The role of Cytomegalovirus and Epstein-Barr virus in the development and progression of Salivary Gland Cancer

Abstract

Introduction: Salivary gland carcinomas (SGC) are rare tumors characterized by an enormous morphological diversity between different subtypes going along with diverse clinical courses. The etiology of SGC is still unknown, although a correlation has been shown between the occurrence of SGC and some environmental factors, however, only a very small percentage of malignancies develop as a direct result of these factors. There is growing evidence that infectious agents are frequently associated with human cancer. Recent studies show that Cytomegalovirus (CMV) and Epstein-Barr virus (EBV) CMV infections are associated with various epithelial malignancies. It has been shown that in various tissues CMV and EBV could increase the expression of IL-6, NFκB, MMP-2 and MMP-9. These proteins are associated with certain types of cancer. We hypothesized that CMV and EBV could cause inflammation and deregulation of genes involved in cell proliferation and could induce the development of salivary gland cancer. Aims: The aims of this study were to determine the prevalence of CMV and EBV in SGC tissues, to compare the immunohistochemical and nested PCR detection of CMV and EBV in SGC, to investigate the viral protein expression in different histological types of salivary gland cancer, to investigate the immunohistochemical expression of prognostic markers IL6, MMP2, MMP9 and NFκB, to investigate the association of the presence of CMV and EBV and the immunohistochemical expression of these prognostic markers and to analyze the polymorphisms of IL6, MMP2 and MMP9 genes and investigate the association of the polymorphisms and the corresponding protein expression. Material and Methods: This cross-section study included 93 patients diagnosed with salivary gland cancer (SGC), surgically treated at the Clinic of Otorhinolaryngology and Maxillofacial Surgery, Clinical Center of Serbia from 2004 to 2013. For the immunohistochemical analysis, the control consisted of healthy salivary gland tissue from 20 autopsy cases with no malignancies and salivary gland pathology...

Uvod: Karcinomi pljuvačnih žlezda su retki tumori koji u različitim histološkim tipovima pokazuju spektar različitih morfoloških promena koje odgovaraju različitom kliničkom ispoljavanju i toku. Etiologija karcinoma pljuvačnih žlezda je još uvek nepoznata. Brojna istraživanja su pokazala značajan uticaj faktora sredine na njihov nastanak i progresiju, ali je samo za mali procenat jasno pokazano da je tumor nastao upravo direktnim uticajem nekog od faktora sredine. Sve je više istraživanja koja ukazuju na čestu i tesnu povezanost infektivnih agenasa sa pojavim maligniteta. Novija istraživanja pokazala su direktnu povezanost infekcija Citomegalovirusom (CMV) i Epštajn-Barr virusom (EBV) sa nastankom različitih oblika karcinoma. U različitim tkivima pokazano je da CMV i EBV mogu uzrokovati povećanje ekspresije IL-6, NFκB, MMP-2 i MMP-9, proteina koji su direktno povezani sa određenim tipovima karcinoma. Naša hipoteza je bila da CMV i EBV mogu dovest do zapaljenja i do deregulacije gena ćelijske proliferacije, te uticati na nastanak i razvoj karcinoma pljucačnih žlezda. Ciljevi: Ciljevi ove studije bili su da se utvrdi prisustvo CMV i EBV u tkivu karcinoma pljuvačne žlezde, da se uporedi immunohistohemijska i nested PCR detekcija CMV i EBV u karcinomu pljuvačne žlezde, da se ispita ekspresija virusnih proteina u različitim histološkim tipovima karcinoma pljuvačnih žlezda, da se ispita imunohistohemijska ekspresija prognostičkih markera IL6, MMP2, MMP9 i NFκB, da se ispita povezanost prisustva CMV i EBV sa imunohistohemijskom ekspresijom pomenutih prognostičkih markera i da se uradi analiza polimorfizma IL6, MMP2 i MMP9 gena i ispita asocijacija polimorfizama i odgovarajuće ekspresije proteina. Materijal i metode: Ova studija preseka obuhvatila je 93 pacijenta kod kojih je dijagnostikovan karcinom pljuvačne žlezde, koji su operisani na Klinici za otorinolaringologiju i maksilofacialnu hirurgiju, Kliničkog centra Serbije u periodu od 2004. do 2013. Detekcija CMV i EBV analizirana je imunohistohemijskom i nested PCR metodom...