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The Dysfunction of NK Cells in Patients with Type 2 Diabetes and Colon Cancer

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Archivum Immunologiae et Therapiae Experimentalis Aims and scope

Abstract

Glucose metabolism disorders influence anticarcinogenic function of natural killer (NK) cells. The aim of this study was to evaluate the number and cytotoxic activity of NK cells in type 2 diabetic (T2D) patients with negative family history of cancer, type 2 diabetic subjects with newly diagnosed untreated colon cancer (T2DCC) and patients without type 2 diabetes with newly diagnosed, untreated colon cancer (CC). Incubation tests were performed in 18 T2D patients, treated with diet and oral antidiabetic agents, 16 T2DCC; cT1-4N0M0 (c-clinical diagnosis based on computed tomography, colonoscopy and histopathology) treated with diet and oral antidiabetic agents and 16 normoglycemic CC; cT1-4N0M0. Control group included 18 metabolically healthy (with normal fasting glucose and normal glucose tolerance) subjects (HS) with negative family history of cancer, matched by age, BMI and waist circumference. Peripheral blood mononuclear cells were isolated by means of gradient centrifugation. The K562 human erythroleukemia cell line served as the standard target for human NK cytotoxicity assay. The T2D revealed an increased number of NK cells (13.56 ± 5.9 vs 9.50 ± 4.8 %; p < 0.05) when compared with HS, yet these cells had a decreased activity (3.3 ± 2.5 vs 9.4 ± 3.6 %; p < 0.01). The CC demonstrated a decreased activity (2.9 ± 1.8 %; p < 0.01) but a similar number (8.82 ± 3.7 %; not significant) of NK cells when compared to HS. The T2DCC NK cells were characterized by trace cytotoxic activity (1.1 ± 0.7 %; p < 0.01) and nearly three times greater amount (21.24 ± 7.5 %; p < 0.01) when compared to T2D. Type 2 diabetes and CC are associated with disadvantageous alterations of NK cells, leading to impairment in their cytotoxic activity. The impaired activity of NK cells in T2D can be involved in the increased carcinogenic risk and can promote a higher incidence of CC.

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References

  • Armitage P (1971) Statistical methods in medical research, 3rd edn. Blackwell Scientific Publications, Oxford

    Google Scholar 

  • Atchison EA, Gridley G, Carreon JD et al (2011) Risk of cancer in a large cohort of US veterans with diabetes. Int J Cancer 128:635–643

    Article  PubMed  CAS  Google Scholar 

  • Berster JM, Göke B (2008) Type 2 diabetes mellitus as risk factor for colon cancer. Arch Physiol Biochem 114:84–98

    Article  PubMed  CAS  Google Scholar 

  • Burt RW, Barthel JS, Dunn KB et al (2010) NCCN clinical practice guidelines in oncology. Colorectal cancer screening. J Natl Compr Canc Netw 8:8–61

    PubMed  Google Scholar 

  • Buzzai M, Jones RG, Amaravadi RK et al (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67:6745–6752

    Article  PubMed  CAS  Google Scholar 

  • Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52:1766–1777

    Article  PubMed  CAS  Google Scholar 

  • Czech A, Piatkiewicz P, Tatoń J (2009) Cellular glucose transport and glucotransporter 4 expression as a therapeutic target: clinical and experimental studies. Arch Immunol Ther Exp 57:467–473

    Article  CAS  Google Scholar 

  • Feng YH, Velazquez-Torres G, Gully C et al (2011) The impact of type 2 diabetes and antidiabetic drugs on cancer cell growth. J Cell Mol Med 15:825–836

    Article  PubMed  CAS  Google Scholar 

  • Flood A, Strayer L, Schairer C et al (2010) Diabetes and risk of incident colorectal cancer in a prospective cohort of women. Cancer Causes Control 21:1277–1284

    Article  PubMed  Google Scholar 

  • Gallagher EJ, LeRoith D (2011) Diabetes, cancer and metformin: connections of metabolism and cell proliferation. Ann NY Acad Sci 1243:54–68

    Article  PubMed  CAS  Google Scholar 

  • Gonzalez-Angulo AM, Meric-Bernstam F (2010) Metformin: a therapeutic opportunity in breast cancer. Clin Cancer Res 16:1695–1700

    Article  PubMed  CAS  Google Scholar 

  • Hannet I, Erkeller-Yurksel F, Deneys V et al (1992) Lymphocyte populations as a function of age. Immunol Today 13:215–218

    Article  PubMed  CAS  Google Scholar 

  • Held W, Kijima M, Angelov G et al (2011) The function of natural killer cells: education, reminders and some good memories. Curr Opin Immunol 23:228–233

    Article  PubMed  CAS  Google Scholar 

  • Hemminki K, Li X, Sundquist J, Sundquist K (2010) Risk of cancer following hospitalization for type 2 diabetes. Oncologist 15:548–555

    Article  PubMed  Google Scholar 

  • Herberman RB, Ortaldo JR (1981) Natural killer cells: their role in defenses against disease. Science 214:24–30

    Article  PubMed  CAS  Google Scholar 

  • Herberman RB, Nunn ME, Lavrin DH (1975a) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. I. Distribution of reactivity and specificity. Int J Cancer 16:216–229

    Article  PubMed  CAS  Google Scholar 

  • Herberman RB, Nunn ME, Holden HT et al (1975b) Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells. Int J Cancer 16:230–239

    Article  PubMed  CAS  Google Scholar 

  • Hercend T, Takvorian T, Nowill A et al (1986) Characterization of natural killer cells with antileukemia activity following allogeneic bone marrow transplantation. Blood 67:722–728

    PubMed  CAS  Google Scholar 

  • Hjartåker A, Langseth H, Weiderpass E (2008) Obesity and diabetes epidemics: cancer repercussions. Adv Exp Med Biol 630:72–93

    Article  PubMed  Google Scholar 

  • Inoue M, Iwasaki M, Otani T et al (2006) Diabetes mellitus and the risk of cancer: results from a large-scale population-based cohort study in Japan. Arch Intern Med 166:1871–1877

    Article  PubMed  Google Scholar 

  • Iovino F, Meraviglia S, Spina M et al (2011) Immunotherapy targeting colon cancer stem cells. Immunotherapy 3:97–106

    Article  PubMed  CAS  Google Scholar 

  • Jaime-Ramirez AC, Mundy-Bosse BL, Kondadasula S et al (2011) IL-12 enhances the antitumor actions of trastuzumab via NK cell IFN-γ production. J Immunol 186:3401–3409

    Article  PubMed  CAS  Google Scholar 

  • Jenab M, Riboli E, Cleveland RJ et al (2007) Serum C-peptide, IGFBP-1 and IGFBP-2 and risk of colon and rectal cancers in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer 121:368–376

    Article  PubMed  CAS  Google Scholar 

  • Johann S, Blümel G, Lipp M et al (1995) A versatile flow cytometry-based assay for the determination of short- and long-term natural killer cell activity. J Immunol Methods 185:209–216

    Article  PubMed  CAS  Google Scholar 

  • Kaaks R, Toniolo P, Akhmedkhanov A et al (2000) Serum C-peptide, insulin-like growth factor (IGF)-I, IGF-binding proteins, and colorectal cancer risk in women. J Natl Cancer Inst 92:1592–1600

    Article  PubMed  CAS  Google Scholar 

  • Kahi CJ, Imperiale TF, Juliar BE et al (2009) Effect of screening colonoscopy on colorectal cancer incidence. Clin Gastroenterol Hepatol 7:770–775

    Article  PubMed  Google Scholar 

  • Kane KL, Ashton FA, Schmitz JL et al (1996) Determination of natural killer cell function by flow cytometry. Clin Diagn Lab Immunol 3:295–300

    PubMed  CAS  Google Scholar 

  • Keever CA, Pekle K, Gazzola MV et al (1989) Natural killer and lymphokine-activated killer cell activities from human marrow precursors. II. The effects of IL-3 and IL-4. J Immunol 143:3241–3249

    PubMed  CAS  Google Scholar 

  • Lanier LL, Phillips JH, Hackett J Jr et al (1986) Natural killer cells: definition of a cell type rather than a function. J Immunol 137:2735–2739

    PubMed  CAS  Google Scholar 

  • Larsson SC, Orsini N, Wolk A (2005) Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 97:1679–1687

    Article  PubMed  Google Scholar 

  • LeRoith D, Novosyadlyy R, Gallagher EJ et al (2008) Obesity and type 2 diabetes are associated with an increased risk of developing cancer and a worse prognosis; epidemiological and mechanistic evidence. Exp Clin Endocrinol Diabetes 116(Suppl 1):S4–S6

    Article  PubMed  CAS  Google Scholar 

  • Libby G, Donnelly LA, Donnan PT et al (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625

    Article  PubMed  CAS  Google Scholar 

  • Ma J, Giovannucci E, Pollak M et al (2004) A prospective study of plasma C-peptide and colorectal cancer risk in men. J Natl Cancer Inst 96:546–553

    Article  PubMed  CAS  Google Scholar 

  • Migliorati G, Cannarile L, Herberman RB et al (1989) Effect of various cytokines and growth factors on the interleukin-2- dependent in vitro differentiation of natural killer cells from bone marrow. Nat Immun Cell Growth Regul 8:48–55

    PubMed  CAS  Google Scholar 

  • Moretta L, Moretta A (2004) Unravelling natural killer cell function: triggering and inhibitory human NK receptors. EMBO J 23:255–259

    Article  PubMed  CAS  Google Scholar 

  • Moretta L, Bottino C, Pende D et al (2005) Human natural killer cells: molecular mechanisms controlling NK cell activation and tumor cell lysis. Immunol Lett 100:7–13

    Article  PubMed  CAS  Google Scholar 

  • Moutschen MP, Scheen AJ, Lefebvre PJ (1992) Impaired immune responses in diabetes mellitus: analysis of the factors and mechanisms involved. Relevance to the increased susceptibility of diabetic patients to specific infections. Diabetes Metab 18:187–201

    CAS  Google Scholar 

  • Ozer H, Strelkauskas AJ, Callery RT et al (1979) The functional dissection of human peripheral null cells with respect to antibody-dependent cytotoxicity and natural killing. Eur J Immunol 9:112–118

    Article  PubMed  CAS  Google Scholar 

  • Piątkiewicz P, Czech A (2011) Glucose metabolism disorders and the risk of cancer. Arch Immunol Ther Exp 59:215–230

    Article  Google Scholar 

  • Piątkiewicz P, Czech A, Piątkiewicz A (2010) The pathophysiology of the NK (natural killer) cells. Med Metabol 15:71–76

    Google Scholar 

  • Pross HF (1986) The involvement of natural killer cells in human malignant disease. In: Lotzova E, Herberman RB (eds) Immunobiology of natural killer cells, vol 2. CRC, Boca Raton, p 11

    Google Scholar 

  • Rex DK, Johnson DA, Anderson JC et al (2009) American Collage of Gastroenterology guidelines for colorectal cancer screening 2009. Am J Gastroenterol 104:739–750

    Article  PubMed  Google Scholar 

  • Ritz J, Schmidt RE, Michon J et al (1988) Characterization of functional surface structures on human natural killer cells. Adv Immunol 42:181–211

    Article  PubMed  CAS  Google Scholar 

  • Robertson MJ, Ritz J (1990) Biology and clinical relevance of human natural killer cells. Blood 76:2421–2438

    PubMed  CAS  Google Scholar 

  • Roder JC, Haliotis T, Klein M et al (1980) A new immunodeficiency disorder in humans involving NK cells. Nature 284:553–555

    Article  PubMed  CAS  Google Scholar 

  • Rooney CM, Wimperis JZ, Brenner MK et al (1986) Natural killer cell activity following T-cell depleted allogeneic bone marrow transplantation. Br J Haematol 62:413–420

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg EB, Herberman RB, Levine PH et al (1972) Lymphocyte cytotoxicity reactions to leukemia-associated antigens in identical twins. Int J Cancer 9:648–658

    Article  PubMed  CAS  Google Scholar 

  • Sakakibara M, Kanto T, Hayakawa M et al (2011) Comprehensive immunological analyses of colorectal cancer patients in the phase I/II study of quickly matured dendritic cell vaccine pulsed with carcinoembryonic antigen peptide. Cancer Immunol Immunother 60:1565–1575

    Article  PubMed  CAS  Google Scholar 

  • Spooren PF, Vermes I, Soons JW (1993) Similar alterations of lymphocyte subpopulations in type I and type II diabetes. Neth J Med 42:163–167

    PubMed  CAS  Google Scholar 

  • Sullivan JL, Byron KS, Brewster FE et al (1980) Deficient natural killer cell activity in X-linked lymphoproliferative syndrome. Science 210:543–545

    Article  PubMed  CAS  Google Scholar 

  • Timonen T, Ortaldo JR, Herberman RB (1981) Characteristics of human large granular lymphocytes and relationship to natural killer and K cells. J Exp Med 153:569–582

    Article  PubMed  CAS  Google Scholar 

  • Trinchieri G (1989) Biology of natural killer cells. Adv Immunol 47:187–376

    Article  PubMed  CAS  Google Scholar 

  • Tseng CH (2012) Diabetes, metformin use, and colon cancer: a population-based cohort study in Taiwan. Eur J Endocrinol 167:409–416

    Article  PubMed  CAS  Google Scholar 

  • Van den Brink MR, Boggs SS, Herberman RB et al (1990) The generation of natural killer (NK) cells from NK precursor cells in rat long-term bone marrow cultures. J Exp Med 172:303–313

    Article  PubMed  Google Scholar 

  • Wei EK, Ma J, Pollak MN et al (2005) A prospective study of C-peptide, insulin-like growth factor-I, insulin-like growth factor binding protein-1, and the risk of colorectal cancer in women. Cancer Epidemiol Biomark Prev 14:850–8555

    Article  CAS  Google Scholar 

  • Zheng C, Feng J, Lu D et al (2011) A novel anti-CEACAM5 monoclonal antibody, CC4, suppresses colorectal tumor growth and enhances NK cells-mediated tumor immunity. PLoS ONE 6:e21146

    Article  PubMed  CAS  Google Scholar 

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Correspondence to Paweł Piątkiewicz.

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Piątkiewicz, P., Miłek, T., Bernat-Karpińska, M. et al. The Dysfunction of NK Cells in Patients with Type 2 Diabetes and Colon Cancer. Arch. Immunol. Ther. Exp. 61, 245–253 (2013). https://doi.org/10.1007/s00005-013-0222-5

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  • DOI: https://doi.org/10.1007/s00005-013-0222-5

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