最近,，來(lái)自美國(guó)密西根州的研究者已經(jīng)鑒別出進(jìn)入卵巢腫瘤內(nèi)部血管細(xì)胞的獨(dú)特標(biāo)記物,。盡管該發(fā)現(xiàn)處于預(yù)備階段，但終將在未來(lái)的某一天提高對(duì)該疾病的篩查,、診斷和治療,。來(lái)自美國(guó)密西根州立大學(xué)、賓西法尼亞州立大學(xué),，希臘和意大利的大學(xué)的研究組應(yīng)用激光技術(shù)從21例卵巢腫瘤和4例正常卵巢組織樣本分離血管細(xì)胞,，從而確定血管細(xì)胞表達(dá)的基因。該結(jié)果鑒別出在癌組織血管中大量存在,，但在正常組織血管中不存在的70多種標(biāo)記物,。研究者繼續(xù)深入研究了以前與腫瘤血管不相關(guān)的12種標(biāo)志物。該研究刊登在《臨床腫瘤學(xué)》（Clinical Oncology）雜志3月第1期上,。
“這些基因中一部分因?yàn)橐蕾囉谒鼈冊(cè)谀[瘤脈管的高表達(dá),，因此成為病人生存的預(yù)后因子。我們懷疑當(dāng)這些基因高表達(dá)時(shí)意味著腫瘤能更為有效地生長(zhǎng)血管,，因此更具侵襲性,。這能幫助我們?yōu)橹委煵呗灾该鞣较颉?rdquo;首席研究作者、密西根醫(yī)學(xué)院內(nèi)科學(xué)和婦產(chǎn)科學(xué)的副教授Ronald Buckanovich醫(yī)學(xué)博士指導(dǎo)了這項(xiàng)研究,。該研究分析了大量的腫瘤脈管系統(tǒng)或血管,、剖面的樣本數(shù),。盡管本次分離的許多基因早已顯示與其他類(lèi)型癌相關(guān)聯(lián)，還是有一些標(biāo)記物是新發(fā)現(xiàn)的,。
另外,，研究者能夠確定在大量卵巢腫瘤中表達(dá)的標(biāo)記物在正常卵巢或其他健康器官中不表達(dá)。研究者同時(shí)發(fā)現(xiàn)這些標(biāo)記物在進(jìn)行血管生長(zhǎng)的正常生殖組織中不存在,，例如胎盤(pán)或子宮內(nèi)膜,。因此可以確定，這些標(biāo)記物對(duì)腫瘤具有特異性,，同時(shí)不會(huì)誤判為處于生殖期女性正常的血管生長(zhǎng),。
如果這些標(biāo)志物確實(shí)顯示對(duì)卵巢腫瘤具有特異性，研究者認(rèn)為有望發(fā)展使腫瘤窒息的針對(duì)腫瘤血管的藥物,。
生物標(biāo)記物作為潛在的篩查工具,，已可見(jiàn)于其他類(lèi)型癌。檢測(cè)卵巢癌的新方法可以明顯彌補(bǔ)那些70%的病人只有在腫瘤長(zhǎng)大或播散時(shí)才能診斷的缺陷,。這些疾病早期很少有或沒(méi)有癥狀,，并且無(wú)有效的篩查試驗(yàn)。但早期診斷是極為重要的,，早期診斷決定著95%生存率和晚期診斷的20%生存率之間的差異,。Buckanovich說(shuō)，“我們目前所有可以期望的事情就是：可能的診斷,，成像,，治療和預(yù)知。這需要更多的工作和得到更多的證實(shí),，而我們?cè)缙诘慕Y(jié)論是值得期望的,。”持續(xù)的研究將著眼于發(fā)展抗體和檢測(cè)這些新蛋白質(zhì)的方法。
部分英文原文：
Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 852-861
© 2007 American Society of Clinical Oncology.
DOI: 10.1200/JCO.2006.08.8583
Tumor Vascular Proteins As Biomarkers in Ovarian Cancer
Ronald J. Buckanovich, Dimitra Sasaroli, Anne O'Brien-Jenkins, Jeffrey Botbyl, Rachel Hammond, Dionysios Katsaros, Raphael Sandaltzopoulos, Lance A. Liotta, Phyllis A. Gimotty, George Coukos
From the Center for Research on Reproduction and Women's Health, Abramson Family Cancer Research Institute, Department of Medicine Division of Hematology-Oncology, and Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA; University of Michigan, Ann Arbor, MI; Center for Applied Proteomics and Molecular Medicine, George Mason University, Fairfax, VA; Department of Obstetrics and Gynecology, University of Turin, Turin, Italy; and Molecular Biology and Genetics Program, Democritus University of Thrace, Komotini, Greece
Address reprint requests to George Coukos, MD, PhD, 1315 BRB II/III, 421 Curie Blvd, Philadelphia, PA, 19104; e-mail: [email protected]
Purpose: This study aimed to identify novel ovarian cancer biomarkers and potential therapeutic targets through molecular analysis of tumor vascular cells.
Methods: Immunohistochemistry-guided laser-capture microdissection and genome-wide transcriptional profiling were used to identify genes that were differentially expressed between vascular cells from human epithelial ovarian cancer and healthy ovaries. Tumor vascular markers (TVMs) were validated through quantitative real-time polymerase chain reaction (qRT-PCR) of immunopurified tumor endothelial cells, in situ hybridization, immunohistochemistry, and Western blot analysis. TVM expression in tumors and noncancerous tissues was assessed by qRT-PCR and was profiled using gene expression data.
Results: We identified a tumor vascular cell profile of ovarian cancer that was distinct from the vascular profile of normal ovary and other tumors. We validated 12 novel ovarian TVMs. These were expressed by immunopurified tumor endothelial cells and localized to tumor vasculature. select TVMs were found to be specifically expressed in ovarian cancer and were absent in all normal tissues tested, including female reproductive tissues with physiologic angiogenesis. Many ovarian TVMs were expressed by a variety of other solid tumors. Finally, overexpression of any one of three ovarian TVMs by vascular cells was associated with decreased disease-free interval (all P < .005).
Conclusion: We have identified for the first time the molecular profile of ovarian tumor vasculature. We demonstrate that TVMs may serve as potential biomarkers and molecular targets for ovarian cancer and a variety of other solid tumors.
Supported by National Institutes of Health (NIH) Grant No. R01 CA098951; National Cancer Institute (NCI) Ovarian Cancer Specialized Program of Research Excellence (SPORE) Grant No. P50-CA083638; US Army Medical Research and Materiel Command Grant No. OC-050314; and the Marcia and Philip Rothblum Foundation. R.J.B. was supported by NIH/National Institute of Child Health and Human Development Grant No. K12-HD43459 and the Ovarian Cancer Research Fund. The laser-capture microdissection facility was supported by a generous grant by the Fannie Rippel Foundation.
R.J.B and D.S. contributed equally to this work.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
