Rodriguez Fausto J, Orr Brent A, Ligon Keith L, Eberhart Charles G
Department of Pathology, Division of Neuropathology, Johns Hopkins University, MD, USA.
Oncotarget. 2012 Jan;3(1):98-106. doi: 10.18632/oncotarget.427.
Microvascular proliferation is a key biological and diagnostic hallmark of human glioblastoma, one of the most aggressive forms of human cancer. It has recently been suggested that stem-like glioblastoma cells have the capacity to differentiate into functional endothelial cells, and that a significant proportion of the vascular lining in tumors has a neoplastic origin. In principle, this finding could significantly impact the efficacy and development of antiangiogenic therapies targeting the vasculature. While the potential of stem-like cancer cells to form endothelium in culture seems clear, in our clinical experience using a variety of molecular markers, neoplastic cells do not contribute significantly to the endothelial-lined vasculature of primary human glioblastoma. We sought to confirm this impression by analyzing vessels in glioblastoma previously examined using chromogenic in situ hybridization (CISH) for EGFR and immunohistochemistry for mutant IDH1. Vessels containing cells expressing these definitive neoplastic markers were identified in a small fraction of tumors, but only 10% of vessel profiles examined contained such cells and when identified these cells comprised less than 10% of the vascular cellularity in the cross section. Interestingly, these rare intravascular cells showing EGFR amplification by CISH or mutant IDH1 protein by immunohistochemistry were located in the middle or outer portions of vessel walls, but not amongst the morphologic boundaries of the endothelial lining. To more directly address the capacity of glioblastoma cells to contribute to the vascular endothelium, we performed double labeling (Immunofluorescence/FISH) for the endothelial marker CD34 and EGFR gene locus. This analysis did not identify EGFR amplified CD34+ endothelial cells within vascular linings, and further supports our observation that incorporation of glioblastoma cells into the tumor vessels is, at best, extremely rare of questionable clinical or therapeutic significance.
微血管增殖是人类胶质母细胞瘤的一个关键生物学和诊断标志，胶质母细胞瘤是人类癌症中最具侵袭性的形式之一。最近有人提出，干细胞样胶质母细胞瘤细胞有能力分化为功能性内皮细胞，并且肿瘤中相当一部分血管内衬具有肿瘤起源。原则上，这一发现可能会显著影响针对脉管系统的抗血管生成疗法的疗效和开发。虽然干细胞样癌细胞在培养中形成内皮的潜力似乎很明显，但根据我们使用各种分子标记的临床经验，肿瘤细胞对原发性人类胶质母细胞瘤的内皮衬里脉管系统的贡献并不显著。我们试图通过分析先前使用针对表皮生长因子受体（EGFR）的显色原位杂交（CISH）和针对异柠檬酸脱氢酶1（IDH1）突变体的免疫组织化学检查的胶质母细胞瘤中的血管来证实这一印象。在一小部分肿瘤中发现了含有表达这些明确肿瘤标记物的细胞的血管，但在所检查的血管轮廓中只有10%含有此类细胞，并且当发现这些细胞时，它们在横截面中占血管细胞成分的比例不到10%。有趣的是，这些通过CISH显示EGFR扩增或通过免疫组织化学显示IDH1突变蛋白的罕见血管内细胞位于血管壁的中部或外部，而不在内皮衬里的形态学边界内。为了更直接地研究胶质母细胞瘤细胞形成血管内皮的能力，我们对内皮标记物CD34和EGFR基因位点进行了双重标记（免疫荧光/荧光原位杂交）。该分析未在血管内衬中鉴定出EGFR扩增的CD34+内皮细胞，进一步支持了我们的观察结果，即胶质母细胞瘤细胞融入肿瘤血管的情况，充其量极为罕见，临床或治疗意义存疑。
