最近，来自美国密西根州的研究者已经鉴别出进入卵巢肿瘤内部血管细胞的独特标记物。尽管该发现处于预备阶段，但终将在未来的某一天提高对该疾病的筛查、诊断和治疗。来自美国密西根州立大学、宾西法尼亚州立大学，希腊和意大利的大学的研究组应用激光技术从21例卵巢肿瘤和4例正常卵巢组织样本分离血管细胞，从而确定血管细胞表达的基因。该结果鉴别出在癌组织血管中大量存在，但在正常组织血管中不存在的70多种标记物。研究者继续深入研究了以前与肿瘤血管不相关的12种标志物。该研究刊登在《临床肿瘤学》（Clinical Oncology）杂志3月第1期上。
“这些基因中一部分因为依赖于它们在肿瘤脉管的高表达，因此成为病人生存的预后因子。我们怀疑当这些基因高表达时意味着肿瘤能更为有效地生长血管，因此更具侵袭性。这能帮助我们为治疗策略指明方向。”首席研究作者、密西根医学院内科学和妇产科学的副教授Ronald Buckanovich医学博士指导了这项研究。该研究分析了大量的肿瘤脉管系统或血管、剖面的样本数。尽管本次分离的许多基因早已显示与其他类型癌相关联，还是有一些标记物是新发现的。
另外，研究者能够确定在大量卵巢肿瘤中表达的标记物在正常卵巢或其他健康器官中不表达。研究者同时发现这些标记物在进行血管生长的正常生殖组织中不存在，例如胎盘或子宫内膜。因此可以确定，这些标记物对肿瘤具有特异性，同时不会误判为处于生殖期女性正常的血管生长。
如果这些标志物确实显示对卵巢肿瘤具有特异性，研究者认为有望发展使肿瘤窒息的针对肿瘤血管的药物。
生物标记物作为潜在的筛查工具，已可见于其他类型癌。检测卵巢癌的新方法可以明显弥补那些70%的病人只有在肿瘤长大或播散时才能诊断的缺陷。这些疾病早期很少有或没有症状，并且无有效的筛查试验。但早期诊断是极为重要的，早期诊断决定着95%生存率和晚期诊断的20%生存率之间的差异。Buckanovich说，“我们目前所有可以期望的事情就是：可能的诊断，成像，治疗和预知。这需要更多的工作和得到更多的证实，而我们早期的结论是值得期望的。”持续的研究将着眼于发展抗体和检测这些新蛋白质的方法。
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: gcks@mail.med.upenn.edu
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.
