Hoffmann Sebastian, Wunderlich Annette, Lingelbach Susanne, Musholt Petra B, Musholt Thomas J, von Wasielewski Reinhard, Zielke Andreas
Department of Surgery, Philipps-University Marburg, Marburg, Baldingerstrasse, Germany.
Ann Surg Oncol. 2008 Dec;15(12):3601-8. doi: 10.1245/s10434-008-0170-1. Epub 2008 Sep 26.
In thyroid cancer (TC) endostatin was identified as a powerful negative regulator of tumor angiogenesis in vitro. It is currently being evaluated in phase I trials for antiangiogenic therapy in various solid tumors. The aim of this study was to evaluate endostatin expression in archival TC specimens and its secretion following stimulation with thyrotropin (TSH) and epidermal growth factor (EGF) in TC cell lines.
Tissue microarrays of 44 differentiated and 7 anaplastic TC and their metastasis were immunostained for endostatin protein expression and compared with corresponding non-neoplastic thyroid tissue (NT). In vitro, six differentiated (FTC133, FTC236, HTC, HTC-TSHr, XTC, and TPC1) and three anaplastic (C643, Hth74, Kat4.0) TC cell lines were evaluated for basal as well as TSH (1-100 mU/ml) and EGF stimulated (1-100 ng/ml) endostatin.
Endostatin was detected in all TC and more than half of the NT. Endostatin expression was more frequent and intense in differentiated as compared to anaplastic TC. In vitro, basal endostatin secretion varied between 33 +/- 5 pg/ml (FTC236) and 549 +/- 65 pg/ml (TPC1) and was doubled in FTC, when the "primary" (FTC133) was compared with the metastasis (FTC236). Some cell lines showed TSH-induced (e.g., 60% in XTC) or EGF-induced (e.g., 120% in TPC1) upregulation of endostatin secretion, while others did not, despite documented receptor expression.
This study demonstrates endostatin expression in TC, metastasis and--less frequently and intensely--in NT, suggesting a possible association to tumor progression. In vitro, endostatin secretion of some cell lines is regulated by TSH and EGF, however the individual differences deserve further functional studies. These results support rather tumor-specific than histotype-specific expression and regulation of endostatin in TC.
在甲状腺癌（TC）中，内皮抑素在体外被确定为肿瘤血管生成的一种强大的负调节因子。目前它正在多种实体瘤抗血管生成治疗的I期试验中接受评估。本研究的目的是评估存档TC标本中内皮抑素的表达情况，以及TC细胞系在促甲状腺激素（TSH）和表皮生长因子（EGF）刺激后的分泌情况。
对44例分化型和7例未分化型TC及其转移灶的组织微阵列进行内皮抑素蛋白表达的免疫染色，并与相应的非肿瘤性甲状腺组织（NT）进行比较。在体外，对6种分化型（FTC133、FTC236、HTC、HTC-TSHr、XTC和TPC1）和3种未分化型（C643、Hth74、Kat4.0）TC细胞系进行基础以及TSH（1-100 mU/ml）和EGF刺激（1-100 ng/ml）后的内皮抑素评估。
在所有TC以及超过一半的NT中检测到内皮抑素。与未分化型TC相比，分化型TC中内皮抑素的表达更频繁且更强烈。在体外，基础内皮抑素分泌量在33±5 pg/ml（FTC236）至549±65 pg/ml（TPC1）之间变化，当将“原发灶”（FTC133）与转移灶（FTC236）比较时，FTC中的分泌量增加了一倍。一些细胞系显示出TSH诱导（如XTC中为60%）或EGF诱导（如TPC1中为120%）的内皮抑素分泌上调，而其他细胞系则没有，尽管有记录显示受体表达。
本研究证明了内皮抑素在TC、转移灶中表达，在NT中表达较少且强度较低，提示其可能与肿瘤进展有关。在体外，一些细胞系的内皮抑素分泌受TSH和EGF调节，然而个体差异值得进一步进行功能研究。这些结果支持TC中内皮抑素的表达和调节是肿瘤特异性而非组织学类型特异性的。
