Petr Busek1, Zdislava Vanickova2, Petr Hrabal3, Marek Brabec4, Premysl Fric5, Miroslav Zavoral5, Jan Skrha6, Klara Kmochova5, Martin Laclav5, Bohus Bunganic5, Koen Augustyns7, Pieter Van Der Veken7, Aleksi Sedo8. 1. Laboratory of Cancer Cell Biology, Institute of Biochemistry & Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Czech Republic. Electronic address: busekpetr@seznam.cz. 2. Laboratory of Cancer Cell Biology, Institute of Biochemistry & Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Czech Republic. 3. Department of Pathology, Military University Hospital Prague, Czech Republic. 4. Department of Nonlinear Modeling, Institute of Computer Science, The Czech Academy of Sciences, Prague, Czech Republic. 5. Department of Internal Medicine of First Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic. 6. 3rd Department of Medicine - Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, Czech Republic. 7. Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, UAMC University of Antwerp, Belgium. 8. Laboratory of Cancer Cell Biology, Institute of Biochemistry & Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Czech Republic. Electronic address: aleksi@cesnet.cz.
Abstract
BACKGROUND/ OBJECTIVES: Pancreatic ductal adenocarcinoma (PDAC) is frequently heralded by an impairment of glucose homeostasis. Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein alpha (FAP) are aminopeptidases that regulate several bioactive peptides involved in glucoregulation, and are frequently dysregulated in cancer. The present study analyzes blood plasma levels and the quantity and localization of DPP-IV and FAP in PDAC tissues. METHODS: DPP-IV and FAP concentration and enzymatic activity were evaluated in the plasma from 93 PDAC, 39 type 2 diabetes mellitus (T2DM) and 29 control subjects, and in matched paired non-tumorous and tumor tissues from 48 PDAC patients. The localization of DPP-IV and FAP was determined using immunohistochemistry and catalytic histochemistry. RESULTS: The enzymatic activity and concentration of DPP-IV was higher in PDAC tumor tissues compared to non-tumorous pancreas. DPP-IV was expressed in cancer cells and in the fibrotic stroma by activated (myo)fibroblasts including DPP-IV(+)FAP(+) cells. FAP was expressed in stromal cells and in some cancer cells and its expression was increased in the tumors. Plasmatic DPP-IV enzymatic activity, and in particular the ratio between DPP-IV enzymatic activity and concentration in PDAC with recent onset DM was higher compared to T2DM. In contrast, the plasmatic FAP enzymatic activity was lower in PDAC compared to T2DM and controls and rose after tumor removal. CONCLUSIONS: DPP-IV-like enzymatic activity is upregulated in PDAC tissues. PDAC patients with recent onset diabetes or prediabetes have increased plasmatic DPP-IV enzymatic activity. These changes may contribute to the frequently observed association of PDAC and recent onset impairment of glucoregulation.
BACKGROUND/ OBJECTIVES:Pancreatic ductal adenocarcinoma (PDAC) is frequently heralded by an impairment of glucose homeostasis. Dipeptidyl peptidase-IV (DPP-IV) and fibroblast activation protein alpha (FAP) are aminopeptidases that regulate several bioactive peptides involved in glucoregulation, and are frequently dysregulated in cancer. The present study analyzes blood plasma levels and the quantity and localization of DPP-IV and FAP in PDAC tissues. METHODS:DPP-IV and FAP concentration and enzymatic activity were evaluated in the plasma from 93 PDAC, 39 type 2 diabetes mellitus (T2DM) and 29 control subjects, and in matched paired non-tumorous and tumor tissues from 48 PDACpatients. The localization of DPP-IV and FAP was determined using immunohistochemistry and catalytic histochemistry. RESULTS: The enzymatic activity and concentration of DPP-IV was higher in PDACtumor tissues compared to non-tumorous pancreas. DPP-IV was expressed in cancer cells and in the fibrotic stroma by activated (myo)fibroblasts including DPP-IV(+)FAP(+) cells. FAP was expressed in stromal cells and in some cancer cells and its expression was increased in the tumors. Plasmatic DPP-IV enzymatic activity, and in particular the ratio between DPP-IV enzymatic activity and concentration in PDAC with recent onset DM was higher compared to T2DM. In contrast, the plasmatic FAP enzymatic activity was lower in PDAC compared to T2DM and controls and rose after tumor removal. CONCLUSIONS:DPP-IV-like enzymatic activity is upregulated in PDAC tissues. PDACpatients with recent onset diabetes or prediabetes have increased plasmatic DPP-IV enzymatic activity. These changes may contribute to the frequently observed association of PDAC and recent onset impairment of glucoregulation.
Authors: Simone E Jaenisch; Catherine A Abbott; Mark D Gorrell; Peter Bampton; Ross N Butler; Roger Yazbeck Journal: Clin Transl Gastroenterol Date: 2022-01-19 Impact factor: 4.396