文章：

小鼠膀胱癌建模：机遇与挑战

Modelling bladder cancer in mice: opportunities and challenges

原文发布日期：2014-12-23

DOI: 10.1038/nrc3858

类型: Review Article

开放获取: 否

要点：

1. Bladder cancers arise in the urothelium, a specialized epithelium that comprises basal, intermediate and superficial (umbrella) cells. Bladder cancer represents a heterogeneous set of tumours that vary in histopathology, molecular alterations and potentially cells of origin; the vast majority (more than 90%) are urothelial carcinomas, which are the subject of this Review.
2. Basal cells can serve as urothelial progenitors as well as cells of origin of bladder cancer, particularly of more aggressive subtypes; however, other urothelial cell types can also serve as progenitors in normal bladder as well as cells of origin of bladder cancer, potentially of different subtypes.
3. Urothelial carcinomas fall into two major categories: most (approximately 75%) are non-muscle-invasive, which include low-grade superficial (or papillary) and high-grade carcinoma in situ; the remainder (approximately 25%) are muscle-invasive.
4. Most non-muscle-invasive bladder cancers, particularly low-grade tumours, have favourable prognosis; these can be managed clinically with bladder-sparing treatments, which are generally effective but very costly.
5. Muscle-invasive bladder cancers have relatively poor prognosis; those that have not metastasized are often treated by cystectomy (surgical removal of the bladder), which is reasonably effective (5-year survival of approximately 50%) but associated with high morbidity.
6. Metastatic bladder cancer has a very poor prognosis (5-year survival of approximately 15%) and is treated using chemotherapy, which is neither well-tolerated nor highly effective. Unlike many other cancers, neither the prognosis nor treatment of bladder cancer has improved substantially in the past 20 years, and bladder cancer remains a major cause of cancer mortality.
7. The molecular pathways that give rise to low-grade non-muscle-invasive versus high-grade muscle-invasive bladder cancer are distinct but not mutually exclusive. The recent elucidation of genetic and genomic alterations that are prevalent in muscle-invasive bladder cancer provides new avenues for understanding the underlying molecular mechanisms, as well as new targets for therapeutic intervention.
8. Currently available in vivo models of bladder cancer include carcinogen-based and genetically engineered mouse (GEM) models, as well as orthotopic and renal grafting, each of which has advantages and limitations. Bladder cancer is relatively under-represented by GEM models, particularly those that model more aggressive phenotypes.
9. The mouse bladder may be relatively recalcitrant to developing invasive tumours, which has made it challenging to develop GEM models. Other challenges to developing GEM models include inadequate approaches for restricting gene targeting to the urothelium, and particularly to selected cells of origin. Improved GEM models will lead to opportunities for preclinical evaluation of new treatment options for bladder cancer.

要点翻译：

1. 膀胱癌起源于尿路上皮，这是一种包含基底细胞、中间细胞和表层细胞（伞状细胞）的特化上皮组织。膀胱癌代表了一组异质性肿瘤，其在组织病理学、分子改变及潜在起源细胞方面存在差异；绝大多数（超过90%）为尿路上皮癌，这也是本综述探讨的主题。
2. 基底细胞可作为尿路上皮祖细胞及膀胱癌的起源细胞，尤其是更具侵袭性的亚型；然而，其他尿路上皮细胞类型在正常膀胱中也可作为祖细胞，并可能成为不同亚型膀胱癌的起源细胞。
3. 尿路上皮癌分为两大类别：大多数（约75%）为非肌层浸润性，包括低度恶性浅表性（或乳头状）癌和高度恶性原位癌；其余（约25%）为肌层浸润性。
4. 大多数非肌层浸润性膀胱癌，特别是低度恶性肿瘤，预后良好；临床上可采用保留膀胱的治疗方案，这些方案通常有效但成本高昂。
5. 肌层浸润性膀胱癌预后相对较差；对于未发生转移的病例，常采用膀胱切除术（手术切除膀胱）治疗，该方法疗效尚可（5年生存率约50%），但伴随较高并发症发生率。
6. 转移性膀胱癌预后极差（5年生存率约15%），主要采用化疗治疗，但患者耐受性差且疗效有限。与许多其他癌症不同，膀胱癌的预后和治疗在过去20年均未取得显著改善，它仍是癌症死亡的主要原因之一。
7. 导致低度恶性非肌层浸润性与高度恶性肌层浸润性膀胱癌的分子通路各不相同，但并非互斥。近期对肌层浸润性膀胱癌中普遍存在的遗传和基因组改变的阐释，为理解其潜在分子机制提供了新途径，也为治疗干预带来了新靶点。
8. 目前可用的膀胱癌体内模型包括基于致癌物的模型、基因工程小鼠模型，以及原位移植和肾包膜下移植模型，每种模型各有优势与局限。基因工程小鼠模型在膀胱癌研究中的应用相对不足，特别是模拟侵袭性表型的模型。
9. 小鼠膀胱可能相对难以形成侵袭性肿瘤，这给开发基因工程小鼠模型带来了挑战。开发这类模型的其他挑战包括：缺乏将基因靶向精准限定于尿路上皮（特别是特定起源细胞）的有效方法。改进的基因工程小鼠模型将为膀胱癌新治疗方案的临床前评估创造机遇。

英文摘要：

The prognosis and treatment of bladder cancer have improved little in the past 20 years. Bladder cancer remains a debilitating and often fatal disease, and is among the most costly cancers to treat. The generation of informative mouse models has the potential to improve our understanding of bladder cancer progression, as well as to affect its diagnosis and treatment. However, relatively few mouse models of bladder cancer have been described, and in particular, few that develop invasive cancer phenotypes. This Review focuses on opportunities for improving the landscape of mouse models of bladder cancer.

摘要翻译： 

在过去20年中，膀胱癌的预后和治疗几乎没有改善。膀胱癌仍然是一种令人虚弱且常常致命的疾病，并且是治疗成本最高的癌症之一。建立具有信息价值的小鼠模型有望增进我们对膀胱癌进展的理解，并对其诊断和治疗产生影响。然而，目前描述的膀胱癌小鼠模型相对较少，特别是能够发展为侵袭性癌症表型的模型更少。本综述聚焦于改善膀胱癌小鼠模型格局的机遇。

原文链接：

Modelling bladder cancer in mice: opportunities and challenges