Colorectal cancer (CRC) is one of the most common cancer and leading cause of death worldwide. In the last decades, a tight connection between CRC development and intestinal chronic inflammatory state has been established. Indeed, patients affected by inflammatory bowel diseases (IBD), such as ulcerative colitis (UC) and Crohn¿s disease (CD), show an increased risk of developing colon cancer. Recently, specific cell types have been reported to substantially contributeto these inflammatory states. Enteric glial cells (EGCs) are cellular population composing enteric nervous system (ENS) distributed in submucosal and mioenteric plexi located along the intestinal wall and display a pivotal role in the sustaining and perpetuation of inflammatory conditions, due to their capability to induce immune-inflammatory responses following detrimental noxia, through the release of pro-inflammatory cytokines and factors, such as S100B, NO and IL-1ß. The putative involvement of EGCs in CRC onset has been hypothesized and the possible targeting of EGCs may represents an innovative strategy in the prevention of inflammation-related CRC. In this context, palmitoylethanolamide (PEA) may be an intriguing compound able to prevent the neoplastic drift from a long-standing inflammation through its well-known capability to modulate EGCs activation added to its anti-angiogenic activity in vitro. PEA efficacy has been already demonstrated in a murine model of colitis, but its putative role as drug able to reduce CRC risk have not investigated yet. To this aim the present study will evaluate, in a murine model of colitis-associated colon cancer, the role exerted by EGCs in neoplastic processes from chronic inflammation and the preventive effect of PEA in colon cancer outbreak. Data obtained will be useful to better understand the cellular mechanisms promoting carcinogenic processes and to identify a promising approach in the prevention of intestinal chronic inflammation-associated colon cancer.
In the last years, it has been assumed that enteric glial cells (EGCs) are involved in gut homeostasis and, especially, in intestinal chronic inflammation (Capoccia et al, Int J Immunopathol Pharmacol. 2015; 28(4) 443¿451). Not surprisingly, a persistent activation of EGCs evolving toward neoplastic drift has been hypothesized, although the molecular mechanisms underlying this process are not fully understood. The present study is therefore aimed, for the first time, to elucidate the enteroglial mechanisms responsible for colorectal cancer (CRC) outcome from a chronic inflammatory condition, identifying a new promising target in the preventive strategy against CRC. Accordingly, targeting EGCs activity takes on a considerable pharmacological relevance in the prevention of colon cancer and, in parallel, may support the current knowledge about the etiology and the pathological mechanisms of non-sporadic CRC deriving from intestinal chronic inflammatory conditions. In this scenario, palmitoylethanolamide (PEA) represents an intriguing candidate because of its well-known pharmacological and toxicological profile. Beside its neuroprotective and analgesic properties, recent studies have demonstrated that PEA is able to counteract EGCs activation, responsible for its antinflammatory and antiangiogenic effects (IBD) (Esposito G et al, Gut. 2014; 63(8):1300-12; Sarnelli G et al, PLoS ONE. 2016; 11(5):e0156198). Nevertheless, PEA effects against the tumorigenic drift of a long-standing state of inflammation have not investigated yet in vivo. For this reason, PEA preventive efficacy in a model of colitis-associated colon cancer represents a potential milestone of this research project. PEA may be a potential, manageable and low-cost tool in the prevention of colon cancer, due to its safety profile and current use as dietary supplement. Indeed, PEA is already introduced in clinical practice , as anti-inflammatory and analgesic preparations in dermatology and gynaecology (eg, Normast, Pelvilen) (Petrosino S et al, Biochemie. 2010; 92:724-7) Finally, data obtained from this project will represent a first step towards an alternative approach to CRC prevention, guaranteeing a high life quality and promote a healthy aging.