Turkiye Klinikleri Journal of Internal Medicine

.: REVIEW
Kanser ve İmmün Sistem: Sistematik Derleme
Cancer and Immune System: Systematic Review
Ali AYTAÇa, Sabri BARUTCAa
aAdnan Menderes Üniversitesi Tıp Fakültesi, Tıbbi Onkoloji BD, Aydın, Türkiye
Turkiye Klinikleri J Intern Med. 2022;7(1):29-40
doi: 10.5336/intermed.2021-87901
Article Language: TR
Full Text
ÖZET
İmmün sistem hücreleri, bir yandan kanser hücrelerine karşı antitümöral etkinlik gösterirken diğer yandan kronik inflamasyon zemininde tümör gelişimi ve progresyonunda rol alırlar. Yani inflamasyon, tümör hücrelerini ortadan kaldırabildiği gibi karsinogeneze katkı da sağlayabilir. İnflamasyonun bu ikili rolü, immün yetmezliği olan hastalarda daha çok kanser gelişimi yönünde kendini gösterir. Kronik inflamasyon kanserde önemli bir role sahipken, akut inflamasyonun tümör ilerlemesi üzerindeki etkisi hakkında daha az şey bilinmektedir. İlginç bir şekilde, uzun süreli nonsteroid antiinflamatuar ilaçların kullanımı sonucu kronik inflamasyonun baskılanması, özellikle kolorektal kanserler için risk azalımı sağlamaktadır. Dolayısıyla inflamatuar yanıtı terapötik olarak ayarlayabilmek, kansere karşı mücadelede çok önemli olacaktır. Adaptif T hücrelerini ve antikorları içeren pasif immünoterapilerle son zamanlarda yüz güldürücü sonuçlar elde edilmiştir. Ancak doğuştan gelen (innate) immün sistemin, endojen olarak ortaya çıkan kanseri nasıl tanıdığı, moleküler düzeyde yeterince anlaşılmamıştır ve bu, aktif kanser immünoterapisinin geliştirilmesinde önemli bir engel teşkil etmektedir. Kanser hücreleri ve doğuştan gelen (innate) immün sistem hücrelerinin doğrudan veya dolaylı yollarla etkileşim mekanizmalarını aydınlatmak, mevcut immünoterapilerin de etkisini potansiyelize edecektir. Güncel literatür daha çok immün hücrelerin aktivasyonunun kanser hücreleri ile savaşta önemli role sahip olduklarından bahsetmektedir. Bu derlemede, kanserin gelişiminden son evresine dek olan süreçte, özellikle doğal (innate) immün sistem elemanlarının kronik inflamasyon zemininde kanser oluşumu ve progresyonundaki rollerini değerlendirmeye çalıştık.

Anahtar Kelimeler: Karsinogenez; bağışıklık sistemi; doğal bağışıklık; kazanılmış bağışıklık
ABSTRACT
Immune system cells show antitumoral activity against cancer cells but they also play a role in tumor development and progression on the basis of chronic inflammation. In other words, inflammation can both eliminate tumor cells and contribute to carcinogenesis. This dual role of inflammation is more evident in the development of cancer in immunocompromised patients. Although chronic inflammation has an important role in cancer, the effect of acute inflammation on tumor progression is less known. Suppression of chronic inflammation as a result of long-term use of nonsteroidal anti-inflammatory drugs interestingly provides a reduced risk, especially for colorectal cancers. Therefore therapeutically adjusting the inflammatory response will be crucial in the fight against cancer. Promising results have been obtained with passive immunotherapy including adaptive T cells and antibodies, recently. However, how the innate immune system recognizes endogenous cancer is poorly understood at the molecular level, and this still represents a major obstacle to the development of active cancer immunotherapy. Illüminating the interaction mechanisms of cancer cells and innate immune system cells directly or indirectly will potentiate the effect of exist immunotherapies. Current literature generally mentions that the activation of immune cells has an important role in the fight against cancer cells. In this review, we tried to evaluate the role of innate immune system elements in the formation and progression of cancer in the context of chronic inflammation, from the development of cancer to its final stage.

Keywords: Carcinogenesis; immune system; innate immunity; adaptive immunitiy
REFERENCES:
  1. Monica Escamilla-Tilch, Georgina Filio-Rodriquez, Rosario García-Rocha, Macilla-Herrara I, Mitchison NA, Ruiz-Pacheco JA, et al. The interplay between pathogen‐associated and danger‐associated molecular patterns: an inflammatory code in cancer? Immunol Cell Biol. 2013;91(10):601-10. [Crossref]  [PubMed] 
  2. Mantovani A. Cancer: inflaming metastasis. Nature. 2009;457(7225):36-7. [Crossref]  [PubMed] 
  3. Bosch FX, Lorincz A, Mu-oz N, Meijer CJLM, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55(4):244-65. [Crossref]  [PubMed]  [PMC] 
  4. Lakatos PL, Lakatos L. Risk for colorectal cancer in ulcerative colitis: changes, causes and management strategies. World J Gastroenterol. 2008;14(25):3937-47. [Crossref]  [PubMed]  [PMC] 
  5. Samraj AN, Pearce OM, Läubli H, Crittenden AN, Bergfeld AK, Banda K, et al. A red meat-derived glycan promotes inflammation and cancer progression. Proc Natl Acad Sci U S A. 2015;112(2):542-7. [Crossref]  [PubMed]  [PMC] 
  6. Howe LR, Subbaramaiah K, Hudis CA, Dannenberg AJ. Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res. 2013;19(22):6074-83. [Crossref]  [PubMed]  [PMC] 
  7. Balkwill F, Mantovani A. Inflammation and cancer: back to Virchow? Lancet. 2001;357(9255):539-45. [Crossref]  [PubMed] 
  8. Ratliff TL, Gillen D, Catalona WJ. Requirement of a thymus dependent immune response for BCG-mediated antitumor activity. J Urol. 1987;137(1):155-8. [Crossref]  [PubMed] 
  9. Stanton SE, Adams S, Disis ML. Variation in the incidence and magnitude of tumor-infiltrating lymphocytes in breast cancer subtypes. JAMA Oncol. 2016;2(10):1354-60. [Crossref]  [PubMed] 
  10. Ladjemi MZ, Jacot W, Chardès T, Pèlegrin A, Navarro-Teulon I. Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol Immunother. 2010;59(9):1295-312. [Crossref]  [PubMed]  [PMC] 
  11. Baselga J, Albanell J. Mechanism of action of anti-HER2 monoclonal antibodies. Ann Oncol. 2001;12(Suppl 1):S35-41. [Crossref]  [PubMed] 
  12. Dasanu CA, Bockorny B, Grabska J, Codreanu I. Prevalence and pattern of autoimmune conditions in patients with marginal zone lymphoma: a single ınstitution experience. Conn Med. 2015;79(4):197-200. [PubMed] 
  13. Fallah M, Liu X, Ji J, Forsti A, Sundquist K, Hemminki K. Hodgkin lymphoma after autoimmune diseases by age at diagnosis and histological subtype. Ann Oncol. 2014;25(7):1397-404. [Crossref]  [PubMed] 
  14. Ehrenfeld M. Cancer and autoimmunity. In: Anaya JM, Cervera R, Levy RA, Rojas-Villarraga A, Shoenfeld Y, eds. Autoimmunity: From Bench to Bedside. 1st ed. Bogota, Colombia : Center for Autoimmune Diseases Research, School of Medicine and Health Sciences, El Rosario University; 2013. p.683-9.
  15. Nayak P, Luo R, Elting L, Zhao H, Suarez-Almazor ME. Impact of rheumatoid arthritis on the mortality of elderly patients who develop cancer: a population-based study. Arthritis Care Res (Hoboken). 2017;69(1):75-83. [Crossref]  [PubMed] 
  16. Liang Y, Yang Z, Qin B, Zhong R. Primary Sjogren's syndrome and malignancy risk: a systematic review and meta-analysis. Ann Rheum Dis. 2014;73(6):1151-6. [Crossref]  [PubMed] 
  17. Mao S, Shen H, Zhang J. Systemic lupus erythematosus and malignancies risk. J Cancer Res Clin Oncol. 2016;142(1):253-62. [Crossref]  [PubMed] 
  18. Giat E, Ehrenfeld M, Shoenfeld Y. Cancer and autoimmune diseases. Autoimmun Rev. 2017;16(10):1049-57. [Crossref]  [PubMed] 
  19. Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. J Intern Med. 2000;248(3):171-83. [Crossref]  [PubMed] 
  20. Lucas SB. Squamous cell carcinoma of the bladder and schistosomiasis. East Afr Med J. 1982;59(5):345-51. [PubMed] 
  21. Palucka AK, Coussens LM. The basis of oncoimmunology. Cell. 2016;164(6):1233-47. [Crossref]  [PubMed]  [PMC] 
  22. Clemente CG, Mihm MC Jr, Bufalino R, Zurrida S, Collini P, Cascinelli N. Prognostic value of tumor infiltrating lymphocytes in the vertical growth phase of primary cutaneous melanoma. Cancer. 1996;77(7):1303-10. [Crossref]  [PubMed] 
  23. Dieu-Nosjean MC, Antoine M, Danel C, Heudes D, Wislez M, Poulot V, et al. Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J Clin Oncol. 2008;26(27):4410-7. [Crossref]  [PubMed] 
  24. Zhang QW, Liu L, Gong CY, Shi HS, Zeng YH, Wang XZ, et al. Prognostic significance of tumor-associated macrophages in solid tumor: a meta-analysis of the literature. PLoS One. 2012;7(12):e50946. [Crossref]  [PubMed]  [PMC] 
  25. Lavin Y, Mortha A, Rahman A, Merad M. Regulation of macrophage development and function in peripheral tissues. Nat Rev Immunol. 2015;15(12):731-44. [Crossref]  [PubMed]  [PMC] 
  26. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol. 2002;23(11):549-55. [Crossref]  [PubMed] 
  27. Qian BZ, Zhang H, Li J, He T, Yeo EJ, Soong DY, et al. FLT1 signaling in metastasis-associated macrophages activates an inflammatory signature that promotes breast cancer metastasis. J Exp Med. 2015;212(9):1433-48. [Crossref]  [PubMed]  [PMC] 
  28. Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, et al. Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008;28(4):546-58. [Crossref]  [PubMed] 
  29. Shojaei F, Zhong C, Wu X, Yu L, Ferrara N. Role of myeloid cells in tumor angiogenesis and growth. Trends Cell Biol. 2008;18(8):372-8. [Crossref]  [PubMed] 
  30. Kessenbrock K, Plaks V, Werb Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell. 2010;141(1):52-67. [Crossref]  [PubMed]  [PMC] 
  31. Kamp DW, Graceffa P, Pryor WA, Weitzman SA. The role of free radicals in asbestos-induced diseases. Free Radic Biol Med. 1992;12(4):293-315. [Crossref]  [PubMed] 
  32. Iguchi H, Kojo S, Ikeda M. Nitric oxide (NO) synthase activity in the lung and NO synthesis in alveolar macrophages of rats increased on exposure to asbestos. J Appl Toxicol. 1996;16(4):309-15. [Crossref]  [PubMed] 
  33. Donskov F. Immunomonitoring and prognostic relevance of neutrophils in clinical trials. Semin Cancer Biol. 2013;23(3):200-7. [Crossref]  [PubMed] 
  34. Chang SH, Mirabolfathinejad SG, Katta H, Cumpian AM, Gong L, Caetano MS, et al. T helper 17 cells play a critical pathogenic role in lung cancer. Proc Natl Acad Sci U S A. 2014;111(15):5664-9. [Crossref]  [PubMed]  [PMC] 
  35. Houghton AM, Rzymkiewicz DM, Ji H, Gregory AD, Egea EE, Metz HE, et al. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nat Med. 2010;16(2):219-23. [Crossref]  [PubMed]  [PMC] 
  36. Cools-Lartigue J, Spicer J, Najmeh S, Ferri L. Neutrophil extracellular traps in cancer progression. Cell Mol Life Sci. 2014;71(21):4179-94. [Crossref]  [PubMed]  [PMC] 
  37. Tohme S, Yazdani HO, Al-Khafaji AB, Chidi AP, Loughran P, Mowen K, et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res. 2016;76(6):1367-80. [Crossref]  [PubMed]  [PMC] 
  38. Perera Molligoda Arachchige AS. Human NK cells: From development to effector functions. Innate Immun. 2021;27(3):212-29. [Crossref]  [PubMed]  [PMC] 
  39. Marcus A, Gowen BG, Thompson TW, Iannello A, Ardolino M, Deng W, et al. Recognition of tumors by the innate immune system and natural killer cells. Adv Immunol. 2014;122:91-128. [Crossref]  [PubMed]  [PMC] 
  40. Coca S, Perez-Piqueras J, Martinez D, Colmenarejo A, Saez MA, Vallejo C, et al. The prognostic significance of intratumoral natural killer cells in patients with colorectal carcinoma. Cancer. 1997;79(12):2320-8. [Crossref]  [PubMed] 
  41. Ishigami S, Natsugoe S, Tokuda K, Nakajo A, Che X, Iwashige H, et al. Prognostic value of intratumoral natural killer cells in gastric carcinoma. Cancer. 2000;88(3):577-83. [Crossref]  [PubMed] 
  42. Iannello A, Thompson TW, Ardolino M, Lowe SW, Raulet DH. p53-dependent chemokine production by senescent tumor cells supports NKG2D-dependent tumor elimination by natural killer cells. J Exp Med. 2013;210(10):2057-69. [Crossref]  [PubMed]  [PMC] 
  43. Voskoboinik I, Smyth MJ, Trapani JA. Perforin-mediated target-cell death and immune homeostasis. Nat Rev Immunol. 2006;6(12):940-52. [Crossref]  [PubMed] 
  44. Andrews DM, Sullivan LC, Baschuk N, Chan CJ, Berry R, Cotterell CL, et al. Recognition of the nonclassical MHC class I molecule H2-M3 by the receptor Ly49A regulates the licensing and activation of NK cells. Nat Immunol. 2012;13(12):1171-7. [Crossref]  [PubMed]  [PMC] 
  45. Glasner A, Ghadially H, Gur C, Stanietsky N, Tsukerman P, Enk J, et al. Recognition and prevention of tumor metastasis by the NK receptor NKp46/NCR1. J Immunol. 2012;188(6):2509-15. [Crossref]  [PubMed] 
  46. Mildner A, Jung S. Development and function of dendritic cell subsets. Immunity. 2014;40(5):642-56. [Crossref]  [PubMed] 
  47. Tran Janco JM, Lamichhane P, Karyampudi L, Knutson KL. Tumor-infiltrating dendritic cells in cancer pathogenesis. J Immunol. 2015;194(7):2985-91. [Crossref]  [PubMed]  [PMC] 
  48. Ma Y, Adjemian S, Mattarollo SR, Yamazaki T, Aymeric L, Yang H, et al. Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells. Immunity. 2013;38(4):729-41. [Crossref]  [PubMed] 
  49. Wilgenhof S, Corthals J, Heirman C, van Baren N, Lucas S, Kvistborg P, et al. Phase II Study of Autologous monocyte-derived mRNA electroporated dendritic cells (TriMixDC-MEL) plus ıpilimumab in patients with pretreated advanced melanoma. J Clin Oncol. 2016;34(12):1330-8. [Crossref]  [PubMed] 
  50. Böttcher JP, Bonavita E, Chakravarty P, Blees H, Cabeza-Cabrerizo M, Sammicheli S, et al. NK cells stimulate recruitment of cdc1 into the tumor microenvironment promoting cancer immune control. Cell. 2018;172(5):1022-37.e14. [Crossref]  [PubMed]  [PMC] 
  51. Kusuda T, Shigemasa K, Arihiro K, Fujii T, Nagai N, Ohama K. Relative expression levels of Th1 and Th2 cytokine mRNA are independent prognostic factors in patients with ovarian cancer. Oncol Rep. 2005;13(6):1153-8. [Crossref]  [PubMed] 
  52. Tosolini M, Kirilovsky A, Mlecnik B, Fredriksen T, Mauger S, Bindea G, et al. Clinical impact of different classes of infiltrating T cytotoxic and helper cells (Th1, th2, treg, th17) in patients with colorectal cancer. Cancer Res. 2011;71(4):1263-71. [Crossref]  [PubMed] 
  53. Kondo T, Nakazawa H, Ito F, Hashimoto Y, Osaka Y, Futatsuyama K, et al. Favorable prognosis of renal cell carcinoma with increased expression of chemokines associated with a Th1-type immune response. Cancer Sci. 2006;97(8):780-6. [Crossref]  [PubMed] 
  54. Vesalainen S, Lipponen P, Talja M, Syrjänen K. Histological grade, perineural infiltration, tumour-infiltrating lymphocytes and apoptosis as determinants of long-term prognosis in prostatic adenocarcinoma. Eur J Cancer. 1994;30A(12):1797-803. [Crossref]  [PubMed] 
  55. Ubukata H, Motohashi G, Tabuchi T, Nagata H, Konishi S, Tabuchi T. Evaluations of interferon-γ/interleukin-4 ratio and neutrophil/lymphocyte ratio as prognostic indicators in gastric cancer patients. J Surg Oncol. 2010;102(7):742-7. [Crossref]  [PubMed] 
  56. Shankaran V, Ikeda H, Bruce AT, White JM, Swanson PE, Old LJ, et al. IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. Nature. 2001;410(6832):1107-11. [Crossref]  [PubMed] 
  57. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140(6):883-99. [Crossref]  [PubMed]  [PMC] 
  58. Teng MW, Galon J, Fridman WH, Smyth MJ. From mice to humans: developments in cancer immunoediting. J Clin Invest. 2015;125(9):3338-46. [Crossref]  [PubMed]  [PMC] 
  59. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-64. [Crossref]  [PubMed]  [PMC] 
  60. Ward-Hartstonge KA, Kemp RA. Regulatory T-cell heterogeneity and the cancer immune response. Clin Transl Immunology. 2017;6(9):e154. [Crossref]  [PubMed]  [PMC] 
  61. Bos PD, Plitas G, Rudra D, Lee SY, Rudensky AY. Transient regulatory cell ablation deters oncogene-driven breast cancer and enhances radiotherapy. J Exp Med. 2013;210(11):2435-66. [Crossref]  [PubMed]  [PMC] 
  62. Allaoui R, Hagerling C, Desmond E, Warfvinge CF, Jirström K, Leandersson K. Infiltration of γ⁢δ T cells, IL-17+ T cells and FoxP3+ T cells in human breast cancer. Cancer Biomark. 2017;20(4):395-409. [Crossref]  [PubMed]  [PMC] 
  63. Erfani N, Mehrabadi SM, Ghayumi MA, Haghshenas MR, Mojtahedi Z, Ghaderi A, et al. Increase of regulatory T cells in metastatic stage and CTLA-4 over expression in lymphocytes of patients with non-small cell lung cancer (NSCLC). Lung Cancer. 2012;77(2):306-11. [Crossref]  [PubMed] 
  64. Wang Q, Feng M, Yu T, Liu X, Zhang P. Intratumoral regulatory T cells are associated with suppression of colorectal carcinoma metastasis after resection through overcoming IL-17 producing T cells. Cell Immunol. 2014;287(2):100-5. [Crossref]  [PubMed] 
  65. Ye LY, Chen W, Bai XL, Xu XY, Zhang Q, Xia XF, et al. Hypoxia-induced epithelial-to-mesenchymal transition in hepatocellular carcinoma induces an immunosuppressive tumor microenvironment to promote metastasis. Cancer Res. 2016;76(4):818-30. [Crossref]  [PubMed] 
  66. De Silva NS, Klein U. Dynamics of B cells in germinal centres. Nat Rev Immunol. 2015;15(3):137-48. [Crossref]  [PubMed]  [PMC] 
  67. Chin Y, Janseens J, Vandepitte J, Vandenbrande J, Opdebeek L, Raus J. Phenotypic analysis of tumor-infiltrating lymphocytes from human breast cancer. Anticancer Res. 1992;12(5):1463-6. [PubMed] 
  68. Yang C, Lee H, Jove V, Deng J, Zhang W, Liu X, et al. Prognostic significance of B-cells and pSTAT3 in patients with ovarian cancer. PLoS One. 2013;8(1):e54029. [Crossref]  [PubMed]  [PMC] 
  69. de Visser KE, Korets LV, Coussens LM. De novo carcinogenesis promoted by chronic inflammation is B lymphocyte dependent. Cancer Cell. 2005;7(5):411-23. [Crossref]  [PubMed] 
  70. Schioppa T, Moore R, Thompson RG, Rosser EC, Kulbe H, Nedospasov S, et al. B regulatory cells and the tumor-promoting actions of TNF-α during squamous carcinogenesis. Proc Natl Acad Sci U S A. 2011;108(26):10662-7. [Crossref]  [PubMed]  [PMC] 
  71. Olkhanud PB, Damdinsuren B, Bodogai M, Gress RE, Sen R, Wejksza K, et al. Tumor-evoked regulatory B cells promote breast cancer metastasis by converting resting CD4⁺ T cells to T-regulatory cells. Cancer Res. 2011;71(10):3505-15. [Crossref]  [PubMed]  [PMC] 
  72. Pylayeva-Gupta Y, Das S, Handler JS, Hajdu CH, Coffre M, Koralov SB. IL35-producing B cells promote the development of pancreatic neoplasia. Cancer Discov. 2016;6(3):247-55. [Crossref]  [PubMed]  [PMC] 

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4.5. "USER"s accept and undertake that the information and context they provided to the "SITE" are accurate and legal. "Turkiye Klinikleri" is not liable and responsible for promising and guaranteeing the verification of the information and context transmitted to "Turkiye Klinikleri" by the "USER"s, or uploaded, changed and provided through the "SITE" by them and whether these information are safe, accurate and legal.

4.6. "USER"s agree and undertake that they will not perform any action leading to unfair competition, weakening the personal and commercial credit of "Turkiye Klinikleri" and a third party,  encroaching and attacking on personal rights within the "SITE" in accordance with the Turkish Commercial Code Law.

4.7. "Turkiye Klinikleri" reserves the right to change the services and the context within the "SITE"  anytime. "Turkiye Klinikleri" may use this right without any notification and timelessly. "USER"s have to make the changes and/or corrections "Turkiye Klinikleri" required immediately. Any changes and/or corrections that are required by "Turkiye Klinikleri", may be made by "Turkiye Klinikleri" when needed. Any harm, criminal and civil liability resulted or will result from changes and/or corrections required by "Turkiye Klinikleri" and were not made on time by the "USER"s belongs completely to the users.

4.8. "Turkiye Klinikleri" may give links through the "SITE" to other websites and/or "CONTEXT"s and/or folders that are outside of their control and owned and run by third parties. These links are provided for ease of reference only and do not hold qualification for support the respective web SITE or the admin or declaration or guarantee for the information inside. "Turkiye Klinikleri" does not hold any responsibility over the web-sites connected through the links on the "SITE", folders and context, the services or products on the websites provided through these links or their context.

4.9. "Turkiye Klinikleri" may use the information provided to them by the "USERS" through the "SITE" in line with the terms of the "PRIVACY POLICY" and "USER CONTRACT". It may process the information or classify and save them on a database. "Turkiye Klinikleri" may also use the USER's or visitor's identity, address, e-mail address, phone number, IP number, which sections of the "SITE" they visited, domain type, browser type, date and time information to provide statistical evaluation and customized services.

5. PROPRIETARY RIGHTS

5.1. The information accessed through this "SITE" or provided by the users legally and all the elements (including but not limited to design, text, image, html code and other codes) of the "SITE" (all of them will be called as studies tied to "Turkiye Klinikleri"s copyrights) belongs to "Turkiye Klinikleri". Users do not have the right to resell, process, share, distribute, display or give someone permission to access or to use the "Turkiye Klinikleri" services, "Turkiye Klinikleri" information and the products under copyright protection by "Turkiye Klinikleri". Within hereby "Terms of Use" unless explicitly permitted by "Turkiye Klinikleri" nobody can reproduce, process, distribute or produce or prepare any study from those under "Turkiye Klinikleri" copyright protection.

5.2. Within hereby "Terms of Use", "Turkiye Klinikleri" reserves the rights for "Turkiye Klinikleri" services, "Turkiye Klinikleri" information, the products associated with "Turkiye Klinikleri" copyrights, "Turkiye Klinikleri" trademarks, "Turkiye Klinikleri" trade looks or its all rights for other entity and information it has through this website unless it is explicitly authorized by "Turkiye Klinikleri".

6. CHANGES IN THE TERMS OF USE

"Turkiye Klinikleri" in its sole discretion may change the hereby "Terms of Use" anytime announcing within the "SITE". The changed terms of the hereby "Terms of Use" will become valid when they are announced. Hereby "Terms of Use" cannot be changed by unilateral declarations of users.

7. FORCE MAJEURE

"Turkiye Klinikleri" is not responsible for executing late or never of this hereby "Terms of Use", privacy policy and "USER Contract" in any situation legally taken into account as force majeure. Being late or failure of performance or non-defaulting of this and similar cases like this will not be the case from the viewpoint of "Turkiye Klinikleri", and "Turkiye Klinikleri" will not have any damage liability for these situations. "Force majeure" term will be regarded as outside of the concerned party's reasonable control and any situation that "Turkiye Klinikleri" cannot prevent even though it shows due diligence. Also, force majeure situations include but not limited to natural disasters, rebellion, war, strike, communication problems, infrastructure and internet failure, power cut and bad weather conditions.

8. LAW AND AUTHORISATION TO FOLLOW

Turkish Law will be applied in practicing, interpreting the hereby "Terms of Use" and managing the emerging legal relationships within this "Terms of Use" in case of finding element of foreignness, except for the rules of Turkish conflict of laws. Ankara Courts and Enforcement Offices are entitled in any controversy happened or may happen due to hereby contract.

9. CLOSING AND AGREEMENT

Hereby "Terms of Use" come into force when announced in the "SITE" by "Turkiye Klinikleri". The users are regarded to agree to hereby contract terms by using the "SITE". "Turkiye Klinikleri" may change the contract terms and the changes will be come into force by specifying the version number and the date of change on time it is published in the "SITE".

 

30.03.2014

Privacy Policy

We recommend you to read the terms of use below before you visit our website. In case you agree these terms, following our rules will be to your favor. Please read our Terms of Use thoroughly.

www.turkiyeklinikleri.com website belongs to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. and is designed in order to inform physicians in the field of health

www.turkiyeklinikleri.com cannot reach to user’s identity, address, service providers or other information. The users may send this information to the website through forms if they would like to. However, www.turkiyeklinikleri.com may collect your hardware and software information. The information consists of your IP address, browser type, operating system, domain name, access time, and related websites. www.turkiyeklinikleri.com cannot sell the provided user information (your name, e-mail address, home and work address, phone number) to the third parties, publish it publicly, or keep it in the website. Gathered information has a directing feature to be a source for the website’s visitor profile, reporting and promotion of the services.

www.turkiyeklinikleri.com uses the taken information:

-To enhance, improve and maintain the quality of the website

-To generate visitor’s profile and statistical data

-To determine the tendency of the visitors on using our website

-To send print publications/correspondences

-To send press releases or notifications through e-mail

-To generate a list for an event or competition

By using www.turkiyeklinikleri.com you are considered to agree that;

-Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. cannot be hold responsible for any user’s illegal and immoral behavior,

-Terms of use may change from time to time,

-It is not responsible for other websites’ contents it cannot control or the harms they may cause although it uses the connection they provided.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. may block the website to users in the following events:

-Information with wrong, incomplete, deceiving or immoral expressions is recorded to the website,

-Proclamation, advertisement, announcement, libelous expressions are used against natural person or legal identity,

-During various attacks to the website,

-Disruption of the website because of a virus.

Written, visual and audible materials of the website, including the code and the software are under protection by legal legislation.

Without the written consent of Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. the information on the website cannot be downloaded, changed, reproduced, copied, republished, posted or distributed.

All rights of the software and the design of the website belong to Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc.

Ortadoğu Advertisement Presentation Publishing Tourism Education Architecture Industry and Trade Inc. will be pleased to hear your comments about our terms of use. Please share the subjects you think may enrich our website or if there is any problem regarding our website.

info@turkiyeklinikleri.com