Institut für Pathologie

Medizinische Universität Graz

Metabolically triggered lung cancer

For many decades cancer research was mainly focused on the fight against fast growing cancer cells. About a century ago however, it became clear that the metabolism of cancer cells is probably quite different to the metabolism of most normal cells in our body. Based on this principle, several new routes to fight cancer are tested and established, nowadays. Our research group focuses on the role of an enzyme that is needed to activate energy from fat depots. Therefore, it is called Adipose TriGlyceride Lipase, or in short, ATGL.

Simplified overview of the intracellular lipolysis pathway at lipid droplet membranes of higher eukaryotes. Enzymes necessary for activation of cellular lipid stores from lipid droplets. ATGL and, to a lesser extend HSL, cleave FA from TG to produce DG. Biochemically, ATGL has a strong preference for the hydrolysis of FA esters at the sn-2 position of the glycerol backbone but will also act at sn-1, when its co-activator comparative gene identification 58 (ABHD5/CGI58), is present. HSL’s main lipolytic function is hydrolysis of ATGL’s hydrolysis products, sn-1,3 and sn-2,3 DG, with the former one being its preferred substrate. On both substrates, HSL was reported to exhibit sn-3 selectivity generating sn-1 and sn-2 MG. The third major lipase in this cascade, MGL, does not discriminate between MG stereoisomers.

Interestingly, we have recently found out that absence of ATGL is linked to lung cancer and that animals where ATGL is absent, get lung cancer. Follow the link to the article:
http://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=view&path%5B%5D=9418&path%5B%5D=29165
In a time when the metabolic syndrome is a spreading pandemic, it is an intriguing idea that analysis of metabolic cancer markers and potential correction of metabolic cell dysfuntions could help us to fight cancer.

Ectopic fat accumulation is apparent in airways of animals lacking ATGL. See, red oil-red-o staining on the left with representative insert, and grey circles in TEM image on the right.

Early neoplastic lesions in lungs of animals lacking ATGL are seen on H&E images

Currently, we think that ATGL is needed for normal function of lung cells. Hence, we hypothesize that without ATGL, the lung cannot properly react to the manifold normal challenges that it has to face at a daily basis. These include dust, smoke, pathogens, airborne chemicals and even normal lung surface regeneration processes. As a result, we believe that loss of the metabolic function of ATGL could lead to persistent low level inflammation, eventually triggering cancer.

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