Kraan J, van den Broek P, Verhoef C, Grunhagen D J, Taal W, Gratama J W, Sleijfer S
Department of Medical Oncology, Erasmus MC Cancer Institute, box 2040, 3000 CA Rotterdam, The Netherlands.
Department of Surgical Oncology, Erasmus MC Cancer Institute, box 2040, 3000 CA Rotterdam, The Netherlands.
Br J Cancer. 2014 Jul 8;111(1):149-56. doi: 10.1038/bjc.2014.286. Epub 2014 Jun 3.
Mature circulating endothelial cells (CEC) are surrogate markers of endothelial damage. CEC measured in patients with advanced cancer are thought not only to derive from damaged normal vasculature (n-CEC), but also from damaged (t-CEC). Therefore, assays that allow the discrimination between these two putative types of CEC are thought to improve the specificity of the enumeration of CEC in cancer.
Identification of tumour-associated endothelial markers (TEM) by comparing antigen expression on normal vs t-CEC and assess the presence of t-CEC in peripheral blood of cancer patients by incorporating TEM in our novel flow cytometry-based CEC detection assay.
No difference in antigen expression between normal and malignant endothelial cells (ECs) was found for CD54, CD109, CD137, CD141, CD144 and CXCR7. In contrast, overexpression for CD105, CD146, CD276 and CD309 was observed in tumour ECs compared with normal ECs. CD276 was most differentially expressed and chosen as a marker for further investigation. CD276-expressing CEC were significantly higher in 15 patients with advanced colorectal cancer (median 9 (range 1-293 cell per 4 ml); P<0.005), in 83 patients with a glioblastoma multiforme (median 10 (range 0-804); P<0.0001) and in 14 patients with advanced breast cancer (median 14 (range 0-390) P<0.05) as compared with 24 healthy individuals (median 3 (range 0-11)). Of all patients with malignancies, 58% had CD276(+) CEC counts above the ULN (8 cell per 4 ml).
The present study shows that CD276 can be used to discriminate ECs from malignant tissue from ECs from normal tissue. In addition, CD276(+) CEC do occur in higher frequencies in patients with advanced cancer.
成熟循环内皮细胞（CEC）是内皮损伤的替代标志物。晚期癌症患者中检测到的CEC不仅被认为来源于受损的正常血管（n-CEC），还来源于受损的肿瘤血管（t-CEC）。因此，能够区分这两种假定类型CEC的检测方法被认为可以提高癌症中CEC计数的特异性。
通过比较正常与肿瘤CEC上的抗原表达来鉴定肿瘤相关内皮标志物（TEM），并将TEM纳入我们基于新型流式细胞术的CEC检测方法中，以评估癌症患者外周血中t-CEC的存在情况。
在CD54、CD109、CD137、CD141、CD144和CXCR7方面，正常与恶性内皮细胞（EC）之间未发现抗原表达差异。相比之下，与正常EC相比，肿瘤EC中观察到CD105、CD146、CD276和CD309的过表达。CD276差异表达最为明显，被选为进一步研究的标志物。与24名健康个体（中位数3（范围0 - 11））相比，15例晚期结直肠癌患者（中位数9（范围每4 ml 1 - 293个细胞）；P<0.005）、83例多形性胶质母细胞瘤患者（中位数10（范围0 - 804）；P<0.0001）和14例晚期乳腺癌患者（中位数14（范围0 - 390）；P<0.05）中表达CD276的CEC显著更高。在所有恶性肿瘤患者中，58%的患者CD276(+) CEC计数高于正常上限（每4 ml 8个细胞）。
本研究表明，CD276可用于区分来自恶性组织的EC与来自正常组织的EC。此外，晚期癌症患者中CD276(+) CEC的出现频率更高。
