文章目录

尿路上皮肿瘤发生：不同途径的故事

Urothelial tumorigenesis: a tale of divergent pathways

原文发布日期：2005-08-19

DOI: 10.1038/nrc1697

类型: Review Article

开放获取: 否

要点：

要点翻译：

英文摘要：

摘要翻译：

原文链接：

文章：

尿路上皮肿瘤发生：不同途径的故事

Urothelial tumorigenesis: a tale of divergent pathways

原文发布日期：2005-08-19

DOI: 10.1038/nrc1697

类型: Review Article

开放获取: 否

要点：

Urothelial tumours arise and evolve through divergent phenotypic pathways. Some tumours progress from urothelial hyperplasia to low-grade non-invasive superficial papillary tumours. More aggressive variants arise either from flat, high-grade carcinoma in situ and progress to invasive tumours, or they arise de novo as invasive tumours.
These two important phenotypic variants of urothelial tumours exhibit drastically different biological behaviours and prognoses. The low-grade papillary variant is often multifocal and tends to recur, but it infrequently progresses to muscle invasive stages, whereas most of the invasive variants develop into incurable metastases despite radical cystectomy.
It is becoming clear that the two urothelial tumour variants harbour distinctive genetic defects: the low-grade non-invasive papillary tumours are characterized by activating mutations in the HRAS gene and fibroblast growth factor receptor 3 gene; and the high-grade invasive tumours are characterized by structural and functional defects in the p53 and retinoblastoma protein (RB) tumour-suppressor pathways.
The deletion of both arms of chromosome 9 is prevalent in urothelial carcinomas and occurs during the earliest stages of tumorigenesis. However, these chromosomal aberrations do not seem to distinguish between the two tumour development pathways.
Tumour invasion and progression in the bladder seems to be a multifactorial process, promoted by microenvironmental changes that include the upregulation of N-cadherin, the downregulation of E-cadherin, the overexpression of matrix metalloproteinases 2 and 9, an imbalance between angiogenic and anti-angiogenic factors, and increased synthesis of prostaglandin.
Urothelial carcinomas are particularly amenable to pathway- and target-based therapies. The low-grade non-invasive papillary tumours could benefit tremendously from receptor tyrosine kinase (RTK)–Ras pathway inhibition by means such as small molecule inhibitors, monoclonal antibodies, farnesyl and geranylgeranyl inhibitors, and RAF and mitogen-activated protein kinase kinase (MEK) inhibitors. The invasive tumours, on the other hand, could benefit from replacement therapies that restore the functions of p53 and RB.
The intravesical (within the bladder) route of drug delivery provides a unique advantage because it locally enriches the drug while preventing systemic toxicity in urothelial carcinoma treatment.
The identification of specific carcinogens that precipitate each urothelial tumour pathway holds the key to eventually preventing this disease from occurring.

要点翻译：

尿路上皮肿瘤通过不同的表型途径发生并演变。部分肿瘤从尿路上皮增生进展为低级别非浸润性浅表乳头状肿瘤；更具侵袭性的变异类型则要么起源于扁平的高级别原位癌并进展为浸润性肿瘤，要么直接以浸润性肿瘤的形式新生。
这两种重要的尿路上皮肿瘤表型变异表现出截然不同的生物学行为和预后。低级别乳头状变异常为多灶性且易复发，但很少进展至肌层浸润阶段；而大多数浸润性变异尽管接受根治性膀胱切除术，仍会发展成无法治愈的转移灶。
研究逐渐明确，这两种尿路上皮肿瘤变异携带独特的基因缺陷：低级别非浸润性乳头状肿瘤以HRAS基因和成纤维细胞生长因子受体3基因的激活突变為特征；高级别浸润性肿瘤则表现为p53和视网膜母细胞瘤蛋白（RB）肿瘤抑制通路的结构和功能缺陷。
9号染色体双臂缺失在尿路上皮癌中普遍存在，并发生于肿瘤发生的最早期阶段。然而这些染色体畸变似乎并不能区分两种肿瘤发展途径。
膀胱中的肿瘤侵袭和进展是一个多因素过程，由微环境变化促进，包括N-钙黏蛋白上调、E-钙黏蛋白下调、基质金属蛋白酶2和9的过度表达、血管生成与抗血管生成因子失衡以及前列腺素合成增加。
尿路上皮癌特别适合采用基于通路和靶点的疗法。低级别非浸润性乳头状肿瘤可通过小分子抑制剂、单克隆抗体、法尼基和香叶基香叶基抑制剂、RAF及丝裂原活化蛋白激酶激酶（MEK）抑制剂等方式抑制受体酪氨酸激酶（RTK）-Ras通路而显著获益；而浸润性肿瘤则可通过恢复p53和RB功能的替代疗法受益。
在尿路上皮癌治疗中，膀胱内给药途径具有独特优势，可在局部富集药物的同时避免全身毒性。
识别促使各尿路上皮肿瘤通路发展的特定致癌物，是最终预防该疾病发生的关键。

英文摘要：

Urothelial carcinoma of the bladder is unique among epithelial carcinomas in its divergent pathways of tumorigenesis. Low-grade papillary tumours rarely become muscle-invasive and they frequently harbour gene mutations that constitutively activate the receptor tyrosine kinase–Ras pathway. By contrast, most high-grade invasive tumours progress to life-threatening metastases and have defects in the p53 and the retinoblastoma protein pathways. Correcting pathway-specific defects represents an attractive strategy for the molecular therapy of urothelial carcinomas.