Cannabinoids in pancreatic cancer: Correlation with survival and pain

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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.

Keywords: pancreatic cancer, cannabinoids, pain, survival

Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which is scarcely affected by any therapeutic regimen due to its aggressive growth, early metastases and poor response to chemo-, radio- and targeted therapies. Severe pain and cachexia render the late, palliative stages of the disease a medical challenge for which new treatment strategies are needed.

In recent years, there has been increasing interest in cannabinoids due to their antineoplastic, anticachectic and analgesic potential. Synthetic cannabinoids mimic the function of their endogenous counterparts, such as anandamide (AEA) and arachidonoylglycerol (AG), by activating specific Gi/o protein-coupled cannabinoid receptors. Of these, cannabinoid receptor-1 (CB1) is abundantly found in neural tissues, while cannabinoid receptor-2 (CB2)is particularly expressed on cells of the immune system. Endocannabinoids are then metabolized by enzymes such as fatty acid amide hydrolase (FAAH) and monoacyl glycerol lipase (MGLL). Growth inhibitory activities of cannabinoids have been demonstrated for various malignant tumors, including brain, breast, prostate, colorectal, skin and recently also pancreatic cancer. Regarding pancreatic cancer, these effects have not only been shown in vivo, but also in xenograft models. Cannabinoids can induce apoptosis in cancer cells, but have also been shown to inhibit tumor vascularization by altering blood vessel morphology and decreasing proangiogenic factors such as VEGF. Furthermore, they have been shown to decrease invasiveness of cancer cells.

Most recently, stress-regulated protein p8 has been identified as a downstream target of the proapoptotic sphingolipid ceramide, serving as an essential mediator of growth inhibitory properties of cannabinoids by upregulating endoplasmic reticulum stress-related genes ATF-4, CHOP and TRB3. Importantly, some of these effects are communicated by the endocannabinoid system in vitro, and inhibition of endocannabinoid inactivation has revealed tumor growth inhibition comparable to that observed with exogenously administered cannabinoids. However, cannabinoids in some cases also exert growth-promoting activities through growth factor/receptor systems or by suppression of an antitumor immune response.

Altogether, antiproliferative effects seem to prevail, and therefore cannabinoids are considered potential candidate drugs in anti-tumor therapies, simultaneously alleviating cancer-related pain and cachexia. In line with a variety of in vitro studies and animal experiments, a recent study showed some response of malignant gliomas to intratumoral cannabinoid infusions in humans, underlining a potential prospect for their in vivo use.

Here, we concomitantly analyze the expression of cannabinoid receptors and endocannabinoid metabolizing enzymes. Our results demonstrate a correlation between longer survival in pancreatic cancer patients, and low CB1 receptor or high FAAH as well as MGLL levels in tissue specimens.

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