Division of Diagnostic Pathology, Keio University School of Medicine, Tokyo, Japan.
Department of Urology, Keio University School of Medicine, Tokyo, Japan.
Lab Invest. 2017 Jul;97(7):854-862. doi: 10.1038/labinvest.2017.26. Epub 2017 Mar 13.
The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.
微血管密度（MVD）由内皮细胞（EC）标志物如 CD31 和 CD34 检测，被认为是血管生成的生物标志物，通常与实体瘤的恶性潜能相关。然而，在透明细胞肾细胞癌（ccRCC）患者中，MVD 与预后之间存在矛盾关系。这可能是因为 EC 标志物不仅在静止的 EC 中表达，也在激活的 EC 中表达，所以 MVD 并不能充分反映 ccRCC 中的血管生成活性。为了研究真实的血管生成活性，我们检测了血管生成抑制素-1（VASH1），它是一种新发现的血管生成调节剂，被证明特异性表达于新形成的血管内皮细胞。对 116 例未经治疗的原发性 ccRCC、10 例未经治疗的转移性 ccRCC 和 9 例接受舒尼替尼治疗的转移性 ccRCC 进行了 VASH1 和 CD34 的免疫组化检查。肿瘤微血管中的 EC 偶尔会被 VASH1 免疫染色，但在非肿瘤性肾组织中未观察到 VASH1 染色。CD34 在 ccRCC 和非肿瘤性肾组织中的所有 EC 中均广泛表达。多变量 Cox 分析表明，升高的 VASH1 密度而非 MVD 是总生存期的显著独立预测因素（比值比，7.71；P=0.003）。与未经治疗的肿瘤相比，舒尼替尼治疗的转移灶中的 MVD 显著降低（P=0.001）。另一方面，与未经治疗的肿瘤相比，接受舒尼替尼治疗的转移性 ccRCC 中的 VASH1 密度显著升高（P=0.010），表明 VASH1 可能与 EC 对舒尼替尼治疗的耐药性有关。因此，VASH1 表达可能反映了血管生成的实际活性，VASH1 可作为 ccRCC 患者的新的预后和预测生物标志物。
