Department of Signal Transduction and Biogenic Amines, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India.
Department of Surgical Oncology, Chittaranjan National Cancer Institute, 37, S. P. Mukherjee Road, Kolkata, 700026, India.
Breast Cancer Res Treat. 2020 Jan;179(2):359-370. doi: 10.1007/s10549-019-05482-8. Epub 2019 Nov 4.
The occurrence of vasculogenic mimicry (VM) and EphA2-mediated tumour progression are associated with poor prognosis in various solid tumours. Here, we aimed to investigate the prognostic implications of VM and its association with phosphorylated EphA2 receptor in invasive carcinoma of the breast.
The patients were stratified based on CD-31/PAS dual staining and subsequently the expression status of phospho-EphA2 (S897), FAK, phospho-ERK1/2 and Laminin 5Ƴ2 was analysed by immunohistochemistry. Survival of patients was correlated within the stratified cohort.
The pathologically defined VM phenotype and phospho-EphA2 (S897) expression status were significantly associated with lower disease-free survival (DFS) and overall survival (OS). Both the features were also found to be significantly associated with higher nodal status, poor Nottingham Prognostic Index (NPI) and were more prevalent in the triple-negative breast cancer (TNBC) group. Incidentally, there were no significant association between age of the patient, grade and size of the tumour with VM and phospho-EphA2 (S897). The effector molecules of phospho-EphA2 (S897) viz., Focal Adhesion Kinase (FAK), phospho-ERK1/2 and Laminin 5Ƴ2 were significantly upregulated in the VM-positive cohort. Survival analysis revealed that the VM and phospho-EphA2 (S897) dual-positive cohort had poorest DFS [mean time = 48.313 (39.992-56.633) months] and OS [mean time = 56.692 (49.055-64.328) months]. Individually, VM-positive [Hazard Ratio (HR) 6.005; 95% confidence interval (CI) 2.002-18.018; P = 0.001 for DFS and HR 11.654; 95% CI 3.195-42.508; P < 0.0001 for OS] and phospho-EphA2 (S897)-positive (HR 4.342; 95% CI 1.717-10.983; P = 0.002 for DFS and HR 5.853; 95% CI 1.663-20.602; P = 0.006 for OS) expression proved to be independent indicators of prognosis.
This study evaluated tumour dependency on oncogenic EphA2 receptor regulation and VM in invasive carcinoma of the breast and their prognostic significance. Significant correlations between VM, phospho-EphA2 and several clinicopathologic parameters of breast cancer were found. Subsequently, the occurrence of VM or phospho-EphA2 expression proved to be major contributors for poor prognosis in patients with breast cancer but their simultaneous expression failed to be an independent risk factor.
血管生成拟态（VM）的发生和 EphA2 介导的肿瘤进展与各种实体瘤的预后不良有关。在这里，我们旨在研究 VM 的预后意义及其在乳腺癌浸润性癌中的磷酸化 EphA2 受体的相关性。
根据 CD-31/PAS 双重染色对患者进行分层，然后通过免疫组织化学分析磷酸化 EphA2（S897）、FAK、磷酸化 ERK1/2 和层粘连蛋白 5Ƴ2 的表达状态。对分层队列中的患者进行生存相关性分析。
病理定义的 VM 表型和磷酸化 EphA2（S897）表达状态与无病生存率（DFS）和总生存率（OS）显著相关。这两个特征也与更高的淋巴结状态、较差的诺丁汉预后指数（NPI）显著相关，并且在三阴性乳腺癌（TNBC）组中更为普遍。此外，VM 和磷酸化 EphA2（S897）与患者年龄、肿瘤分级和大小之间没有显著关联。磷酸化 EphA2（S897）的效应分子，即粘着斑激酶（FAK）、磷酸化 ERK1/2 和层粘连蛋白 5Ƴ2 在 VM 阳性组中显著上调。生存分析显示，VM 和磷酸化 EphA2（S897）双阳性队列的 DFS 最差[平均时间=48.313（39.992-56.633）个月]和 OS 最差[平均时间=56.692（49.055-64.328）个月]。单独来看，VM 阳性（HR 6.005；95%CI 2.002-18.018；P=0.001 用于 DFS 和 HR 11.654；95%CI 3.195-42.508；P<0.0001 用于 OS）和磷酸化 EphA2（S897）阳性（HR 4.342；95%CI 1.717-10.983；P=0.002 用于 DFS 和 HR 5.853；95%CI 1.663-20.602；P=0.006 用于 OS）表达被证明是预后的独立指标。
本研究评估了肿瘤对致癌 EphA2 受体调节和乳腺癌中 VM 的依赖性及其预后意义。发现 VM、磷酸化 EphA2 与乳腺癌的几个临床病理参数之间存在显著相关性。随后，VM 或磷酸化 EphA2 表达的发生被证明是乳腺癌患者预后不良的主要因素，但它们的同时表达不能作为独立的危险因素。
