Understanding Bladder Cancer: A Serious Urologic Threat
Bladder cancer (BLCA) is one of the most common and deadly cancers affecting the urinary system. It originates in the bladder’s mucous membrane and can be classified into two main types: non-muscle invasive bladder cancer (NMIBC) and muscle-invasive bladder cancer (MIBC). Around 75% of patients are initially diagnosed with NMIBC, which typically responds well to surgery and chemotherapy. However, about 20% of NMIBC cases eventually progress to MIBC, a more aggressive form that often requires radical cystectomy and pelvic lymph node dissection.
Despite such intensive treatment, the five-year survival rate remains low, and outcomes for advanced disease remain poor. Current frontline therapies include chemotherapy with cisplatin and gemcitabine, as well as immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1. Yet, fewer than half of patients with advanced disease respond to ICIs. As recurrence and mortality remain high, researchers are urgently seeking new treatment strategies.
In this context, two biological processes have come into focus: angiogenesis, the formation of new blood vessels, and cancer stemness, the ability of cancer cells to self-renew and drive tumor growth. These mechanisms are tightly interconnected and play critical roles in cancer progression and therapy resistance.
Investigating Angiogenesis and Stemness in Bladder Cancer
A new study by Yin et al. from The First Affiliated Hospital of Soochow University explores the genetic factors that regulate angiogenesis and stemness in bladder cancer. The research aimed to uncover how these genes affect chemotherapy and immunotherapy responses.
By analyzing public datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO), the team identified genes that were both differentially expressed in bladder cancer tissue and associated with patient prognosis. From over 16,000 candidates, they narrowed the list to 102 genes involved in both angiogenesis and stemness. Among these, 12 genes showed significant impact on patient survival.
VHL Emerges as a Key Prognostic Marker
The Von Hippel–Lindau (VHL) gene stood out as the most significant marker among the 12. VHL is known for its role as an E3 ubiquitin ligase, regulating the degradation of proteins involved in angiogenesis, such as HIF1α. In this study, high expression of VHL was associated with better survival outcomes and increased sensitivity to both chemotherapy and immunotherapy.
Using advanced statistical modeling, including the LASSO regression method, the researchers developed a six-gene prognostic model. This model included VHL, TRIB3, POU5F1, P4HB, NOTCH3, and FASN. It successfully predicted overall survival in two independent datasets (TCGA and GSE13507), with the VHL gene providing the highest predictive accuracy.
Two Molecular Subtypes with Different Treatment Responses
Through clustering analysis, the team divided patients into two distinct groups based on gene expression:
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Cluster 1 had higher expression of most angiogenesis- and stemness-related genes and showed poorer overall and disease-free survival. However, this group had greater predicted sensitivity to nine standard chemotherapy drugs, including cisplatin and gemcitabine.
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Cluster 2, in contrast, had better survival and lower TIDE scores, indicating greater likelihood of benefiting from immune checkpoint therapy.
This finding emphasizes the need for personalized treatment approaches in bladder cancer. Depending on their molecular profile, some patients may respond better to chemotherapy, while others may benefit more from immunotherapy.
VHL Interacts with HDAC6 in Bladder Cancer
To understand how VHL functions in bladder cancer, the team explored its potential protein interactions. Using protein–protein docking simulations, they discovered a structural interaction between VHL and HDAC6, a histone deacetylase involved in various cancer-related processes.
Immunohistochemical analysis of 40 bladder cancer tissue samples confirmed that both VHL and HDAC6 were more highly expressed in tumor tissue compared to normal bladder tissue. Expression levels were even higher in muscle-invasive cases. A Pearson correlation analysis showed a strong positive correlation between VHL and HDAC6 (correlation coefficient = 0.696).
These results suggest that VHL and HDAC6 may work together to regulate both angiogenesis and stemness in bladder cancer.
Immune Infiltration and Drug Sensitivity Tied to VHL
The study also assessed how VHL expression is linked to immune cell infiltration using the xCell algorithm. High VHL expression correlated with a more favorable immune environment and lower immune evasion, as indicated by TIDE scores.
Additionally, VHL expression was significantly associated with sensitivity to eight chemotherapy drugs, though not to etoposide. This strengthens the case for using VHL status as a biomarker to guide treatment decisions.
Practical Implications for Research and Treatment
This research highlights several key points that could influence future bladder cancer management:
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VHL is a promising biomarker for predicting treatment response and patient survival.
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Patients may benefit from being stratified by gene expression into subgroups for more tailored therapies.
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The interaction between VHL and HDAC6 offers a potential new therapeutic target.
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Drug sensitivity predictions based on gene profiles could help clinicians select the most effective treatments upfront.
Conclusion
By integrating gene expression, survival data, immune profiling, and protein interaction modeling, Yin et al. provide new insights into how angiogenesis and stemness contribute to bladder cancer progression and treatment response. Their findings support a more personalized approach to therapy, using VHL and related gene signatures to guide clinical decision-making.
The study concludes that “VHL emerged as the most significant prognostic indicator,” underlining its potential utility as both a biomarker and a therapeutic target in bladder cancer.
The translation of the preceding English text in Chinese:
认识膀胱癌：一种严重的泌尿系统威胁
膀胱癌（Bladder Cancer，BLCA）是影响泌尿系统最常见且致命的癌症之一。它起源于膀胱的黏膜，可分为两种主要类型：非肌层浸润性膀胱癌（NMIBC）和肌层浸润性膀胱癌（MIBC）。约75%的患者初次被诊断为NMIBC，这种类型通常对手术和化疗反应良好。然而，大约20%的NMIBC最终会进展为更具侵袭性的MIBC，常需进行根治性膀胱切除术和盆腔淋巴结清扫。
尽管进行了如此积极的治疗，五年生存率仍然较低，晚期患者的预后依然不佳。目前的一线治疗包括顺铂联合吉西他滨的化疗方案，以及靶向PD-1/PD-L1的免疫检查点抑制剂（ICIs）。然而，晚期患者中对ICIs有应答者不到一半。由于复发率和死亡率居高不下，研究人员正迫切寻找新的治疗策略。
在这种背景下，两个生物过程成为研究重点：血管生成（新生血管的形成）和癌症干性（癌细胞自我更新并驱动肿瘤生长的能力）。这两个机制彼此高度相关，并在肿瘤进展和治疗耐药中发挥关键作用。
研究膀胱癌中的血管生成与干性机制
来自苏州大学第一附属医院的尹等人开展了一项新研究，探讨调控膀胱癌中血管生成与干性的基因因素。该研究旨在揭示这些基因如何影响化疗和免疫治疗的反应。
通过分析癌症基因组图谱（TCGA）和基因表达综合（GEO）等公共数据库，研究团队筛选出在膀胱癌组织中差异表达并与患者预后相关的基因。从超过16,000个候选基因中，他们最终锁定了102个同时参与血管生成与干性的基因。其中有12个基因对患者生存具有显著影响。
VHL基因成为关键预后标志物
在这12个基因中，冯·希佩尔-林道（Von Hippel–Lindau，VHL）基因最为突出。VHL作为E3泛素连接酶，能调节HIF1α等血管生成相关蛋白的降解。本研究发现，VHL高表达与更好的生存结局及对化疗和免疫治疗的更高敏感性密切相关。
研究人员应用LASSO回归等先进统计建模技术，构建了一个包含6个基因的预后模型，包括VHL、TRIB3、POU5F1、P4HB、NOTCH3和FASN。该模型在两个独立数据库（TCGA和GSE13507）中成功预测了总生存期，其中VHL基因的预测准确率最高。
两种分子亚型具有不同治疗反应
通过聚类分析，研究者将患者分为两个不同的亚型：
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Cluster 1 表达多数与血管生成和干性相关的基因，显示出更差的总生存期和无病生存期，但对包括顺铂和吉西他滨在内的9种常规化疗药物表现出更高的预测敏感性。
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Cluster 2 则表现出更好的生存率和较低的TIDE评分，提示其更可能从免疫检查点治疗中获益。
这一发现强调了膀胱癌治疗中个体化策略的必要性。根据分子表达特征，某些患者可能更适合化疗，而另一些则更适合免疫治疗。
VHL与HDAC6在膀胱癌中的相互作用
为进一步了解VHL在膀胱癌中的功能，研究人员分析了其潜在的蛋白互作。通过蛋白-蛋白对接模拟，他们发现VHL与HDAC6（一种在多种肿瘤过程涉及的组蛋白脱乙酰酶）之间存在结构性互作。
对40例膀胱癌组织样本进行免疫组织化学分析发现，VHL和HDAC6在肿瘤组织中的表达显著高于正常膀胱组织，且在肌层浸润性膀胱癌中表达更高。Pearson相关分析表明VHL与HDAC6之间存在显著正相关（相关系数 = 0.696）。
这些结果提示，VHL与HDAC6可能协同调控膀胱癌中的血管生成和干性机制。
VHL与免疫浸润和药物敏感性相关
研究还使用xCell算法评估了VHL表达与免疫细胞浸润的关系。结果显示，高VHL表达与更有利的免疫微环境和较低的免疫逃逸相关（TIDE评分较低）。
此外，VHL表达水平与8种化疗药物的敏感性显著相关（不包括依托泊苷）。这进一步支持将VHL状态作为治疗决策参考生物标志物的潜力。
研究与临床治疗的实践意义
该研究强调了几个可能影响未来膀胱癌管理的关键点：
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VHL是预测治疗反应和患者生存的重要生物标志物；
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可根据基因表达将患者分层，从而实现更精确的个体化治疗；
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VHL与HDAC6的相互作用或为新的治疗靶点；
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基于基因特征的药物敏感性预测可协助医生优化治疗方案。
结论
通过整合基因表达、生存数据、免疫特征和蛋白互作建模，尹等人提供了膀胱癌中血管生成与干性在疾病进展和治疗反应中作用的新见解。他们的发现支持一种更个性化的治疗方法，借助VHL及相关基因特征来指导临床决策。
研究最后指出：“VHL作为最显著的预后指标脱颖而出”，凸显了其在膀胱癌中作为生物标志物和治疗靶点的潜在价值。
Reference:
Zhi-Xiang Yin, Yifan Qiu, Chenfei Xu, Changsong Pei
Comprehensive analysis of angiogenesis and stemness-related genes in chemotherapy and immunotherapy of bladder cancer.
Biomol Biomed [Internet]. 2025 Apr. 18 [cited 2025 Jul. 14];
Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12046
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