title: Treatment with anti-IL-6 receptor antibody prevented increase in serum hepcidin levels and improved anemia in mice inoculated with IL-6-producing lung carcinoma cells.
abstract: BACKGROUND
  Hepcidin, a key regulator of iron metabolism, is produced mainly by interleukin-6 (IL-6) during inflammation. A mechanism linking cancer-related anemia and IL-6 through hepcidin production is suggested. To clarify the hypothesis that overproduction of IL-6 elevates hepcidin levels and contributes to the development of cancer-related anemia, we evaluated anti-IL-6 receptor antibody treatment of cancer-related anemia in an IL-6-producing human lung cancer xenograft model.
  
  
  METHODS
  Nude mice were subcutaneously inoculated with cells of the IL-6-producing human lung cancer cell line LC-06-JCK and assessed as a model of cancer-related anemia. Mice bearing LC-06-JCK were administered rat anti-mouse IL-6 receptor antibody MR16-1 and their serum hepcidin levels and hematological parameters were determined.
  
  
  RESULTS
  LC-06-JCK-bearing mice developed anemia according to the production of human IL-6 from xenografts, with decreased values of hemoglobin, hematocrit, and mean corpuscular volume (MCV) compared to non-tumor-bearing (NTB) mice. LC-06-JCK-bearing mice showed decreased body weight and serum albumin with increased serum amyloid A. MR16-1 treatment showed significant inhibition of decreased body weight and serum albumin levels, and suppressed serum amyloid A level. There was no difference in tumor volume between MR16-1-treated mice and immunoglobulin G (IgG)-treated control mice. Decreased hemoglobin, hematocrit, and MCV in LC-06-JCK-bearing mice was significantly relieved by MR16-1 treatment. LC-06-JCK-bearing mice showed high red blood cell counts and erythropoietin levels as compared to NTB mice, whereas MR16-1 treatment did not affect their levels. Serum hepcidin and ferritin levels were statistically elevated in mice bearing LC-06-JCK. LC-06-JCK-bearing mice showed lower values of MCV, mean corpuscular hemoglobin (MCH), and serum iron as compared to NTB mice. Administration of MR16-1 to mice bearing LC-06-JCK significantly suppressed levels of both serum hepcidin and ferritin, with increased values of MCV and MCH.
  
  
  CONCLUSIONS
  Our results suggest that overproduction of hepcidin by IL-6 signaling might be a major factor that leads to functionally iron-deficient cancer-related anemia in the LC-06-JCK model. We demonstrated that inhibition of the IL-6 signaling pathway by MR16-1 treatment resulted in significant recovery of iron-deficiency anemia and alleviation of cancer-related symptoms. These results indicate that IL-6 signaling might be one possible target pathway to treat cancer-related anemia disorders.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan. noguchimrk@chugai-pharm.co.jp.
authors.forename: Mariko
authors.initials: M
authors.lastname: Noguchi-Sasaki
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Kazushige
authors.initials: K
authors.lastname: Mori
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Fujimoto-Ouchi
mesh_terms: D000740:Anemia / Q000097:blood / Q000473:pathology; D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage*; D002277:Carcinoma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D045744:Cell Line, Tumor; D064451:Hepcidins / Q000097:blood; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D051381:Rats; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors* / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000888:Antibodies, Anti-Idiotypic; D064451:Hepcidins; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D007501:Iron
keywords: Anemia; Cancer; Hepcidin; Interleukin-6; Iron metabolism