Cannabinoids in pancreatic cancer: correlation with survival and pain.
Cannabinoids exert antiproliferative properties in a variety of malignant tumors, including pancreatic ductal adenocarcinoma (PDAC). In our study, we quantitatively evaluated the immunoreactivity for cannabinoid-1 (CB1) and cannabinoid-2 (CB2) receptors as well as for the endocannabinoid metabolizing enzymes fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGLL). Furthermore, quantitative real-time RT-PCR for CB1, CB2, FAAH and MGLL in normal pancreas and pancreatic cancer tissues was performed. Levels of endocannabinoids were determined by liquid chromatography/mass spectrometry. Immunoreactivity scores and QRT-PCR expression levels were correlated with the clinico-pathological (TNM, survival, pain) status of the patients. Evaluation of endocannabinoid levels revealed that these remained unchanged in PDAC compared to the normal pancreas. Patients with high CB1 receptor levels in enlarged nerves in PDAC had a lower combined pain score (intensity, frequency, duration; p = 0.012). There was a significant relationship between low CB1 receptor immunoreactivity or mRNA expression levels (p = 0.0011 and p = 0.026, respectively), or high FAAH and MGLL cancer cell immunoreactivity (p = 0.036 and p = 0.017, respectively) and longer survival of PDAC patients. These results are underlined by a significant correlation of high pain scores and increased survival (p = 0.0343). CB2 receptor immunoreactivity, CB2 receptor, FAAH and MGLL mRNA expression levels did not correlate with survival. Therefore, changes in the levels of endocannabinoid metabolizing enzymes and cannabinoid receptors on pancreatic cancer cells may affect prognosis and pain status of PDAC patients.
Michalski
Christoph W
CW
Department of General Surgery, Technische Universität Munich, Munich, Germany. christoph.michalski@gmx.de
Oti
Florian E
FE
Erkan
Mert
M
Sauliunaite
Danguole
D
Bergmann
Frank
F
Pacher
Pal
P
Batkai
Sandor
S
Müller
Michael W
MW
Giese
Nathalia A
NA
Friess
Helmut
H
Kleeff
Jörg
J
D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality; D000581:Amidohydrolases / Q000235:genetics / Q000378:metabolism; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism; D002186:Cannabinoids / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000401:mortality; D002851:Chromatography, High Pressure Liquid; D006801:Humans; D007124:Immunoenzyme Techniques; D013058:Mass Spectrometry; D008994:Monoacylglycerol Lipases / Q000235:genetics / Q000378:metabolism; D010146:Pain / Q000188:drug therapy* / Q000209:etiology; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism*; D043885:Receptor, Cannabinoid, CB2 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D002186:Cannabinoids; D008994:Monoacylglycerol Lipases; D012333:RNA, Messenger; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; D000099252:Fatty Acid Amide Hydrolases