*Renata Talar-Wojnarowska1, Łukasz Durko1, Małgorzata Woźniak1, Magdalena Kujawiak2, Janina Grzegorczyk2, Marek Olakowski3, Paweł Lampe3, Ewa Małecka-Panas1
Clinical significance of cathelicidin antimicrobial peptide in patients with pancreatic cancer**
Kliniczne znaczenie katelicydyny u chorych na raka trzustki
1Department of Digestive Tract Diseases, Medical University of Łódź
Head of Department: Professor Ewa Małecka-Panas, MD, PhD
2Department of Microbiology and Laboratory Medical Immunology, Faculty of Medicine, Medical University of Łódź
Head of Department: Professor Janina Grzegorczyk, MD, PhD
3Department of Digestive Tract Surgery, Silesian Medical University, Katowice
Head of Department: Professor Paweł Lampe, MD, PhD
Streszczenie
Wstęp. Dane z badań podstawowych wskazują, że katelicydyna, wielofunkcyjny peptyd antydrobnoustrojowy, może odgrywać istotną rolę w procesie karcynogenezy w trzustce.
Cel pracy. Celem pracy była ocena znaczenia klinicznego katelicydyny u chorych na raka trzustki (RT).
Materiał i metody. Do badania zakwalifikowano 139 chorych: 101 z rozpoznanym RT i 38 zdrowych ochotników. Stężenie katelicydyny w surowicy było mierzone metodą immunoenzymatyczną z użyciem testu USCN life science, INC Houston, USA. Przeanalizowano związek między badanym parametrem a danymi klinicznymi chorych na RT. Uzyskano zgodę komisji bioetycznej Uniwersytetu Medycznego w Łodzi oraz pisemne zgody pacjentów na przeprowadzenie badania.
Wyniki. Stężenie katelicydyny u chorych na RT było wyższe w porównaniu z grupą kontrolną (odpowiednio 2519,1 vs 249,2 ng/ml (p < 0,001)). Wysokie stężenie katelicydyny wiązało się ze wzrostem bilirubiny i niskim poziomem hemoglobiny u chorych na RT (p < 0,05). Nie wykazaliśmy z kolei zależności między katelicydyną a rozmiarem guza, zróżnicowaniem histopatologicznym guza oraz obecnością przerzutów odległych i do węzłów chłonnych. Stężenie katelicydyny nie było też związane z żadnymi innymi danymi klinicznymi chorych.
Wnioski. Podsumowując, wstępne wyniki naszej pracy sugerują prawdopodobną rolę katelicydyny w procesie karcynogenezy w trzustce, potrzebne są jednak dalsze badania, aby jednoznacznie potwierdzić jej rolę.
Summary
Introduction. Cumulative evidence from tumor biology studies indicates that cathelicidin, a multifunctional host defence peptide, might play an important role in carcinogenesis.
Aim. The aim of our study was to assess the clinical significance of cathelicidin antimicrobial peptide (CAMP) in patients with pancreatic cancer.
Material and methods. The study included 139 patients: 101 with pancreatic cancer and 38 gender and age-matched healthy volunteers. The serum concentrations of CAMP were measured by an enzyme-linked immunoassay (USCN life science, INC. Houston, USA). The associations of the analysed cathelicidin and clinical data at diagnosis have been evaluated. The consent of the bioethical committee od Medical University of Łódź, as well as written consent from all the subject were obtained.
Results. Serum levels of cathelicidin were higher in patients with pancreatic cancer compared to control group – 2519.1 vs 249.2 ng/ml respectively (p < 0.001). Increased CAMP levels were associated with with high bilirubin and low hemoglobin levels in PC patients (p < 0.05). The current study failed to show the correlation between cathelicidin and tumor size, its histologic grade and the presence of regional or distant metastases. The CAMP levels were also unrelated to other analysed clinical data of PC patients.
Conclusions. In conclusion, in our preliminary study we suggested the possible role of cathelicidin in pancreatic carcinogenesis however further studies are needed to ultimately define the clinical significance of this peptide.
Introduction
The searching of links between cancer and the human immune system becomes particularly important issue. The cathelicidin is a multifunctional host defence peptide, the full significance of which in the human immune defences is only beginning to be fully recognized (1, 2). The only human cathelicidin peptide, known as LL-37, is a free peptide part of the precursor protein hCAP18, acting as the active form of cathelicidin antimicrobial peptide (CAMP). It is encoded by the CAMP gene, located on chromosome 3p21 (3, 4). Cathelicidin has been discovered to mediate many host responses, including antimicrobial activity, angiogenesis, and activation of chemokine secretion. This peptide is secreted by bone marrow cells, circulating leukocytes, and numerous types of epithelial tissues, such as skin and gastrointestinal mucosa (2, 5). Cathelicidin is also a promoter of islet paracrine signaling that enhances islet function and glucoregulation (6).
Cumulative evidence from tumor biology studies indicates that cathelicidin plays a prominent role in carcinogenesis. An increasing amount of evidence suggests that LL-37 can have two different and contradictory effects and may act either as a pro-tumorigenic or anti-cancer agent, dependently on tumor biology (7). Expression of cathelicidin is upregulated in various ovarian cancer types, including serous adenocarcinomas, mucinous adenocarcinomas and granulosa cell tumors when compared with normal ovarian tissues (8). It has been also shown that LL-37 stimulates proliferation and independent growth of cultured lung cancer cells as well as promotes tumorigenicity and formation of larger tumors in a lung cancer xenograft model (9).
On the other hand the expression of cathelicidin was remarkably downregulated in human colon cancer tissues whereas exogenous LL-37 induced apoptotic cell death in cultured colon cancer cells (10). Cheng et al. also reported that cathelicidin inhibits colon cancer development by interfering with epithelial-mesenchymal transition and cancer associated fibroblast (11). Results of other study show that during progression from atrophic gastritis to adenocarcinoma, the expression of LL-37 is reduced. It has been observed that this peptide is absent or expressed at very low levels in gastric hyperplastic polyps, tubular adenomas, and adenocarcinomas (12).
Little is known about role of cathelicidin in pancreatic carcinogenesis. Recently, Sainz et al. have reported that hCAP-18/LL-37 was strongly expressed in the stroma of advanced primary and secondary pancreatic duct adenocarcinomas and was secreted by immune cells of the stroma in response to tumour growth factor-β1 (13). To the best of our knowledge there are no other studies concerning the role of this peptide in pancreatic cancer.
Aim
The aim of our study was to assess the clinical significance of cathelicidin antimicrobial peptide in patients with pancreatic cancer.
Material and methods
The study included 139 patients: 101 with pancreatic adenocarcinoma (48 men and 53 women aged 51-83) and 38 gender and age-matched healthy volunteers. Analysed patients were hospitalized in Department of Digestive Tract Diseases of Medical University of Łodź or Department of Digestive Tract Surgery of Silesian Medical University between 2012 and 2014. The pathologic diagnosis of ductal pancreatic adenocarcinoma were confirmed in all cases. Nineteen patients (18.8%) with PA underwent Whipple resection or distal pancreatectomy, 25 patients (24.8%) – palliative surgery and 57 patients (56.4%) – palliative chemotherapy and/or palliative endoscopic treatment.
The associations of the cathelicidin levels and clinical data at diagnosis have been evaluated. The following demographic and clinical data have been analysed: age, tumor size, lymph node involvement, histological grade, distant metastases, history of smoking, weight loss > 10% as well as selected laboratory parameters: Ca 19-9, total bilirubin, hemoglobin and glucose serum levels.
Peripheral venous blood samples were obtained from all analysed patients at the time of hospital admission. All subjects were free of known infection or renal disease and were not taking immunosuppressive medications. Sera were separated by centrifugation at 3000 revolutions per minute and were stored at -80°C until the levels of analysed markers were assessed. The serum concentrations of CAMP were measured by an enzyme-linked immunoassay (USCN life science, INC. Houston, TX, USA), according to the manufacturer’s recommendations. The minimum detectable dose of human CAMP was less than 46 pg/mL. The sensitivity of this assay, or lower limit of detection was defined as the lowest protein concentration that could be differentiated from zero.
Statistical analysis comprised arithmetical mean, median and standard deviation. To determined differences between groups Mann-Whitney t-test were used. Association between continues variables was analyzed with Pearson’s correlation test. P-values < 0.05 were considered to be significant.
The consent of the bioethical committee od Medical University of Łódź, as well as written consent from all the subject were obtained.
Results
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Piśmiennictwo
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