Gastrointestinal nöroendokrin tümörlerde GLP-2 reseptör ekspresyonunun değerlendirilmesi

Öz

Giriş ve Amaç: Nöroendokrin tümörler, nöroendokrin sistem hücrelerinden kaynaklanır. Bu hücreler hem sinir hem de endokrin hücre özelliği gösterirler ve vücuttaki birçok organda bulunabilirler. GLP-1 ve GLP-2, gıda alımını takiben 1:1 oranında bağırsak L hücrelerinden salınır. GLP-2 reseptörü, GLP-2'yi tanır. GLP-2 reseptör mRNA transkriptleri mide, ince ve kalın bağırsak, beyin ve akciğerde tespit edilmiştir. GLP-2'nin proliferatif etkisi farelerde, sıçanlarda, domuzlarda ve insanlarda eksojen GLP-2 uygulanarak gösterilmiştir. Amaç, gastroenteropankreatik nöroendokrin tümörler ile glukagon benzeri peptid-2 ve GLP-2 reseptör arasındaki ilişkiyi değerlendirmektir. Gereç ve Yöntem: 2006-2009 yılları arasında patolojik olarak gastroenteropankreatik nöroendokrin tümör tanısı alan hastalar çalışmaya dahil edildi. Çalışmaya 47 hasta (27 kadın, 20 erkek, ortalama yaş: 54 ± 15.5) alındı. Ayrıca 46 kontrol grubu hastası (25 kadın, 21 erkek, ortalama yaş: 57.5 ± 14.8) vardı. Poli-L-lisin mikroskop lamlarında hazırlanan patolojik doku blokları, GLP-2 reseptör antikoru (1:100 - 1:200, 1 mg/ml) immünohistokimyasal boyama ile boyandı. Bulgular: Kolon nöroendokrin tümör grubunun GLP-2 reseptör pozitifliği %30 (4/13), kolon kontrol grubunun GLP-2 reseptör pozitifliği %100 bulundu. Pankreas nöroendokrin tümör grubunun GLP-2 reseptör pozitifliği %25 (3/12) iken, pankreas kontrol grubunda %100 idi. Kolon nöroendokrin tümör ile kontrol grubunun karşılaştırılmasında anlamlı farklılık görüldü (p: 0.003). Pankreas nöroendokrin tümör ile kontrol grubunun karşılaştırılması da istatistiksel olarak anlamlı farklılık gösterdi (p < 0.001). Gastrik nöroendokrin tümörlerin kontrol ile karşılaştırılması karşılaştırılabilir sonuçlar verdi (p: 0.22). Sonuç: GLP-2 reseptörünün bu tümörlerin tanı ve tedavisinde somatostatin reseptörleri kadar yararlı olamayacağı sonucuna vardık. Bu konuda farklı yöntemlerle daha fazla çalışmaya ihtiyaç vardır.

Anahtar Kelimeler

• GLP-2 reseptörü
• nöroendokrin tümörler
• GEP-NET

Evaluation of GLP-2 receptor expression in gastrointestinal neuroendocrine tumors

Öz

Evaluation of GLP-2 receptor expression in gastrointestinal neuroendocrine tumors Background and Aims: Neuroendocrine tumors arise from cells of the neuroendocrine system. These cells show both nerve and endocrine cell characteristics and can be found in many organs in the body. GLP-1 and GLP-2 are released from intestinal L cells in a 1:1 ratio following food intake. GLP-2 receptor recognizes GLP-2. GLP-2 receptor mRNA transcripts have been detected in the stomach, small and large intestine, brain, and lung. The proliferative effect of GLP-2 has been demonstrated in mice, rats, pigs, and humans by administering exogenous GLP-2. The objective is to evalaute the relation between gastroenteropancreatic neuroendocrine tumors and glukagon like peptid-2 and GLP-2 receptor. Materials and Methods: The patients, who were pathologically diagnosed with gastroenteropancreatic neuroendocrine tumor between 2006-2009 were included in the study. There were 47 patients (27 females, 20 males, avarage age: 54 ± 15.5) in the study. There were also 46 control group patients (25 females, 21 males, avarage age: 57.5 ± 14.8). Pathological tissue blocks prepared on poly-L-lysine microscope slides were stained by GLP-2 receptor antibody (1:100 - 1:200, 1 mg/ml) immunohistochemical stain. Results: GLP-2 receptor positivity of colon neuroendocrine tumor group was 30% (4/13) and colon control group was %100. GLP-2 receptor positivity of pancreas neuroendocrine tumor group was 25% (3/12) while it was 100% in pancreas control group. The comparison of colon neuroendocrine tumor and control group showed significant difference (p: 0.003). The comparison of pancreas neuroendocrine tumor and control group also showed statistically significant difference (p < 0.001). The comparison of gastric neuroendocrine tumor with the control yielded comparable results (p: 0.22). Conclusions: We concluded that GLP-2 receptor cannot be as useful as somatostatin receptors in diagnosis and treatment of these tumors. More studies are needed on this subject with different methods.

Anahtar Kelimeler

• GLP-2 receptor
• neuroendocrine tumours
• GEP-NET

Kaynakça

1. 1. Modlin IM, Champaneria MC, Bornschein J, Kidd M. Evolution of the diffuse neuroendocrine system--clear cells and cloudy origins. Neuroendocrinology 2006;84:69-82.
2. 2. Ahmed M. Gastrointestinal neuroendocrine tumors in 2020. World J Gastrointest Oncol 2020;12:791-807.
3. 3. Cives M, Strosberg J. An update on gastroenteropancreatic neuroendocrine tumors. Oncology (Williston Park) 2014;28:749-756, 758.
4. 4. Grande E, Capdevila J, Barriuso J, Antón-Aparicio L, Castellano D. Gastroenteropancreatic neuroendocrine tumor cancer stem cells: do they exist? Cancer Metastasis Rev 2012;31:47-53.
5. 5. Klöppel G, Anlauf M, Perren A. Endocrine precursor lesions of gastroenteropancreatic neuroendocrine tumors. Endocr Pathol 2007;18:150-5.
6. 6. Dhanvantari S, Seidah NG, Brubaker PL. Role of prohormone convertases in the tissue-specific processing of proglucagon. Mol Endocrinol 1996;10:342-55.
7. 7. Furuta M, Yano H, Zhou A, et al. Defective prohormone processing and altered pancreatic islet morphology in mice lacking ac active SPC2. Proc Natl Acad Sci USA 1997;94:6646-51.
8. 8. Larsen PJ, Tang-Christensen M, Holst JJ, Orskov C. Distribution of glucagon like peptide-1 and other preproglucagonderived peptides in the rat hypothalamus and brainstem. Neuroscience 1997;77:257-70.

9. 9. Drucker DJ. Biological actions and therapeutic potential of the glucagon-like peptides. Gastroenterology 2002;122:531-44.
10. 10. Ghatei MA, Uttenthal LO, Christofides ND, Bryant MG, Bloom SR. Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. J Clin Endocrinol Metab 1983;57:488-95.
11. 11. Roberge JN, Brubaker PL. Secretion of proglucagon-derived peptides in response to intestinal luminal nutrients. Endocrinology 1991;128:3169-74.
12. 12. Munroe DG, Gupta AK, Kooshesh F, et al. Prototypic G protein-coupled receptor for the intestinotrophic factor glucagon-like peptide 2. Proc Natl Acad Sci USA 1999;96:1569-73.
13. 13. DaCambra MP, Yusta B, Sumner-Smith M, et al. Structural determinants for activity of glucagon-like peptide-2. Biochemistry 2000;39:8888-94.
14. 14. Lovshin JA, Huang Q, Seaberg R, Brubaker PL, Drucker DJ. Extrahypothalamic expression of the glucagonlike peptide-2 receptor is coupled to reduction of glutamate-induced cell death in cultured hippocampal cells. Endocrinology 2004;145:3495-506.
15. 15. Tang-Christensen M, Larsen PJ, Thulesen J, Romer J, Vrang N. The proglucagon-derived peptide, glucagonlike peptide-2, is a neurotransmitter involved in the regulation of food intake. Nat Med 2000;6:802-7.
16. 16. Yusta B, Huang L, Munroe D, et al. Enteroendocrine localization of GLP-2 receptor expression in humans and rodents. Gastroenterology 2000;119:744-55.
17. 17. Bjerknes M, Cheng H. Modulation of specific intestinal epithelial progenitors by enteric neurons. Proc Natl Acad Sci USA 2001;98:12497-502.
18. 18. Orskov C, Hartmann B, Poulsen SS, et al. GLP-2 stimulates colonic growth via KGF, released by subepithelial myofibroblasts with GLP-2 receptors. Regul Pept 2005;124:105-12.
19. 19. Benjamin MA, McKay DM, Yang PC, Cameron H, Perdue MH. Glucagonlike peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse. Gut 2000;47:112-9.
20. 20. Jasleen J, Ashley SW, Shimoda N, Zinner MJ, Whang EE. Glucagon-like peptide 2 stimulates intestinal epithelial proliferation in vitro. Dig Dis. Sci 200;47:1135-40.
21. 21. Bulut K, Meier JJ, Ansorge N, et al. Glucagonlike peptide 2 improves intestinal wound healing through induction of epithelial cell migration in vitro evidence for a TGF-beta-mediated effect. Regul Pept 2004;121:137-43.
22. 22. Rocha FG, Shen KR, Jasleen J, et al. Glucagon-like peptide-2: divergent signaling pathways. J Surg Res 2004;121:5-12.
23. 23. Martins NB, Peppercorn MA. Inflammatory bowel disease. Am J Manag Care 2004;10:544-52.
24. 24. Chance WT, Sheriff S, Foley-Nelson T, Thomas I, Balasubramaniam A. Maintaining gut integrity during parenteral nutrition of tumor-bearing rats: effects of glucagon-like peptide 2. Nutr Cancer 2000;37:215-22.
25. 25. Boushey RP, Yusta B, Drucker DJ. Glucagon-like peptide (GLP)-2 reduces chemotherapy-associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res 2001;61:687-93.
26. 26. Thulesen J, Hartmann B, Kissow H, et al. Intestinal growth adaptation and glucagonlike peptide 2 in rats with ileal–jejunal transposition or small bowel resection. Dig Dis Sci 2001;46:379-88.
27. 27. Wada H, Matsuda K, Akazawa Y, et al. Expression of somatostatin receptor Type 2A and PTEN in neuroendocrine neoplasms is associated with tumor grade but not with site of origin. Endocr Pathol 2016;27:179-87.
28. 28. Righi L, Volante M, Tavaglione V, et al. Somatostatin receptor tissue distribution in lung neuroendocrine tumours: A clinicopathologic and immunohistochemical study of 218 ‘clinically aggressive’ cases. Ann Oncol 2010;21:548-55.
29. 29. Estall JL, Yusta B, Drucker DJ. Lipid raft-dependent glucagon-likepeptide-2 receptor trafficking occurs independently of agonist-induced desensitization. Mol Biol Cell 2004;15:3673-87.