Endocrine Abstracts

Background: Papillary thyroid cancer (PTC) is a disease with an indolent course, excellent overall prognosis and long-term survival. However, some PTCs are associated with an increased risk of recurrent disease and aggressive behaviour. Many exogenous factors, as obesity, could be implicated in the pathogenesis of thyroid cancer but the biological mechanisms that may explain this connection have been only partially described. Potentially factors that combine overweight with this cancer should be searched for in the immune pathways and chronic inflammation onset. In this study, we evaluated the role of immune system in patients affected by PTC and stratified according to body mass index (BMI).

Methods: Based on BMI, samples were subdivided into four categories: underweight, normal weight, overweight, and obese. The analysis of the expression profiles of >700 immune-related genes was performed in 36 PTCs. Normal weight was considered as reference category. Furthermore, results of gene expression analysis -and thus the existence of an effective concordance between gene expression and protein synthesis- were confirmed by immunohistochemistry (IHC), calculating the H-score, a semiquantitative measure based on the combined assessment of staining intensity and the percentage of positive neoplastic cells.

Results: The immune microenvironment of PTC does not seem strongly influenced by BMI; however, we identify a statistically significant downregulation of CASP3, FCGR2A, HMGB1, MAPK1, SPP1 and an upregulation of ARG2, BCL2, NT5E, RORA in the obese category. One of these genes, the mitochondrial arginase-2 (ARG2), was significant upregulated after application of Benjamini-yekutieli correction. A directly proportional and statistically significant correlation was observed between H-score and ARG2-mRNA, and between H-score and BMI, therefore the IHC results agree with those of the molecular analysis and show that the expression of ARG2 in the tumor microenvironment of PTC patients increases in relation to the increase in BMI, being significantly more intense in obese patients.

Conclusions: ARG2, which hydrolysed arginine into urea and ornithine, can influence the endogenous level of polyamines, proline, and NO (nitric oxide), key components for collagen system, tissue proliferation, immune system regulation and inflammatory response. In the last years, many studies have focused on the relationship between altered metabolism and the activity of immune system. Although, molecular mechanisms linking excessive adiposity with the development of cancer are complex and still not completely known. The investigation of molecular processes in tumor microenvironment may provide an opportunity to understand the role of immunometabolism in thyroid cancer.