title: The Immune Interplay between Thyroid Papillary Carcinoma and Hepatic Fibrosis.
abstract: BACKGROUND
  A 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.
  
  
  OBJECTIVE
  We aimed to study the immune-modulatory interactions between thyroid papillary carcinoma and hepatic-fibrosis.
  
  
  METHODS
  Hepatic-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.
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: Liver and Gastroenterology Units, Division of Medicine, Hadassah University Medical Center, Jerusalem, Israel; Department of Otolaryngology, Head & Neck Surgery, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Nidal
authors.initials: N
authors.lastname: Muhanna
authors.affiliation: Liver and Gastroenterology Units, Division of Medicine, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Johnny
authors.initials: J
authors.lastname: Amer
authors.affiliation: Liver and Gastroenterology Units, Division of Medicine, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Salhab
authors.affiliation: Department of Otolaryngology, Head & Neck Surgery, Shaare Zedek Medical Center, Jerusalem, Israel.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Sichel
authors.affiliation: Liver and Gastroenterology Units, Division of Medicine, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Rifaat
authors.initials: R
authors.lastname: Safadi
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride; D063646:Carcinogenesis / Q000276:immunology / Q000473:pathology; D002291:Carcinoma, Papillary / Q000097:blood / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D007694:Killer Cells, Natural / Q000276:immunology; D008103:Liver Cirrhosis / Q000097:blood / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology; D008297:Male; D008819:Mice, Nude; D013964:Thyroid Neoplasms / Q000097:blood / Q000150:complications* / Q000276:immunology* / Q000473:pathology; D013974:Thyroxine / Q000378:metabolism; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D042461:Vascular Endothelial Growth Factor A; D002251:Carbon Tetrachloride; D013974:Thyroxine