Can Fibulin-5 Induce Gastrointestinal Stromal Tumor Development?

Objective: Gastrointestinal stromal tumors are the most common primary mesenchymal tumors of the gastrointestinal tract and show Cajal cell differentiation. Fibulin-5 is a multifunctional extracellular matrix protein that inhibits epithelial and endothelial cell proliferation. Expression of fibulin-5 is down-regulated in various carcinomas. In contrast, fibulin-5 stimulates fibroblast and fibrosarcoma cells. In this study we aimed to investigate the expression of fibulin-5 in Cajal cells and gastrointestinal stromal tumors. Materials and Methods: Immunohistochemical fibulin-5 staining is performed on 34 (22 gastric and 12 small intestinal) gastrointestinal stromal tumors. Fibulin-5 staining intensity was scored in 4 quantitative categories and compared with clinicopathological features of the patients. Results: There was no staining in 4 of the gastrointestinal stromal tumors; weak staining in 20 cases, moderate staining in 6 cases, and strong staining in 4 cases were observed. In 3 cases Cajal cells were detected with fibulin-5 by moderately staining. The relationship between fibulin-5 staining intensity and age and gender of the cases, localization, size, grade, and the risk groups of the tumors wasn’t statistically significant. Conclusion: A great proportion of gastrointestinal stromal tumors show fibulin-5 expression, even if weak, in contrast to the infrequent fibulin-5 expression in Cajal cells. Based on these findings, it can be speculated that the expression of fibulin-5 in Cajal cells can be increase cell proliferation, but it would be useful to conduct new studies with larger series to clarify this issue. There is no correlation between fibulin-5 expression intensity and clinicopathological and prognostic data of gastrointestinal stromal tumors.

Anahtar Kelimeler:

FBLN5, fibulin-5, gastrointestinal stromal tumor, GIST

Background: In this study, our intent was to determine whether serum levels of B12 and folic acid in patients diagnosed with iron deficiency anemia undergo change in response to iron supplements. Methods: In this retrospective study, 202 female patients with iron deficiency anemia and only iron treatment were included. Complete blood count, vitamin B12, ferritin, folate levels of patients at the time of initial presentation and 4-8 weeks after treatment were examined. Results: Overall, significant increases were detected in mean hemoglobin, mean hematocrit, mean mean corpuscular volume, median white blood cell and median serum ferritin levels in all patients treated with iron therapy (both oral and intravenous); significant decreases were observed in post-treatment median platelet, median folate, and median B12 levels in this patient cohort. Conclusions: We conclude that deficiencies in serum levels B12, folate and iron, which are critical factors promoting erythropoiesis may effectively mask one another in a basic clinical assessment of anemia.

Keywords:

vitamin b12, folic acid, iron therapy, Iron deficiency anemia,

PDF

___

1-Fukayama M, Goldblum JR, Miettinen M, et al. Mesenchymal tumours of the digestive system. In WHO Classification of Tumours Editorial Board, editors. Digestive system Tumours. 5th ed:439-444. Lyon, IARC Press, 2019.
2-Sanders KM, Koh SD, Ward SM. Interstitial cells of Cajal as pacemakers in the gastrointestinal tract. Annu Rev Physiol. 2006;68:307-343. PMID: 16460275 DOI: 10.1146/annurev.physiol.68.040504.094718
3-Ördög T, Redelman D, Horváth VJ, et al. Quantitative analysis by flowcytometry of interstitial cells of Cajal, pacemakers, and mediators of neurotransmission in the gastrointestinal tract. Cytometry Part A: The Journal of the International Society for Analytical Cytology. 2004;62(2):139-149. PMID: 15536638 DOI: 10.1002/cyto.a.20078
4- Sanders KM, Ward SM. Kit mutants and gastrointestinal physiology. The Journal of physiology. 2007;578(1):33-42. PMID: 17095561 DOI: 10.1113/jphysiol.2006.122473
5- Mostafa RM, Moustafa YM, Hamdy H. Interstitial cells of Cajal, the Maestro in health and disease. World journal of gastroenterology: WJG. 2010;16(26):3239. PMID: 20614479 DOI: 10.3748/wjg.v16.i26.3239
6- Bülbül GD. Gastrointestinal stromal tumors: A multicenter study of 1160 Turkish cases. The Turkish journal of gastroenterology: the official journal of Turkish Society of Gastroenterology. 2012;23(3):203-211. PMID: 22798108
7- Albig AR, Schiemann WP. Fibulin-5 function during tumorigenesis. Future Oncol. 2005 Feb;1(1):23-35. PMID: 16555973 DOI: 10.1517/14796694.1.1.23
8- Mohamedi Y, Fontanil T, Solares L, et al. Fibulin-5 downregulates Ki-67 and inhibits proliferation and invasion of breast cancer cells. Int J Oncol. 2016 Apr;48(4):1447-56. PMID: 26891749 doi: 10.3892/ijo.2016.3394.
9- Lee YH, Albig AR, Regner M, et al. Fibulin-5 initiates epithelial-mesenchymal transition (EMT) and enhances EMT induced by TGF-beta in mammary epithelial cells via a MMP dependent mechanism. Carcinogenesis. 2008;29:2243–2251. PMID: 18713838 doi: 10.1093/carcin/bgn199
10- Guadall A, Orriols M, Rodríguez-Calvo R, et al. Fibulin-5 is up-regulated by hypoxia in endothelial cells through a hypoxia-inducible factor-1 (HIF-1alpha)-dependent mechanism. J BiolChem. 2011; 286:7093–7103. PMID:21193390 doi: 10.1074/jbc.M110.162917
10- Schiemann WP, Blobe GC, Kalume DE, et al. Context-specific effects of fibulin-5 (DANCE/EVEC) on cell proliferation, motility, and invasion. Fibulin-5 is induced by transforming growth factor-beta and affects protein kinase cascades. J BiolChem. 2002 Jul 26;277(30):27367-77. PMID: 12021267 DOI: 10.1074/jbc.M200148200
11- Yanagisawa H, Schluterman MK, Brekken RA. Fibulin-5, an integrin-binding matricellular protein: its function in development and disease. Journal of cell communication and signaling. 2009;3(3-4), 337-347.
12- Albig AR, Schiemann WP. Fibulin-5 antagonizes vascular endothelial growth factor (VEGF) signaling and angiogenic sprouting by endothelial cells. DNA and cell biology. 2004; 23(6): 367-379. PMID: 15231070 DOI: 10.1089/104454904323145254
13- Argraves WS, Greene LM, Cooley MA, et al. Fibulins: physiological and disease perspectives. EMBO Rep. 2003 Dec;4(12):1127-31. PMID: 14647206 DOI: 10.1038/sj.embor.7400033
14- Yue W, Sun Q, Landreneau R, et al. Fibulin-5 suppresses lung cancer invasion by inhibiting matrix metalloproteinase-7 expression. Cancer research. 2009; 69(15): 6339-6346. PMID: 19584278 DOI: 10.1158/0008-5472.CAN-09-0398
15- Li H, Ren G, Cai R, et al. A correlation research of Ki67 index, CT features, and risk stratification in gastrointestinal stromal tumor. Cancer medicine. 2018;7(9), 4467-4474.
16- Zhou Y, Hu W, Chen P, et al. Ki67 is a biological marker of malignant risk of gastrointestinal stromal tumors: a systematic review and meta-analysis. Medicine. 2017;96(34).
17- Cerski MR, Pereira F, Matte US, et al. Exon 11 mutations, Ki67, and p16INK4A as predictors of prognosis in patients with GIST. Pathology-Research and Practice. 2011;207(11), 701-706.
18- Basilio-de-Oliveira RP, Pannain VLN. Prognostic angiogenic markers (endoglin, VEGF, CD31) and tumor cell proliferation (Ki67) for gastrointestinal stromal tumors. World Journal of Gastroenterology: WJG. 2015;21(22), 6924.
19- Jiang L, Cao M, Hu J, et al. Expression of PIN1 in Gastrointestinal Stromal Tumours and its Clinical Significance. Anticancer research. 2016;36(3), 1275-1280.
20- Zhu K, Li K, Yuan DW, et al. Clinicopathological and Prognostic Significance of Expression of B-Cell-Specific Moloney Murine Leukemia Virus Insertion Site 1 (BMI-1) Gene and Protein in Gastrointestinal Stromal Tumors. Medical science monitor: international medical journal of experimental and clinical research. 2018;24, 6414.
21- Lu J, Chen S, Li X, et al. Gastrointestinal stromal tumors: Fibrinogen levels are associated with prognosis of patients as blood-based biomarker. Medicine. 2018;97(17).
22- Liu Q, Li Y, Dong M, et al. Gastrointestinal bleeding is an independent risk factor for poor prognosis in GIST patients. BioMed research international. 2017;2017.
23- Yi M, Xia L, Zhou Y, et al. Prognostic value of tumor necrosis in gastrointestinal stromal tumor: A meta-analysis. Medicine. 2019;98(17).
24- Haller F, Cortis J, Helfrich J, et al. Epithelioid/mixed phenotype in gastrointestinal stromal tumors with KIT mutation from the stomach is associated with accelerated passage of late phases of the cell cycle and shorter disease-free survival. Modern Pathology. 2011;24(2), 248-255.