NEOPTERİN: GASTROİNTESTİNAL KANSERDE OLASI BİR BİYOBELİRTEÇ

Year 2018, Volume: 42 Issue: 2, 32 - 41, 31.05.2018

Aysun Hacısevkı Burcu Baba Sebahattin Aslan Yesim Ozkan

Abstract

Amaç: Dünyadaki başlıca ölüm nedenlerinden biri olan kanser, hiperproliferatif bir bozukluk olarak tanımlanmaktadır. Bozulmuş doku homeostazına karşı doğal bir immün yanıt olan inflamasyon, kanserin önemli bir özelliği haline gelmiştir. Neopterin, proinflamatuvar sitokinlerin uyarımı ile aktive olan makrofajlar tarafından üretilmektedir. Neopterin, kanser dahil immün aktivasyon ile ilişkili farklı bozukluklarda artanimmün aktivasyon biyobelirtecidir. Çalışmamızda gastrointestinal kanserlerde neopterin düzeylerini tayin etmeyi ve alt gruplar arasındaki farklılıkları değerlendirmeyi amaçladık.

Gereç ve Yöntem: Bu çalışmaya 108 gastrointestinal kanserli hasta ve 25 sağlıklı kontrol dahil edildi. Hastalar üç alt gruba ayrıldı. Birinci grup mide kanserli 40 kişi, ikinci grup kolorektal kanserli 40 kişi ve üçüncü grup pankreas, karaciğer ya da özofagus kanserli 28 kişiden oluştu. Serum neopterin düzeyleri ELISA ile ölçüldü.

Sonuç ve Tartışma: Neopterin, kontrollerle karşılaştırıldığında tüm hasta gruplarında anlamlı olarak daha yüksekti (p<0.05). Tüm hasta gruplarında HDL-kolesterol, albümin ve total protein düzeyleri kontrol grubuna göre anlamlı derecede düşük bulundu. Sonuçlarımız neopterin düzeylerinin, gastrointestinal kanserlerde arttığını göstermektedir. Dolayısıyla, neopterin, gastrointestinal kanserli hastalarda potansiyel tahmini bir belirteç olabilir.

Keywords

biyobelirteç, inflamasyon, kolorektal kanser, mide kanseri, neopterin

NEOPTERIN: A POSSIBLE BIOMARKER IN GASTROINTESTINAL CANCER

Abstract

Objective: Cancer, one of the major causes of death in the world, is described as a hyperproliferative disorder. Inflammation which is a primary innate immune response to perturbed tissue homeostasis, has become an important hallmark of cancer. Neopterin is produced by activated macrophages upon stimulation with proinflammatory cytokines. It is immune activation biomarker increased in different disorders associated with immune activation, including cancer. We aimed to determine the neopterin levels in gastrointestinal cancers (GIC) and to evaluate the differences among the subgroups.

Material and Method: The study included 108 patients with GIC and 25 healthy controls. Patients were divided into three subgroups. The first group consisted of 40 individuals with gastric cancer, the second group consisted of 40 individuals with colorectal cancer, and the third group consisted of 28 individuals with pancreatic, liver or esophageal cancer. Serum neopterin levels were measured by ELISA.

Result and Discussion: Neopterin was significantly higher in all patient groups compared to controls (p<0.05). It was found that HDL-cholesterol, albumin and total protein levels were significantly lower in all patient groups compared to controls. Our results show that neopterin levels are elevated in gastrointestinal cancers. Therefore, neopterin may be a potential predictive marker in GIC patients.

Keywords

biomarker, colorectal cancer, gastric cancer, inflammation, neopterin

References

• Lin, W.W., Karin, M. (2007). A cytokine-mediated link between innate immunity, inflammation, and cancer. Journal of Clinical Investigation, 117(5), 1175-1183.
• Ciaramella, V., Della Corte, C.M., Ciardiello, F., Morgillo, F. (2018). Kisspeptin and Cancer: Molecular interaction, Biological Functions, and Future Perspectives. Frontiers in Endocrinology, 9(115), 1-5. 3.
• Sun, Y., Wang, R., Qiao, M., Xu, Y., Guan, W., Wang, L. (2018). Cancer associated fibroblasts tailored tumor microenvironment of therapy resistance in gastrointestinal cancers. J Cell Physiol. doi: 10.1002/jcp.26433. [Epub ahead of print]
• Hassanzade, J., Molavi E. Vardanjani, H., Farahmand, M., Rajaiifard, A.R. (2011). Incidence and Mortality Rate of Common Gastrointestinal Cancers in South of Iran, a Population Based Study. Iranian Journal of Cancer Prevention, 4(4):163-169.
• Beutner, U., Lorenz, U., Illert, B., Rott, L., Timmermann, W., Vollmers, H.P., Müller-Hermelink, H.K., Thiede, A., Ulrichs, K. (2008). Neoadjuvant therapy of gastric cancer with the human monoclonal IgM antibody SC-1: impact on the immune system. Oncology Reports, 19(3), 761-769.
• Elinav, E., Nowarski, R., Thaiss, C.A., Hu, B., Jin, C., Flavell, R.A. (2013). Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nature Reviews Cancer, 13(11), 759-771.
• Shah, N.M., Herasimtschuk, A.A., Boasso, A., Benlahrech, A., Fuchs, D., Imami, N., Johnson, M.R. (2017). Changes in T Cell and Dendritic Cell Phenotype from Mid to Late Pregnancy Are Indicative of a Shift from Immune Tolerance to Immune Activation”. Frontiers in Immunology, 8(1138), 1-14.
• Inancli, S.S., Caner, S., Balkan, F., Tam, A.A., Guler, G., Ersoy R., Cakir, B. (2014). Urinary neopterin levels in patients with thyroid cancer. Indian Journal of Otolaryngology and Head & Neck Surgery, 66(3), 302-328.
• Akgul, E.O., Aydın, İ., Caycı, T., Kurt, Y.G., Aydın, F.N., Agıllı, M. (2013). The Indicator of Cellular Immun Response in Body Fluids: Neopterin. Gülhane Tıp Dergisi, 55, 1-7.
• Chuang, S.C., Boeing, H., Vollset, S.E., Midttun, Q., Ueland, P.M., Bueno-de-Mesquita, B., Lajous, M., Fagherazzi, G., Boutron-Ruault, M.C., Kaaks, R., Küehn, T., Pischon, T., Drogan, D., Tjønneland, A., Overvad, K., Quirós, J.R., Agudo, A., Molina-Montes, E., Dorronsoro, M., Huerta, J.M., Barricarte, A., Khaw, K.T., Wareham, N.J., Travis, R.C., Trichopoulou, A., Lagiou, P., Trichopoulos, D., Masala, G., Agnoli, C., Tumino, R., Mattiello, A., Peeters, P.H., Weiderpass, E., Palmqvist, R., Ljuslinder, I., Gunter, M., Lu, Y., Cross, A.J., Riboli, E., Vineis, P., Aleksandrova, K. (2016). Cellular immune activity biomarker neopterin is associated hyperlipidemia: results from a large population-based study. Immun Ageing, 13(5), 1-11.
• Zuo, H., Tell, G.S., Vollset, S.E., Ueland, P.M., Nygård, O., Midttun, Q., Meyer, K., Ulvik, A., Eussen, S.J. (2014). Interferon-γ-induced inflammatory markers and the risk of cancer: the Hordaland Health Study. Cancer, 120(21), 3370-3377.
• Volgger, B.M., Windbichler, G.H., Zeimet, A.G., Graf, A.H., Bogner, G., Angleitner-Boubenizek, L., Rohde, M., Denison, U., Sliutz, G., Fuith, L.C., Fuchs, D., Marth, C. (2016). Long-term significance of urinary neopterin in ovarian cancer: a study by the Austrian Association for Gynecologic Oncology (AGO). Annals of Oncology, 27(9), 1740-1746.
• Engin, A.B., Karahalil, B., Karakaya, A.E., Engin, A. (2015). Helicobacter pylori and serum kynurenine-tryptophan ratio in patients with colorectal cancer. World Journal of Gastroenterology, 21(12), 3636-3643.
• Sucher, R., Schroecksnadel, K., Weiss, G., Margreiter, R., Fuchs, D., Brandacher, G. (2010). Neopterin, a prognostic marker in human malignancies. Cancer Letters, 287(1), 13-22.
• Krcmova, L., Solichova, D., Melichar, B., Kasparova, M., Plisek, J., Sobotka, L., Solich, P. (2011). Determination of neopterin, kynurenine, tryptophan and creatinine in human serum by high throuput HPLC. Talanta, 85(3), 1466-1471.
• Hacışevki, A., Baba, B., Sezer, S., Özkan, Y. (2013). Increased kynurenine/tryptophan and neopterin levels in hemodialysis. Oxidation Communications, 36(1), 246-253.
• Yanchun, L., Zhidong, H. (2011). Significance of humoral neopterin in clinical diagnostics and prognosis. Journal of Medical Colleges of PLA, 26, 45-51.
• Chen, G., Zhang, F.J., Gong, M., Yan, M. (2007). Effect of perioperative autologous versus allogeneic blood transfusion on the immune system in gastric cancer patients. Journal of Zhejiang University SCIENCE B, 8(8), 560-565.
• Armstrong, H., Bording-Jorgensen, M., Dijk, S., Wine, E. (2018). The complex interplay between chronic inflammation, the microbiome, and cancer: Understanding disease progression and what we can do to prevent it. Cancers, 10(3), 1-29.
• Qu, X., Tang, Y., Hua, S. (2018). Immunological approaches towards cancer and inflammation: A cross talk. Frontiers in Immunology, 9(563), 1-19.
• Grivennikov, S.I., Greten, F.R., Karin, M. (2010). Immunity, inflammation, and cancer. Cell, 140(6), 883-899.
• Landskron, G., De la Fuente, M., Thuwajit, P., Thuwajit, C., Hermoso, M.A. (2014). Chronic inflammation and cytokines in the tumor microenvironment. Journal of Immunology Research, 2014(149185), 1-19.
• Yan, M., Chen, G., Fang, L.L., Liu, Z.M., Zhang, X.L. (2005). Immunologic changes to autologous transfusion after operational trauma in malignant tumor patients: neopterin and interleukin-2. Journal of Zhejiang University SCIENCE B, 6(1), 49-52.
• Melichar, B., Spisarová, M., Bartoušková, M., Krčmová, L.K., Javorská, L., Študentová, H. (2017). Neopterin as a biomarker of immune response in cancer patients. Annals of Translational Medicine, 5(13), 1-12.
• El-Akawi, Z.J., Abu-Awad, A.M., Sharara, A.M., Khader, Y. (2010). The importance of alpha-1 antitrypsin (alpha1-AT) and neopterin serum levels in the evaluation of non-small cell lung and prostate cancer patients. Neuro Enocrinology Letters, 31(1), 113-116.
• Isci Bostanci, E., Ugras Dikmen, A., Girgin, G., Gungor, T., Baydar, T., Nuri Danisman, A. (2017). A new diagnostic and prognostic marker in endometrial cancer: Neopterin. International Journal of Gynecological Cancer, 27(4), 754–758.
• Melicharová, K., Kalábová, H., Krcmová, L., Urbánek, L., Solichová, D., Melichar, B. (2010). Effect of comorbidity on urinary neopterin in patients with breast carcinoma. European Journal of Cancer Care, 19(3), 340-345.
• Girgin, G., Tolga Sahin, T., Fuchs, D., Kasuya, H., Yuksel, O., Tekin, E., Baydar, T. (2009). Immune system modulation in patients with malignant and benign breast disorders: tryptophan degradation and serum neopterin. The International Journal of Biological Markers, 24(4), 265-270.
• Kalábová, H., Krcmová, L., Kasparová, M., Plísek, J., Laco, J., Hyspler, R., Klozová, H., Solichová, D., Melichar, B. (2011). Prognostic significance of increased urinary neopterin concentrations in patients with breast carcinoma. European journal of gynaecological oncology, 32(5), 525-529.
• Thein, M.S., Kohli, A., Ram, R., Ingaramo, M.C., Jain, A., Fedarko, N.S. (2017). Chitotriosidase, a marker of innate immunity, is elevated in patients with primary breast cancer. Cancer Biomark, 19(4), 383-391.
• Babic, A., Schnure, N., Neupane, N.P., Zaman, M.M., Rifai, N., Welch, M.W., Brais, L.K., Rubinson, D.A., Morales-Oyarvide, V., Yuan, C., Zhang, S., Poole, E.M., Wolpin, B.M., Kulke, M.H., Barbie, D.A., Wong, K., Fuchs, C.S., Ng, K. (2018). Plasma inflammatory cytokines and survival of pancreatic cancer patients. Clinical and Translational Gastroenterology, 9(4), 145: 1-12.
• Talar-Wojnarowska, R., Gasiorowska, A., Olakowski, M., Lekstan, A., Lampe, P., Malecka-Panas, E. (2010). Clinical value of serum neopterin, tissue polypeptide-specific antigen and CA19-9 levels in differential diagnosis between pancreatic cancer and chronic pancreatitis. Pancreatology, 10(6), 689-694.
• Huang, J.Y., Butler, L.M., Midttun, Ø., Ulvik, A., Wang, R., Jin, A., Gao, Y.T., Ueland, P.M., Koh, W.P., Yuan, J.M. (2018). A prospective evaluation of serum kynurenine metabolites and risk of pancreatic cancer. PLoS One, 13(5), e0196465.
• Melichar, B., Solichová, D., Svobodová, I., Urbánek, L., Veselý, P., Melicharová, K. (2006). Urinary neopterin in patients with liver tumors. Tumori, 92(4), 318-322.
• Aleksandrova, K., Chuang, S.C., Boeing, H., Zuo, H., Tell, G.S., Pischon, T., Jenab, M., Bueno-de-Mesquita, B., Vollset, S.E., Midttun, Ø., Ueland, P.M., Fedirko, V., Johansson, M., Weiderpass, E., Severi, G., Racine, A., Boutron-Ruault, M.C., Kaaks, R., Kühn, T., Tjønneland, A., Overvad, K., Quirós, J.R., Jakszyn, P., Sánchez, M.J., Dorronsoro, M., Chirlaque, M.D., Ardanaz, E., Khaw, K.T., Wareham, N.J., Travis, R.C., Trichopoulou, A., Lagiou, P., Trichopoulos, D., Palli, D., Sieri, S., Tumino, R., Panico, S., May, A.M., Palmqvist, R., Ljuslinder, I., Kong, S.Y., Freisling, H., Gunter, M.J., Lu, Y., Cross, A.J., Riboli, E., Vineis, P. (2015). A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk. Journal of the National Cancer Institute. 107(4), 1-18.
• Melichar, B., Solichová, D., Melicharová, K., Malírová, E., Cermanová, M., Zadák, Z. (2006). Urinary neopterin in patients with advanced colorectal carcinoma. The International Journal of Biological Markers, 21(3), 190–198.
• Hronek, M., Zadak, Z., Solichova, D., Jandik, P., Melichar, B. (2000). The association between specific nutritional antioxidants and manifestation of colorectal cancer. Nutrition, 16(3), 189-191.
• Unal, B., Kocer, B., Altun, B., Surmeli, S., Aksaray, S., Balci, M., Ozlu, B., Cengiz, O. (2009). Serum neopterin as a prognostic indicator in patients with gastric carcinoma. Journal of Investigative Surgery, 22(6), 419–425.
• Engin, A.B., Engin, A., Sepici-Dincel, A. (2010). Influence of surgical trauma on neopterin concentrations in gastric carcinoma patients. Tumori, 96(4), 589-593.
• Hacışevki, A., Baba, B., Gönenç, A., Aslan, S. (2012). Protein carbonyl content as the most general and well-used biomarker of severe oxidative stress. Oxidation Communications, 35(2), 413-422.
• Gupta, D., Lis, C.G. (2010). Pretreatment serum albumin as a predictor of cancer survival: a systematic review of the epidemiological literature. Nutrition Journal. 9(69), 1-41.
• Du, X.J., Tang, L.L., Mao, Y.P., Sun, Y., Zeng, M.S., Kang, T.B., Jia, W.H., Lin, A.H., Ma, J. (2014). The pretreatment albumin to globulin ratio has predictive value for long-term mortality in nasopharyngeal carcinoma. Plos One. 9(4), e94473, 1-8.
• Hrnciarikova, D., Hyspler, R., Vyroubal, P., Klemera, P., Hronek, M., Zadak, Z. (2009). Serum lipids and neopterin in urine as new biomarkers of malnutrition and inflammation in the elderly. Nutrition, 25(3), 303-308.
• Battelli, M. G., Polito, L., Bortolotti, M., Bolognesi, A. (2016). Xanthine oxidoreductase in cancer: more than a differentiation marker. Cancer Medicine, 5(3), 546-557.
• Fini, M.A., Elias, A., Johnson, R.J., Wright, R.M. (2012). Contribution of uric acid to cancer risk, recurrence, and mortality. Clinical and Translational Medicine, 1(1), 16.