Correlation of vascular endothelial growth factor and vascular endothelial growth factor receptor-1 levels in serum and thyroid nodules with histopathological and radiological variables

Abstract

BACKGROUND/AIM: Vascular endothelial growth factor (VEGF) is a major cytokine in angiogenesis and has a role on aggressivity of various tumors. The expression of VEGF has been shown to increase in differential thyroid cancer. The aim of the study was to evaluate serum and intranodular VEGF (nVEGF) and VEGF receptor-1 (VEGFR-1) levels in patients with thyroid nodules and their relevance to ultrasonographic and pathological results.

MATERIALS AND METHODS: A total of eighty patients were included in the study. Thyroid fine-needle aspiration biopsies were performed, and the levels of serum and nVEGF and VEGFR-1 were measured. Any possible correlations between serum and nVEGF, VEGFR-1, and biochemical/radiological variables were investigated.

RESULTS: There were no significant differences between serum VEGF (sVEGF), nVEGF, sVEGFR-1, nVEGFR-1 levels, number of nodules, size of nodules, and benign and malignant ultrasonographic features. sVEGF and nVEGF were higher in malignant or suspicious nodules than that in benign nodules, but did not reach statistical significance (P > 0.05). sVEGFR-1 and nVEGFR-1 levels were higher in hyperthyroid patients than that in euthyroid patients (P < 0.05 and P = 0.003, respectively). nVEGFR-1 level was higher in hypothyroid patients than that in euthyroid patients (P = 0.016). sVEGF level was found to be higher in hyperactive nodules than that in others. Both sVEGFR-1 (P = 0.008) and nVEGF levels (P = 0.01) significantly increased with increasing age. nVEGFR-1 decreased with increasing body mass index (BMI) (P = 0.004).

CONCLUSIONS: Our study showed the relationships of sVEGF, nVEGF, sVEGFR-1, and nVEGFR-1 levels with age, gender, BMI, and hyperthyroidism. To determine the role of VEGF/VEGFR-1 in thyroid nodules, further studies are required with a large number of patients.

Key words

Malignancy - nodule - thyroid

Publication History

Received: 26 March 2018

Accepted: 22 November 2018

Article published online:
06 April 2020

• References

• 1 American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19:1167-214.
• 2 Mehanna HM, Jain A, Morton RP, Watkinson J, Shaha A. Investigating the thyroid nodule. BMJ 2009;338:b733.
• 3 Jin J, McHenry CR. Thyroid incidentaloma. Best Pract Res Clin Endocrinol Metab 2012;26:83-96.
• 4 Shao YY, Wang L, Ballock RT. Thyroid hormone and the growth plate. Rev Endocr Metab Disord 2006;7:265-71.
• 5 Fellmer PT, Sato K, Tanaka R, Okamoto T, Kato Y, Kobayashi M, et al. Vascular endothelial growth factor-C gene expression in papillary and follicular thyroid carcinomas. Surgery 1999;126:1056-61.
• 6 Bikfalvi A. Recent developments in the inhibition of angiogenesis: Examples from studies on platelet factor-4 and the VEGF/VEGFR system. Biochem Pharmacol 2004;68:1017-21.
• 7 Yamaguchi R, Yano H, Iemura A, Ogasawara S, Haramaki M, Kojiro M, et al. Expression of vascular endothelial growth factor in human hepatocellular carcinoma. Hepatology 1998;28:68-77.
• 8 Zachary I, Gliki G. Signaling transduction mechanisms mediating biological actions of the vascular endothelial growth factor family. Cardiovasc Res 2001;49:568-81.
• 9 Clauss M. Molecular biology of the VEGF and the VEGF receptor family. Semin Thromb Hemost 2000;26:561-9.
• 10 Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002;29:15-8.
• 11 Sephel GC, Kennedy R, Kudravi S. Expression of capillary basement membrane components during sequential phases of wound angiogenesis. Matrix Biol 1996;15:263-79.
• 12 Shweiki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature 1992;359:843-5.
• 13 Belletti B, Ferraro P, Arra C, Baldassarre G, Bruni P, Staibano S, et al. Modulation of in vivo growth of thyroid tumor-derived cell lines by sense and antisense vascular endothelial growth factor gene. Oncogene 1999;18:4860-9.
• 14 Soh EY, Duh QY, Sobhi SA, Young DM, Epstein HD, Wong MG, et al. Vascular endothelial growth factor expression is higher in differentiated thyroid cancer than in normal or benign thyroid. J Clin Endocrinol Metab 1997;82:3741-7.
• 15 Klein M, Picard E, Vignaud JM, Marie B, Bresler L, Toussaint B, et al. Vascular endothelial growth factor gene and protein: Strong expression in thyroiditis and thyroid carcinoma. J Endocrinol 1999;161:41-9.
• 16 Hofmann A, Gessl A, Girschele F, Novotny C, Kienast O, Staudenherz A, et al. Vascular endothelial growth factor in thyroid cyst fluids. Wien Klin Wochenschr 2007;119:248-53.
• 17 Tuttle RM, Fleisher M, Francis GL, Robbins RJ. Serum vascular endothelial growth factor levels are elevated in metastatic differentiated thyroid cancer but not increased by short-term TSH stimulation. J Clin Endocrinol Metab 2002;87:1737-42.
• 18 Sato K, Miyakawa M, Onoda N, Demura H, Yamashita T, Miura M, et al. Increased concentration of vascular endothelial growth factor/vascular permeability factor in cyst fluid of enlarging and recurrent thyroid nodules. J Clin Endocrinol Metab 1997;82:1968-73.
• 19 Jebreel A, England J, Bedford K, Murphy J, Karsai L, Atkin S. Vascular endothelial growth factor (VEGF), VEGF receptors expression and microvascular density in benign and malignant thyroid diseases. Int J Exp Pathol 2007;88:271-7.
• 20 Iitaka M, Miura S, Yamanaka K, Kawasaki S, Kitahama S, Kawakami Y, et al. Increased serum vascular endothelial growth factor levels and intrathyroidal vascular area in patients with Graves’ disease and Hashimoto’s thyroiditis. J Clin Endocrinol Metab 1998;83:3908-12.
• 21 Akslen LA, Livolsi VA. Increased angiogenesis in papillary thyroid carcinoma but lack of prognostic importance. Hum Pathol 2000;31:439-42.
• 22 Viglietto G, Romano A, Manzo G, Chiappetta G, Paoletti I, Califano D, et al. Upregulation of the angiogenic factors plGF, VEGF and their receptors (Flt-1, flk-1/KDR) by TSH in cultured thyrocytes and in the thyroid gland of thiouracil-fed rats suggest a TSH-dependent paracrine mechanism for goiter hypervascularization. Oncogene 1997;15:2687-98.
• 23 Sato K, Yamazaki K, Shizume K, Kanaji Y, Obara T, Ohsumi K, et al. Stimulation by thyroid-stimulating hormone and Graves’ immunoglobulin G of vascular endothelial growth factor mRNA expression in human thyroid follicles in vitro and flt mRNA expression in the rat thyroid in vivo. J Clin Invest 1995;96:1295-302.
• 24 Shushanov S, Bronstein M, Adélaïde J, Jussila L, Tchipysheva T, Jacquemier J, et al. VEGFc and VEGFR3 expression in human thyroid pathologies. Int J Cancer 2000;86:47-52.
• 25 Hataya Y, Akamizu T, Kanamoto N, Moriyama K, Shimatsu A, Nakao K, et al. Acase of subclinical hypothyroidism developing marked pleural effusions and peripheral edema with elevated vascular endothelial growth factor. Endocr J 2007;54:577-84.
• 26 Zhao X, Wang G, You J. Measurement and correlation analysis of plasma VEGF level in the patients of hyperthyroidism. Sheng Wu Yi Xue Gong Cheng Xue Za Zhi 2013;30:365-7.
• 27 Figueroa-Vega N, Sanz-Cameno P, Moreno-Otero R, Sánchez-Madrid F, González-Amaro R, Marazuela M, et al. Serum levels of angiogenic molecules in autoimmune thyroid diseases and their correlation with laboratory and clinical features. J Clin Endocrinol Metab 2009;94:1145-53.
• 28 Bunone G, Vigneri P, Mariani L, Butó S, Collini P, Pilotti S, et al. Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 1999;155:1967-76.
• 29 Kajdaniuk D, Marek B, Niedziołka-Zielonka D, Foltyn W, Nowak M, Siemińska L, et al. Transforming growth factor β1 (TGFβ1) and vascular endothelial growth factor (VEGF) in the blood of healthy people and patients with Graves’ orbitopathy – A new mechanism of glucocorticoids action? Endokrynol Pol 2014;65:348-56.
• 30 Oranskiy SP, Yeliseyeva LN, Tsanaeva AV, Zaytseva NV. Body composition and serum levels of adiponectin, vascular endothelial growth factor, and interleukin-6 in patients with rheumatoid arthritis. Croat Med J 2012;53:350-6.