Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans
Sebastian Sailler1, Katja Schmitz1, Elke Jäger2, Nerea Ferreiros1, Sabine Wicker3, Katja Zschiebsch1, Geethanjali Pickert1, Gerd Geisslinger1, Carmen Walter1, Irmgard Tegeder1,*, and Jörn Lötsch1,*
1 pharmazentrum frankfurt/ZAFES, Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt am Main, Germany
2 Department of Hematology and Oncology, Krankenhaus Nordwest, Frankfurt am Main, Germany
3 Occupational Health Service, University Hospital Frankfurt, Frankfurt am Main, Germany.
* These authors contributed equally to this work
Jörn Lötsch , email:
Keywords: Cannabinoids, Human, Mice, Metastasis
Received: January 30, 2014 Accepted: April 30, 2014 Published: April 30, 2014
Background and aims: Endocannabinoids may modify cancer development, progression and associated pain. We determined whether cancer-evoked dysregulations in this system become manifest in altered tissue and plasma endocannabinoids.
Methods: Endocannabinoid changes due to cancer were explored in a local and metastatic syngeneic mouse melanoma model. Endocannabinoid stratification in human cancer was cross-sectionally assessed in the plasma of 304 patients (147 men, 157 women, aged 32 - 87 years) suffering from several types of cancer at Roman Numeral Staging between I and IVc, mostly IV (n = 220), and compared with endocannabinoids of healthy controls.
Results: In mice with local tumor growth, ethanolamide endocannabinoids, i.e., anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA) were downregulated, whereas 2-arachidonoylglycerol (2-AG) was increased. Upon spreading of the cancer cells particularly 2-AG steadily increased in parallel to disease progression while OEA modulated cell migration. Results translated into humans, in whom cancer was associated with a decreased AEA, increased 2-AG and increased OEA correlating with the number of metastases.
Conclusions: The endocannabinoid system was subject to cancer-associated regulations to an extent that led to measurable changes in circulating endocannabinoid levels, emphasizing the importance of the endocannabinoid system in the pathophysiology of cancer.