Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer
Expression of Vascular Notch Ligand Delta-Like 4 and Inflammatory Markers in Breast Cancer
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DOI：
10.2353/ajpath.2010.090908
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发表时间：
2010-04-01
影响因子：
6
通讯作者：
Harris, Adrian L.
中科院分区：
文献类型：
--
作者：
Jubb, Adrian M.;Soilleux, Elizabeth J.;Harris, Adrian L.
δ样配体4 （Dll4）是一种主要表达于内皮细胞的Notch配体。来自异种移植物的证据表明，抑制Dll4可能克服抗血管内皮生长因子治疗的耐药性。本研究的目的是表征Dll4在乳腺癌中的表达，并评估其是否与炎症标志物和预后相关。我们检查了296例乳腺腺癌和38例导管原位癌组织，这些组织在组织微阵列中表现出来。另外包括10例乳腺腺癌、10例正常乳腺组织和16例血管肉瘤的全切片。然后使用针对Dll4， CD68, cd14，树突状细胞特异性细胞间粘附分子-3-捕获非整合素（DC-SIGN）， CD123，中性粒细胞弹性酶，CD31和碳酸酐酶9的有效抗体进行免疫组织化学。在73% - 100%的乳腺腺癌、18%的原位导管癌和所有哺乳期乳腺病例中，Dll4在瘤内内皮细胞中选择性表达，但在正常的非哺乳期乳腺中不表达。内皮细胞Dll4高强度表达在总生存期和无复发生存期的单因素分析（P = 0.002和P = 0.01）和多因素分析（P = 0.03和P = 0.04）中分别是具有统计学意义的不良预后因素。在炎症标志物中，只有CD68和DC-SIGN是单因素（但不是多因素）总生存分析的重要预后因素（P分别= 0.01和0.002）。综上所述，Dll4在乳腺癌细胞中通过内皮表达。在这些回顾性亚群分析中，内皮细胞Dll4表达是一个具有统计学意义的多变量预后因素。（美国病理学杂志，2010,176:2019-2024;DOI: 10.2353/ajpath.2010.090908）
Delta-like ligand 4 (Dll4) is a Notch ligand that is predominantly expressed in the endothelium. Evidence from xenografts suggests that inhibiting Dll4 may overcome resistance to antivascular endothelial growth factor therapy. The aims of this study were to characterize the expression of Dll4 in breast cancer and assess whether it is associated with inflammatory markers and prognosis. We examined 296 breast adenocarcinomas and 38 ductal carcinoma in situ tissues that were represented in tissue microarrays. Additional whole sections representing 10 breast adenocarcinomas, 10 normal breast tissues, and 16 angiosarcomas were included. Immunohistochemistry was then performed by using validated antibodies against Dll4, CD68, CD 14, Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), CD123, neutrophil elastase, CD31, and carbonic anhydrase 9. Dll4 was selectively expressed by intratumoral endothelial cells in 73% to 100% of breast adenocarcinomas, 18% of in situ ductal carcinomas, and all lactating breast cases, but not normal nonlactating breast. High intensity of endothelial Dll4 expression was a statistically significant adverse prognostic factor in univariate (P = 0.002 and P = 0.01) and multivariate analyses (P = 0.03 and P = 0.04) of overall survival and relapse-free survival, respectively. Among the inflammatory markers, only CD68 and DC-SIGN were significant prognostic factors in univariate (but not mullivariate) analyses of overall survival (P = 0.01 and 0.002, respectively). In summary, Dll4 was expressed by endothelium associated with breast cancer cells. In these retrospective subset analyses, endothelial Dll4 expression was a statistically significant multivariate prognostic factor. (Am J Pathol 2010, 176:2019-2024; DOI: 10.2353/ajpath.2010.090908)