The Immune Interplay between Thyroid Papillary Carcinoma and Hepatic Fibrosis

Abstract

BackgroundA high prevalence of thyroid papillary cancer was reported in hepatitis-C-virus (HCV) positive patients. However, the mechanistic role of hepatic-fibrosis in thyroid malignancy progressions is still unclear.AimWe aimed to study the immune-modulatory interactions between thyroid papillary carcinoma and hepatic-fibrosis.MethodsHepatic-fibrosis was induced in nude-nu-male mice by intra-peritoneal administration of carbon-tetrachloride. To induce thyroid-tumor, a thyroid papillary carcinoma cell line (NPA) was injected subcutaneously in the backs. Fibrotic profile was estimated by α-smooth-muscle-actin (αSMA) expression in liver tissue extracts using western-blots and RT-PCR. Intra-hepatic NK cells were isolated and stained for NK activity (CD107a) by flow cytometry. Liver histopathology (H&E staining), thyroid tumor mass and serum alanine aminotransferase (ALT), serum vascular endothelial growth factor (VEGF) and free-T4 levels were also assessed.Results Ex-vivo: NPA cells were co-cultured with intra-hepatic NK cells isolated from fibrotic mice with/without the tumor were analyzed for CFSE-proliferations. Both tumor groups (with/without hepatic-fibrosis) excreted higher serum free T4 levels. Hepatic-fibrosis increased tumor weight and size and serum free-T4 levels. In addition, tumor induction increased liver injury (both hepatic-fibrosis, necro-inflammation and serum ALT levels). In addition, tumor-bearing animals with hepatic-fibrosis had increased NK activity. NPA tumor-bearing animals increased fibrosis in spite of increased NK activity; probably due to a direct effect through increased serum free-T4 excretions. Serum VEGF levels were significantly increased in the fibrotic- bearing tumor groups compared to the non-fibrotic groups. In-vitro, NK cells from fibrotic tumor-bearing animals reduced proliferation of NPA cells. This decrease is attributed to increase NK cells activity in the fibrotic animals with the NPA tumors.ConclusionsOur results propose that NK cells although were stimulated in advanced fibrosis with tumor, they lost their anti-tumor and anti-fibrotic activity probably due to secretions of T4 and VEFG and may explain increased risk of thyroid tumors in chronic HCV patients.

The Clinicopathological Features of Papillary Thyroid Carcinoma Patients with Positive Hepatitis B Surface Antigen

“…Previous studies have found that an increased level of VEGF along with VEGF-C and their receptors VEG-FR-2 and VEGFR-3 are related with LNM of PTC [36,37]. Muhanna et al [38] reported that VEGF level was significantly increased in mice with hepatic fibrosis due to liver function damage. HBV infection can lead to chronic liver injury and then cause hepatic fibrosis.…”

The Potential Role of Virus Infection in the Progression of Thyroid Cancer

“…A study has shown that thyroid autoantibodies were observed in 83% of HCV patients with PTC and 31% of HCV patients without TC, suggesting people may suffer from an increased risk of TC after HCV infection [ 16 ]. However, HCV is an RNA virus that cannot be integrated into the host genome, and its oncogenic potential must be exerted through an indirect mechanism [ 59 ]. Therefore, we can hypothesize that autoimmune thyroid disease mediated by chronic HCV infection may lead to thyroid carcinogenesis.…”