Monoacylglycerol lipase deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer

Abstract

Monoacylglycerol lipase (MGL) expressed in cancer cells influences cancer pathogenesis but the role of MGL in the tumor microenvironment (TME) is less known. Using a syngeneic tumor model with KP cells (Kras LSL-G12D /p53 fl/fl ; from mouse lung adenocarcinoma), we investigated whether TME-expressed MGL plays a role in tumor growth of non-small cell lung cancer (NSCLC). In sections of human and experimental NSCLC, MGL was found in tumor cells and various cells of the TME including macrophages and stromal cells. Mice treated with the MGL inhibitor JZL184 as well as MGL knock-out (KO) mice exhibited a lower tumor burden than the controls. The reduction in tumor growth was accompanied by an increased number of CD8 + T cells and eosinophils. Naïve CD8 + T cells showed a shift toward more effector cells in MGL KOs and an increased expression of granzyme-B and interferon-γ, indicative of enhanced tumoricidal activity. 2-arachidonoyl glycerol (2-AG) was increased in tumors of MGL KO mice, and dose-dependently induced differentiation and migration of CD8 + T cells as well as migration and activation of eosinophils in vitro . Our results suggest that next to cancer cell-derived MGL, TME cells expressing MGL are responsible for maintaining a pro-tumorigenic environment in tumors of NSCLC.

Inhibition of triple negative breast cancer-associated inflammation, tumor growth and brain colonization by targeting monoacylglycerol lipase

“…MAGL plays a major role in the endocannabinoid metabolism in addition to its lipolytic functions. MAGL provides a large pool of arachidonic acid (AA), from which pro-inflammatory prostaglandins are generated 41 . 2-AG, CB1/CB2 receptors and MAGL are key regulators of the endocannabinoid system involve in regulation of various metabolic pathways in vivo.…”

“…2-AG, CB1/CB2 receptors and MAGL are key regulators of the endocannabinoid system involve in regulation of various metabolic pathways in vivo. By inhibiting MAGL, 2-AG levels are increased in tumor cells and in tumor niches, leading to changes in immune cell behavior in the TME and resulting in altered immune cell profile within the tumor niches being shifted from pro-inflammatory profile to a more anti-tumorigenic profile 41 . The effects of 2-AG on immune cells and TME usually involve CB2 cannabinoid receptors, although CB1 independent effects such as leukotriene biosynthesis and LTB4 activation could be observed 41 .…”

“…Since MAGL is expressed in TNBCs and in the immune and stromal cells of the tumor microenvironment, inhibition of MAGL in both compartments is essential for inhibition of tumor growth and pathogenesis. Indeed, recent studies showed that MAGL deficiency in the tumor microenvironment slows tumor growth in non-small cell lung cancer 41 . Further, the MAGL inhibitor JZL184 was shown to reduce osteolytic bone metastasis in mouse models of advanced breast and prostate cancer and osteosarcoma, and inhibited skeletal tumor growth, metastasis, and the formation of ectopic bone in models of osteosarcoma 54 .…”

Untargeted urine metabolite profiling by mass spectrometry aided by multivariate statistical analysis to predict prostate cancer treatment outcome

“…Prior studies revealed that MAGL promotes metastasis in nasopharyngeal carcinoma and lung cells. 37,38 Our study showed that in men with recurrent PCa tumor relapse, decreasing level of monoacylglycerols potentially leads to accelerating motility of highly metastatic cells because of overexpressing MAGL. Meanwhile, monoacylglycerols are formed biochemically via releasing fatty acids of diacylglycerol and triacylglycerol through MAGL.…”

“…The monoacylglycerols portions of urine show a lower intensity in recurred patients, which may be associated with a function of glycerol lipase. 36,37 Glycerol lipase are active mediators involved in intricate biological processes closely associated with the pathological development of cancers. Lipids metabolites initiate from the synthesis of monoacylglycerols, followed by the storage within tissue and cells, and undergo lipolysis, which is regulated by corresponding lipases.…”