PO.TB01.01 · 肿瘤生物学
肾细胞癌中表达PSMA的肿瘤血管系统:空间、功能与治疗意义
PSMA-expressing tumor vasculature in renal cell carcinoma: spatial, functional, and therapeutic implications
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景
前列腺特异性膜抗原(PSMA)是前列腺癌中确立的诊断和治疗靶点,广泛用于PSMA-PET成像和PSMA靶向放射性配体治疗。除前列腺癌外,PSMA也已在多种实体瘤的肿瘤相关血管系统中被报道,提示其作为血管标志物和治疗靶点的潜力。在肾细胞癌(RCC)中,已有PSMA阳性血管的描述,然而其空间分布、诱导机制、对血管生成的贡献及治疗相关性仍未得到充分界定。
方法
进行空间转录组学分析(10x Genomics Visium)以表征RCC组织内FOLH1(PSMA)表达的空间定位及相关转录变化。对45例RCC病例进行PSMA和CD31免疫组化,以评估与复发和静脉侵犯的关联。将内皮细胞暴露于RCC来源的条件培养基和差速离心组分,以评估PSMA诱导、血管生成活性和转录改变。采用Caki1异种移植模型研究PSMA抑制剂2-PMPA的治疗效果。
结果
空间分析显示FOLH1表达集中于瘤周血管区域,并与血管生成相关基因表达增加的区域重叠。免疫组化证实PSMA表达局限于肿瘤相关血管,且强PSMA表达与复发和静脉侵犯显著相关。在RCC来源的组分中,仅10,000 g沉淀能稳固诱导内皮PSMA表达、增强管形成并激活血管生成相关转录程序。在体内,2-PMPA治疗显著降低了肿瘤生长和微血管密度。
结论
RCC中的PSMA阳性血管系统代表了一种由肿瘤来源囊泡诱导的内皮表型,并在功能上促进血管生成。强PSMA表达与侵袭性临床病理特征之间的关联,连同PSMA抑制的抗血管生成效应,凸显PSMA阳性血管作为RCC中有前景的治疗靶点。这些发现为将前列腺癌中已充分确立的PSMA靶向成像和治疗策略扩展至PSMA阳性RCC提供了分子基础。
查看英文原文 English abstract
Background
Prostate-specific membrane antigen (PSMA) is an established diagnostic and therapeutic target in prostate cancer, widely utilized in PSMA-PET imaging and PSMA-directed radioligand therapy. Beyond prostate cancer, PSMA has also been reported in the tumor-associated vasculature of several solid tumors, suggesting its potential as a vascular marker and therapeutic target. In renal cell carcinoma (RCC), PSMA-positive vessels have been described, yet their spatial distribution, mechanisms of induction, contribution to angiogenesis, and therapeutic relevance remain insufficiently defined.
Methods
Spatial transcriptomic analysis (10x Genomics Visium) was performed to characterize the spatial localization of FOLH1 (PSMA) expression and associated transcriptional changes within RCC tissues. Immunohistochemistry for PSMA and CD31 was conducted on 45 RCC cases to evaluate associations with recurrence and venous invasion. Endothelial cells were exposed to RCC-derived conditioned medium and differential centrifugation fractions to assess PSMA induction, angiogenic activity, and transcriptional alterations. A Caki1 xenograft model was used to investigate the therapeutic effect of the PSMA inhibitor 2-PMPA.
Results
Spatial analysis showed that FOLH1 expression was concentrated within peritumoral vascular regions and overlapped with areas exhibiting increased expression of angiogenesis-related genes. Immunohistochemistry confirmed that PSMA expression was restricted to tumor-associated vessels, and strong PSMA expression was significantly associated with recurrence and venous invasion. Among RCC-derived fractions, only the 10,000 g pellet robustly induced endothelial PSMA expression, enhanced tube formation, and activated angiogenesis-related transcriptional programs. In vivo, treatment with 2-PMPA significantly reduced tumor growth and microvessel density.
Conclusions
PSMA-positive vasculature in RCC represents an endothelial phenotype induced by tumor-derived vesicles and functionally contributes to angiogenesis. The association between strong PSMA expression and aggressive clinicopathologic features, together with the anti-angiogenic effect of PSMA inhibition, highlights PSMA-positive vessels as a promising therapeutic target in RCC. These findings provide a molecular basis for extending PSMA-targeted imaging and therapeutic strategies-well established in prostate cancer-to PSMA-positive RCC.
利益披露 Disclosure
R. Watanabe, None..
K. Kagimoto, None..
M. Chosei, None..
T. Sakaue, None..
M. Kurata, None..
N. Miura, None..
R. Kitazawa, None..
T. Kikugawa, None..
S. Higashiyama, None..
T. Saika, None.