Role of endocannabinoid system and its effect on the control of angiogenesis in a murine model of lung carcinoma
Creators: name: Negro, Luana
Publisher: name: Università degli Studi di Napoli Federico II
Year: 2015

description: The present work aims at evaluating the possible role of the endocannabinoid system (ECS) and its effects on the control of angiogenesis in lung carcinoma. 
Worldwide, lung cancer is the most common cause of cancer-related deaths. The target of angiogenesis in solid tumours, including lung cancer, represents a new promising strategy (Giaccone, 2007), since tumour angiogenesis is a process necessary for the growth of the solid tumours. The implant of the tumoural cells in a tissue leads to a release of pro-angiogenic factors that activate endothelial cells, allowing the formation of new capillaries and their subsequent stabilization. Therefore, angiogenesis supplies oxygen and nutrients to the tumour mass. The therapeutic efficacy of anti-angiogenic drugs has been demonstrated in clinical studies and anti-angiogenic compounds currently represent an important coadjuvant approach to the standard anti-cancer therapies. A promising class of anti-angiogenic compounds is represented by Cannabinoids (CBs), all the natural compounds, synthetic and endogenous factors exhibiting the same biological activity of the derivatives of Cannabis Sativa L., Marijuana (De Filippis and Iuvone 2009). ECS is formed by receptors, CB1 and CB2, their ligands mainly anandamide (AEA) and 2-arachidonylglycerol (2-AG) and the main enzymes  involved in the metabolism and transport of these endogenous ligands. 
On the basis of these evidences this Ph.D. study focused attention on the deregulation of ECS associated with the tumoral angiogenesis in a murine model of lung carcinoma to strengthen the numerous evidences  indicating  CBs as possible new coadjuvant molecules to the classic anti-cancer therapy.
In this study, a model of lung cancer induced in C57BL/6 mice injected with Lewis Lung Carcinoma cells was used. The deregulation of the ECS  was evaluated during the various stages of tumor growth and correlate to the process of angiogenesis. The experiments show, for the first time, a strong deregulation of ECS in lung cancer; in fact, there is a significant increase in the levels of the MAGL enzyme, involved in the degradation of the main endogenous ligand for these receptors, 2-AG, and the expression of the CB2 receptor. This deregulation  is, closely, associated with the angiogenic process, given that it is highlighted in the second phase of tumor progression, a phase in which the tumor mass requires oxygen and nutrients for its growth, and the CB2 receptor seems to be the protagonist of this regulation. Considering these results, we tried a therapeutic approach with a selective agonist of the CB2 receptor, JWH133. The treatment with JWH133 improved tumor parameters reducing the principal angiogenic markers, such as VEGF, MMP-9, MMP-3, CXCL16, Endoglin, angiopoietin, aFGF, bFGF, SDF-1. The CB2-mediated activity of JWH133 was confirmed through the use of CB2 knockout animals in which the tumor was induced in the same experimental conditions. An alternative strategy was also used in the agonist treatment, to have a pharmacological intervention only in the tumor mass, the area where the ECS appears deregulated. This alternative approach provided for the use of an inhibitor of MAGL, JZL184. The data demonstrates that JZL184 reduces the tumor mass and the angiogenic process, similarly to the JWH133.

In conclusion, the data here obtained strengthen the possibility to use cannabinomimetics molecules as adjuvants in standard anti-tumor therapies n order to control the ECS deregulation, to reduce angiogenesis associated with tumoral conditions and, consequently, to improve the pathological condition. Moreover, these compounds have lower price and less side effects compared to currently use anti-angiogenic agents.