The involvement of iron and inflammation parameters on overall survival in non-small-cell lung cancer (NSCLC) patients was studied. Furthermore, transferrin receptors 1 (TfR1) and ferritin expression in tumor tissue, tumor stroma, and normal lung tissue were analyzed. Iron metabolism and inflammation parameters were determined by automated laboratory measurements at the time of diagnosis. TfR1 and ferritin expression were determined by immuno-histochemical methods. About 50% of patients survived 12 months only. At the time of diagnosis more than half of the patients had anemia and significantly elevated serum ferritin. Iron content of serum ferritin (ICF) was below the reference values in 90% of patients. Furthermore, ICF showed positive correlation with iron metabolic parameters and survival but negative correlation with serum ferritin and ESR. The expression of TfR1 and ferritin in tumor cells was observed in 88% or 62% of patients, respectively. Tumor stroma was TfR1 negative and sporadically ferritin positive. Tumor tissue ferritin expression showed negative correlation with serum iron and hematokrit (Ht), and positive correlation with ferritin, erythrocyte sedimentation rate (ESR), α-1 globulin, and α-2 globulin. Positive correlation was found between TfR1 expression in tumor tissue and α-globulin. The correlation between TfR1/ferritin expression in tumor tissue and ICF or survival was not observed. Therefore, we conclude that elevated serum ferritin in sera of NSCLC patients is the result of inflammation and oxidative stress rather than body iron overload. Higher expression of ferritin in tumor tissue may be the consequence of iron deficiency or local toxicity induced by environmental factors.
Non-small-cell lung carcinoma Transferrin receptors Ferritin Body iron stores ICF Inflammation
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The study was supported by the Croatian Ministry of Science, Education, and Sport.
Stevens RG, Jones DY, Micozzi MS, Taylor PR. Body iron stores and the risk of cancer. N Engl J Med. 1988;319(16):1047–52.PubMedCrossRefGoogle Scholar
Weinberg ED. Association of iron with respiratory tract neoplasia. J Trace Elem Exp Med. 1993;6:117–23.Google Scholar
Wrba F, Ritzinger E, Reiner A, Holzner JH. Transferrin receptor (TrfR) expression in breast carcinoma and its possible relationship to prognosis. An immunohistochemical study. Virchows Arch A Pathol Anat Histopathol. 1986;410(1):69–73. doi:10.1007/BF00710908.CrossRefPubMedGoogle Scholar
Ponka P, Beaumont C, Richardson DR. Function and regulation of transferrin and ferritin. Semin Hematol. 1998;35(1):35–54.PubMedGoogle Scholar
Yamanishi H, Iyama S, Yamaguchi Y, Kanakura Y, Iwatani Y. Relation between iron content of serum ferritin and clinical status factors extracted by factor analysis in patients with hyperferritinemia. Clin Biochem. 2002;35(7):523–9. doi:10.1016/S0009-9120(02)00380-6.CrossRefPubMedGoogle Scholar
Travis WD, Colby TV, Corrin B, et al. Histological typing of lung and pleural tumours. World Health Organization International Histological Classification of Tumors, XIII. 3rd ed. Berlin/Heidelberg: Springer-Verlag; 1999.Google Scholar
Sobin LH, Wittekind CL. TNM classification of malignant tumors. 6th ed. New York: John Wiley & Sons, Inc.; 2002.Google Scholar
Yovino S, Kwok Y, Krasna M, Bangalore M, Suntharalingam M. An association between preoperative anemia and decreased survival in early-stage non-small-cell lung cancer patients treated with surgery alone. Int J Radiat Oncol Biol Phys. 2005;62(5):1438–43. doi:10.1016/j.ijrobp.2004.12.038.PubMedGoogle Scholar
Li R, Luo C, Mines M, Zhang J, Fan GH. CV hemocine CXCL12 induces binding of ferritin heavy chain to the chemokine receptor CXCR4, alters CXCR4 signaling, and induces phosphorylation and translocation of ferritin heavy chain. J Biol Chem. 2006;281(49):37616–27. doi:10.1074/jbc.M607266200.CrossRefPubMedGoogle Scholar
Moroz C, et al. Treatment of human bone marrow with recombinant placenta immunomodulator ferritin results in myelopoiesis a T-cell suppression through modulation of the cytokine-chemokine networks. Exp Hematol. 2006;34(2):159–66. doi:10.1016/j.exphem.2005.10.006.CrossRefPubMedGoogle Scholar
Dallegri F, Patrone F, Frumento G, Sacchetti C. Antibody-dependent killing of tumor cells by polymorphonuclear leukocytes. Involvement of oxidative and nonoxidative mechanisms. J Natl Cancer Inst. 1984;73(2):331–9.PubMedGoogle Scholar
Dallegri F, Frumento G, Ballestrero A, Goretti R, Patrone F. Relationship between antibody-dependent tumour cell lysis and primary granule exocytosis by human neutrophils. Clin Exp Immunol. 1987;70(2):479–83.PubMedGoogle Scholar
Valerius T, et al. Involvement of the high-affinity receptor for IgG (Fc gamma RI; CD64) in enhanced tumor cell cytotoxicity of neutrophils during granulocyte colony-stimulating factor therapy. Blood. 1993;82(3):931–9.PubMedGoogle Scholar
Prutki M, Poljak-Blazi M, Mihaljevic B, Orescanin V, Zarkovic N. Uptake of anti-anemic substance ferric-sorbitol-citrate by normal and malignant cells and its effects on expression of transferrin receptor 1 and ferritin. Cancer Biother Radiopharm. 2006;21(6):636–44. doi:10.1089/cbr.2006.21.636.CrossRefPubMedGoogle Scholar
Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. 2nd ed. Oxford: Clarendon Press; 1989. 466.Google Scholar