文章：

破解人类癌症组织变异的基础

Decoding the basis of histological variation in human cancer

原文发布日期：2023-12-22

DOI: 10.1038/s41568-023-00648-5

类型: Review Article

开放获取: 否

英文摘要：

Molecular abnormalities that shape human neoplasms dissociate their phenotypic landscape from that of the healthy counterpart. Through the lens of a microscope, tumour pathology optically captures such aberrations projected onto a tissue slide and has categorized human epithelial neoplasms into distinct histological subtypes based on the diverse morphogenetic and molecular programmes that they manifest. Tumour histology often reflects tumour aggressiveness, patient prognosis and therapeutic vulnerability, and thus has been used as a de facto diagnostic tool and for making clinical decisions. However, it remains elusive how the diverse histological subtypes arise and translate into pleiotropic biological phenotypes. Molecular analysis of clinical tumour tissues and their culture, including patient-derived organoids, and add-back genetic reconstruction of tumorigenic pathways using gene engineering in culture models and rodents further elucidated molecular mechanisms that underlie morphological variations. Such mechanisms include genetic mutations and epigenetic alterations in cellular identity codes that erode hard-wired morphological programmes and histologically digress tumours from the native tissues. Interestingly, tumours acquire the ability to grow independently of the niche-driven stem cell ecosystem along with these morphological alterations, providing a biological rationale for histological diversification during tumorigenesis. This Review comprehensively summarizes our current understanding of such plasticity in the histological and lineage commitment fostered cooperatively by molecular alterations and the tumour environment, and describes basic and clinical implications for future cancer therapy.

摘要翻译： 

塑造人类肿瘤的分子异常使其表型景观与健康对应物分离。通过显微镜的视角，肿瘤病理学在组织切片上光学捕捉这些畸变，并根据肿瘤所表现出的多样形态发生和分子程序，将人类上皮肿瘤划分为不同的组织学亚型。肿瘤组织学往往反映肿瘤的侵袭性、患者预后及治疗敏感性，因此已被用作事实上的诊断工具并指导临床决策。然而，这些多样组织学亚型如何产生并转化为多向性生物学表型仍不明确。通过对临床肿瘤组织及其培养物（包括患者来源类器官）的分子分析，以及在培养模型和啮齿动物中通过基因工程对致瘤通路进行回补重建，进一步阐明了形态变异背后的分子机制。这些机制包括细胞身份编码中的基因突变和表观遗传改变，这些改变侵蚀了固有的形态程序，并使肿瘤在组织学上偏离原始组织。有趣的是，随着这些形态学改变，肿瘤获得了独立于生态位驱动的干细胞生态系统而生长的能力，这为肿瘤发生过程中的组织学多样化提供了生物学依据。本综述全面总结了当前对分子改变与肿瘤环境共同促成的组织学和谱系定向可塑性的理解，并阐述了其对未来癌症治疗的基础和临床意义。

原文链接：

Decoding the basis of histological variation in human cancer