Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Department of Urology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan.
Department of Tumor Pathology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Department of Urology, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan; Division of Surgical Pathology, University of Fukui Hospital, Eiheiji, Japan.
Urol Oncol. 2021 May;39(5):302.e9-302.e18. doi: 10.1016/j.urolonc.2021.02.013. Epub 2021 Mar 4.
Given the relatively high frequency of metastatic recurrence of clear cell renal cell carcinoma (ccRCC), reliable prognostic markers of ccRCC, particularly those associated with metastasis, are needed. Here, in search of those factors, we assessed the contribution of sialyl Lewis x (sLe) and sialyl Lewis a (sLe), as well as functional E-selectin ligand carbohydrates expressed on carcinoma cells, to metastasis and consequent poor prognosis in ccRCC.
Patients who underwent surgical resection (curative nephrectomy) for RCC, and whose post-operative pathological diagnosis was ccRCC (n = 117) were enrolled in this study. Expression of sLe/sLe carbohydrate antigens in ccRCC was evaluated by immunohistochemistry with an anti-sLe/sLe monoclonal antibody HECA-452. To evaluate membrane expression of sLe/sLe carbohydrate antigens quantitatively, we employed a histological scoring system used to evaluate membrane expression of human epidermal growth factor receptor 2 (HER2) in breast cancer. We also conducted an E-selectin•IgM chimera in situ binding assay to assess expression of functional E-selectin ligand carbohydrates in ccRCC. We then carried out statistical analysis to determine whether membrane expression of HECA-452-reactive sLe/sLe glycans as well as of E-selectin•IgM-binding functional E-selectin ligand carbohydrates correlates with progression-free, overall, or cancer-specific survival.
Based on HECA-452 immunochemistry, 106 of 117 ccRCC specimens expressed detectable levels of sLe/sLe glycans, primarily on the plasma membrane, and of those, 31 that showed robust membrane expression were judged as HECA-452-positive. Membrane expression of HECA-452-positive sLe/sLe glycans correlated with shortened progression-free and overall survival. Moreover, in in situ analysis, these HECA-452-positive ccRCC tissues were decorated with E-selectin•IgM chimeric proteins, calcium-dependently. Comparable analysis in normal kidney showed both HECA-452 positivity and chimera binding almost exclusively in epithelial cells that constitute proximal tubules. Membrane expression of functional E-selectin ligand carbohydrates, as detected by the E-selectin•IgM chimera, correlated more significantly with poor prognosis of patients, namely, shortened progression-free, overall and cancer-specific survival, than did HECA-452 positivity.
Expression of E-selectin•IgM-binding functional E-selectin ligand carbohydrates can serve as a reliable and potentially superior prognostic biomarker of patients with ccRCC.
鉴于透明细胞肾细胞癌（ccRCC）转移复发的相对高频率，需要可靠的 ccRCC 预后标志物，特别是与转移相关的标志物。在这里，我们通过评估唾液酸化路易斯 x（sLe）和唾液酸化路易斯 a（sLe）以及癌细胞上表达的功能性 E-选择素配体碳水化合物的贡献，来寻找这些因素，以研究它们在 ccRCC 转移和不良预后中的作用。
本研究纳入了 117 名接受根治性肾切除术（治愈性肾切除术）治疗且术后病理诊断为 ccRCC 的患者。通过使用抗 sLe/sLe 单克隆抗体 HECA-452 的免疫组织化学评估 ccRCC 中 sLe/sLe 碳水化合物抗原的表达。为了定量评估 sLe/sLe 碳水化合物抗原的膜表达，我们采用了一种组织学评分系统，用于评估乳腺癌中人类表皮生长因子受体 2（HER2）的膜表达。我们还进行了 E-选择素·IgM 嵌合体的原位结合测定，以评估 ccRCC 中功能性 E-选择素配体碳水化合物的表达。然后，我们进行了统计学分析，以确定 HECA-452 反应性 sLe/sLe 糖蛋白的膜表达以及 E-选择素·IgM 结合的功能性 E-选择素配体碳水化合物的表达是否与无进展生存期、总生存期或癌症特异性生存期相关。
基于 HECA-452 免疫化学，117 例 ccRCC 标本中有 106 例检测到 sLe/sLe 糖蛋白的可检测水平，主要位于质膜上，其中 31 例表现出强烈的质膜表达被判断为 HECA-452 阳性。HECA-452 阳性 sLe/sLe 糖蛋白的膜表达与无进展生存期和总生存期缩短相关。此外，在原位分析中，这些 HECA-452 阳性的 ccRCC 组织与 E-选择素·IgM 嵌合体蛋白结合，该结合依赖于钙。在正常肾脏中的类似分析显示，HECA-452 阳性和嵌合体结合几乎仅存在于构成近端肾小管的上皮细胞中。功能性 E-选择素配体碳水化合物的膜表达，如通过 E-选择素·IgM 嵌合体检测到的，与患者的预后更显著相关，即无进展生存期、总生存期和癌症特异性生存期缩短，优于 HECA-452 阳性。
E-选择素·IgM 结合功能性 E-选择素配体碳水化合物的表达可以作为 ccRCC 患者可靠的、潜在的优越预后生物标志物。
