Gravdal Karsten, Halvorsen Ole J, Haukaas Svein A, Akslen Lars A
The Gade Institute, Section for Pathology, and Department of Surgical Sciences, University of Bergen, Haukeland University Hospital, Bergen, Norway.
Cancer Res. 2009 Jun 1;69(11):4708-15. doi: 10.1158/0008-5472.CAN-08-4417.
Nestin (neuroepithelial stem cell protein) is expressed in immature endothelial cells, and we here introduce coexpression of Nestin and Ki-67 as a novel angiogenesis marker on tissue sections. Including vascular endothelial growth factor (VEGF)-A and hypoxia-inducible factor-1alpha (HIF-1alpha) expression, we studied relation to disease progression in prostate cancer. Different patient series were included. Sections from 104 radical prostatectomies with long follow-up, 33 castration-resistant prostate cancers, 28 nonskeletal metastases, 13 skeletal metastases, and 41 benign prostatic hyperplasias were immunostained for Nestin/Ki-67, VEGF-A, and HIF-1alpha. Vascular proliferation by Nestin/Ki-67-positive vessels was counted within "hotspot" areas. Median vascular proliferation counts were 4- to 5-fold higher in castration-resistant prostate cancers and metastases versus localized cancers and prostatic hyperplasias (P < 0.0005). Among localized cancers, high vascular proliferation was significantly related to adverse clinicopathologic features and was a strong and independent predictor of biochemical failure (P < 0.005), clinical recurrence (P = 0.005), and skeletal metastasis (P = 0.025) in multivariate analysis. Castration-resistant cancers were characterized by reduced VEGF-A and increased HIF-1alpha expression, and vascular proliferation was associated with reduced patient survival in this group. Thus, vascular proliferation was of independent prognostic importance among prostate cancers. When compared with localized cancers, vascular proliferation was significantly increased in castration-resistant cases and metastatic lesions. The castration-resistant tumors exhibited weak VEGF-A but strong HIF-1alpha expression. These novel data might have an effect on clinical evaluation and treatment of prostate cancer patients.
巢蛋白（神经上皮干细胞蛋白）在未成熟内皮细胞中表达，我们在此介绍巢蛋白和Ki-67的共表达作为组织切片上一种新的血管生成标志物。包括血管内皮生长因子（VEGF）-A和缺氧诱导因子-1α（HIF-1α）表达，我们研究了其与前列腺癌疾病进展的关系。纳入了不同的患者系列。对104例有长期随访的根治性前列腺切除术、33例去势抵抗性前列腺癌、28例非骨骼转移瘤、13例骨骼转移瘤和41例良性前列腺增生的切片进行巢蛋白/Ki-67、VEGF-A和HIF-1α免疫染色。在“热点”区域内计数巢蛋白/Ki-67阳性血管的血管增殖情况。去势抵抗性前列腺癌和转移瘤中的血管增殖中位数比局限性癌和前列腺增生高4至5倍（P<0.0005）。在局限性癌中，高血管增殖与不良临床病理特征显著相关，并且在多变量分析中是生化失败（P<0.005）、临床复发（P=0.005）和骨骼转移（P=0.025）的强有力且独立的预测指标。去势抵抗性癌的特征是VEGF-A表达降低和HIF-1α表达增加，并且该组中的血管增殖与患者生存率降低相关。因此，血管增殖在前列腺癌中具有独立的预后重要性。与局限性癌相比，去势抵抗性病例和转移病灶中的血管增殖显著增加。去势抵抗性肿瘤表现出弱的VEGF-A但强的HIF-1α表达。这些新数据可能会对前列腺癌患者的临床评估和治疗产生影响。
