Regulation of circulating endocannabinoids associated with cancer and metastases in mice and humans

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.