The differential expression of EphB2 and EphB4 receptor kinases in normal bladder and in transitional cell carcinoma of the bladder.
The differential expression of EphB2 and EphB4 receptor kinases in normal bladder and in transitional cell carcinoma of the bladder.
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DOI：
10.1371/journal.pone.0105326
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Liu R
中科院分区：
文献类型：
--
作者：
Li X;Choi WW;Yan R;Yu H;Krasnoperov V;Kumar SR;Schuckman A;Klumpp DJ;Pan CX;Quinn D;Gill IS;Gill PS;Liu R
膀胱移行细胞癌的有效治疗需要早期诊断。在膀胱移行细胞癌中发现新的分子标记将指导诊断和治疗靶点的发展。肾上腺素通过调节不同生理和发育过程的酪氨酸激酶活性来调节信号，并且越来越多地与癌症的发生有关。本研究的目的是研究EphB4和EphB2在正常膀胱和40例根治性膀胱切除患者膀胱移行细胞癌中的差异调节。免疫组化和Western blotting显示正常尿路上皮表达EphB2(20/24例，83%)，而不表达EphB4(0/24例，0%)。与之形成鲜明对比的是，膀胱移行细胞癌组织中EphB2表达缺失(0/34，0%)，EphB4表达增强(32/34，94%)。此外，EphB4信号强度与较高的肿瘤分期相关，并倾向于存在原位癌(CIS)。对正常尿路上皮细胞和肿瘤细胞系的分析证实了这些结果。EphB2在正常尿路上皮中不是生存因子，而EphB4在TCC中是生存因子。使用EphB4抑制剂sEphB4-HSA治疗膀胱癌移植瘤，联合贝伐单抗可导致62%的肿瘤消退和完全缓解。此外，组织分析显示，sEphB4-HSA导致细胞凋亡增加，增殖减少，血管密度减少，这表明sEphB4-HSA具有直接的肿瘤靶向和抗血管生成作用。综上所述，EphB2的缺失和EphB4的表达增强代表着TCC发生、生长和可能进展的拐点。针对EphB4的治疗化合物具有诊断和治疗TCC的潜力。
Effective treatment of transitional cell carcinoma (TCC) of the bladder requires early diagnosis. Identifying novel molecular markers in TCC would guide the development of diagnostic and therapeutic targets. Ephrins mediate signals via tyrosine kinase activity that modulates diverse physiologic and developmental processes, and ephrins are increasingly implicated in carcinogenesis. The aim of our study was to examine the differential regulation of EphB4 and EphB2 in normal bladder and in TCC of the bladder in 40 patients undergoing radical cystectomy for curative intent. Immunostaining and Western blotting revealed that normal urothelium expresses EphB2 (20 of 24 cases, 83% of the time) not EphB4 (0 of 24 cases, 0%). In sharp contrast, TCC specimens show loss of EphB2 expression (0 of 34 cases, 0%) and gain of EphB4 expression (32 of 34, 94%). Furthermore, EphB4 signal strength statistically correlated with higher tumor stage, and trended toward the presence of carcinoma in situ (CIS). These results are confirmed by analysis of normal urothelial and tumor cell lines. EphB2 is not a survival factor in normal urothelium, while EphB4 is a survival factor in TCC. Treatment of bladder tumor xenograft with an EphB4 inhibitor sEphB4-HSA leads to 62% tumor regression and complete remission when combined with Bevacizumab. Furthermore, tissue analysis revealed that sEphB4-HSA led to increased apoptosis, decreased proliferation, and reduced vessel density, implicating direct tumor cell targeting as well as anti-angiogenesis effect. In summary loss of EphB2 and gain of EphB4 expression represents an inflection point in the development, growth and possibly progression of TCC. Therapeutic compounds targeting EphB4 have potential for diagnosing and treating TCC.
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影响因子：
5.7
作者：
Spannuth WA;Mangala LS;Stone RL;Carroll AR;Nishimura M;Shahzad MM;Lee SJ;Moreno-Smith M;Nick AM;Liu R;Jennings NB;Lin YG;Merritt WM;Coleman RL;Vivas-Mejia PE;Zhou Y;Krasnoperov V;Lopez-Berestein G;Gill PS;Sood AK
通讯作者：
Sood AK
影响因子：
3.8
作者：
Lee YC;Perren JR;Douglas EL;Raynor MP;Bartley MA;Bardy PG;Stephenson SA
通讯作者：
Stephenson SA
受体酪氨酸激酶EPHB4在卵巢癌中过表达，提供生存信号并预测结果不佳。
影响因子：
8.8
作者：
Kumar, S. R.;Masood, R.;Spannuth, W. A.;Singh, J.;Scehnet, J.;Kleiber, G.;Jennings, N.;Deavers, M.;Krasnoperov, V.;Dubeau, L.;Weaver, F. A.;Sood, A. K.;Gill, P. S.
通讯作者：
Gill, P. S.
影响因子：
16
作者：
Gerety, SS;Wang, HU;Anderson, DJ
通讯作者：
Anderson, DJ
DOI：
10.1001/archotol.132.10.1053
发表时间：
2006-10-01
影响因子：
--
作者：
Sinha, Uttam K.;Mazhar, Kashif;Gill, Parkash S.
通讯作者：
Gill, Parkash S.