressive tumor growth and an increased metastatic potential have been described, for example, in mammary cancer [12,13]. An attractive hypothesis is that PMN-derived matrix-degrading proteases such as the metalloproteinases (MMP) 1, MMP2, and MMP9 or the neutrophil elastase [14][15][16] Results PMN-derived elastase...

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…However, neutrophils are also actively recruited into the tumor microenvironment in both cancer patients and mouse models of cancer. In humans, intratumoral infiltration of neutrophils has been detected in gastric carcinoma [200][201][202], bronchioloalveolar carcinoma [170,203], non-small cell lung carcinoma [204], pancreatic neoplasia [205], pancreatic ductal adenocarcinoma [206], bladder cancer [147], glioma [207], cervical carcinoma [139] and breast carcinoma [4,208] ( Table 1). The clinical consequences of intratumoral and circulating neutrophils in cancer patients will be discussed in "Prognostic Values of Neutrophils and Other Myeloid Subtypes in Cancer Patients" section.…”

“…Neutrophil recruitment to the inflamed submucosa was mediated by the chemokine CXCL2 through the neutrophil receptor CXCR2, resulting in increased neutrophil secretion of MMP-9 and neutrophil elastase, and consequent excessive angiogenesis and cell proliferation [261]. Elastase degrades barrier-forming proteins on epithelial cells [262] and neutrophil-derived elastase was found to degrade the adhesion molecule E-Cadherin on pancreatic ductal adenocarcinoma, leading to tumor cell dyshesion and increased migratory capacity [206]. Neutrophil infiltration of pancreatic ductal adenocarcinoma cells was also associated with epithelial-to-mesenchymal transition (EMT).…”

Neutrophils in cancer

“…Besides increasing proliferation, NE is also able to promote the detachment of tumor cells, which can lead to the formation of metastases. In pancreatic ductal adenocarcinoma, detachment of cancer cells was observed after addition of neutrophils or purified NE, which increased epithelial‐to‐mesenchymal transition and thereby enhanced tumor progression . This detachment was due to the degradation of E‐cadherin on the tumor cells.…”

Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells

“…PDAC is characterized by infiltration of polymorphonuclear neutrophils (PMNs) into the desmoplastic stroma in most cancer samples. PMN infiltration may create a proinflammatory microenvironment affecting tumor progression by diverse mechanisms (5,6).…”