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Serum Vascular Endothelial Growth Factor Levels Are Elevated in Metastatic Differentiated Thyroid Cancer but Not Increased by Short-Term TSH Stimulation

Department of Medicine (R.M.T., R.J.R.), Endocrinology Service, and Department of Clinical Laboratories (M.F.), Clinical Chemistry Service, Memorial Sloan-Kettering Cancer Center, New York, New York 10021; and Department of Pediatrics (G.L.F.), Walter Reed Army Medical Center, Washington, D.C. 20307

Address all correspondence and requests for reprints to: R. Michael Tuttle, M.D., Endocrinology Service, Memorial Sloan-Kettering Cancer Center, Box 419 (H-715), 1275 York Avenue, New York, New York 10021. E-mail: . rmtuttle{at}hotmail.com

Abstract

Solid tumor formation requires the development of a blood supply adequate to meet the metabolic demands of the enlarging tumor mass that cannot be sustained by simple diffusion. One principal stimulant to endothelial cell growth and migration, vascular endothelial growth factor (VEGF), is synthesized and secreted by thyroid cancer cells. Furthermore, VEGF overexpression is associated with an aggressive thyroid cancer phenotype in both animal models and clinical-pathological studies. In other malignancies, elevated serum levels of VEGF often correlate with stage of disease and other poor prognostic clinical features. Therefore, we hypothesized that serum VEGF levels would be significantly higher in patients with persistent or recurrent thyroid cancer than in those cured of the disease. Because TSH stimulates both normal and neoplastic thyroid cells, we also proposed that serum VEGF would be further increased by TSH stimulation. Sixty-nine patients with either papillary or follicular thyroid cancer, status post total thyroidectomy, and prior radioactive iodine ablation, who had undergone routine recombinant human TSH (rhTSH, Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) assisted whole-body radioactive iodine scanning, were included in this study. This cohort (mean age 53 ± 16 yr, 51% female) included 21 patients with no evidence of disease and 48 patients with local or distant metastases. Stored serum samples obtained for standard Tg determinations before and 72 h following standard rhTSH stimulation were identified and assayed for VEGF 165 (R \|[amp ]\| D Systems, Minneapolis, MN). Baseline serum VEGF levels obtained at a time of TSH suppression were significantly higher in patients with known metastatic disease than in those with no evidence of disease (416 ± 62 pg/ml vs. 185 ± 25 pg/ml, P = 0.001). Patients with distant metastases had baseline serum VEGF levels that did not differ significantly from patients with only cervical recurrences (455 ± 90 pg/ml in distant metastases vs. 330 ± 44 pg/ml for local cervical recurrences). Short-term TSH stimulation, although causing a significant rise in serum Tg, resulted in no significant increase in serum VEGF measured 72 h after rhTSH injection in either the patients with known metastatic disease (416 ± 62 pg/ml baseline vs. 419 ± 71 pg/ml after TSH stimulation) or in cured patients (185 ± 25 pg/ml baseline vs. 191 ± 33 pg/ml after TSH stimulation). Subgroup analysis revealed that patients with metastatic disease arising from well differentiated primary thyroid cancers had significantly higher serum VEGF levels than patients with metastatic disease arising from poorly differentiated thyroid cancer primaries (485 ± 74 pg/ml vs. 167 ± 32 pg/ml, P = 0.003 by ANOVA). Poorly differentiated metastatic thyroid cancers had serum VEGF levels indistinguishable from patients cured of disease (167 ± 32 pg/ml vs. 186 ± 25 pg/ml). In summary, serum VEGF is significantly elevated in patients with metastatic differentiated thyroid cancer but not in those with poorly differentiated thyroid cancer metastases. No measurable increase in serum VEGF levels can be detected 72 h after short-term TSH stimulation with rhTSH. We conclude that serum VEGF may serve as a clinical useful marker of residual differentiated thyroid cancer.

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