Increased tissue and circulating levels of dipeptidyl peptidase-IV enzymatic activity in patients with pancreatic ductal adenocarcinoma.
OBJECTIVE
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.
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.
Petr
P
Busek
Laboratory of Cancer Cell Biology, Institute of Biochemistry & Experimental Oncology, First Faculty of Medicine, Charles University in Prague, Czech Republic.
Zdislava
Z
Vanickova
Department of Pathology, Military University Hospital Prague, Czech Republic.
Petr
P
Hrabal
Department of Nonlinear Modeling, Institute of Computer Science, The Czech Academy of Sciences, Prague, Czech Republic.
Marek
M
Brabec
Department of Internal Medicine of First Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic.
Premysl
P
Fric
Department of Internal Medicine of First Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic.
Miroslav
M
Zavoral
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.
Jan
J
Skrha
Department of Internal Medicine of First Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic.
Klara
K
Kmochova
Department of Internal Medicine of First Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic.
Martin
M
Laclav
Department of Internal Medicine of First Faculty of Medicine of Charles University and Military University Hospital Prague, Czech Republic.
Bohus
B
Bunganic
Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, UAMC University of Antwerp, Belgium.
Koen
K
Augustyns
Laboratory of Medicinal Chemistry, Department of Pharmaceutical Sciences, UAMC University of Antwerp, Belgium.
Pieter
P
Van Der Veken
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.
Aleksi
A
Sedo
D000230:Adenocarcinoma / Q000201:enzymology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D021441:Carcinoma, Pancreatic Ductal / Q000201:enzymology*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D010450:Endopeptidases; D005260:Female; D005355:Fibrosis; D018093:Gelatinases / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D058628:Myofibroblasts / Q000201:enzymology; D010179:Pancreas / Q000201:enzymology; D010190:Pancreatic Neoplasms / Q000201:enzymology*; D012697:Serine Endopeptidases / Q000378:metabolism; D017154:Stromal Cells / Q000201:enzymology; D055815:Young Adult; D000099167:Fibroblast Activation Protein Alpha
D018819:Dipeptidyl Peptidase 4; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha; C042807:DPP4 protein, human
Diabetes mellitus; Fibroblast activation protein alpha; Peptide hydrolases; Plasma; Stromal cells