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Tumour heterogeneity and resistance to cancer therapies. ​

文献信息 ​

DOI10.1038/nrclinonc.2017.166
PMID29115304
期刊Nature reviews. Clinical oncology
影响因子82.2
JCR 分区Q1
发表年份2018
被引次数1696
关键词肿瘤异质性, 癌症治疗, 耐药性, 分子特征, 个性化治疗
文献类型Journal Article, Research Support, N.I.H., Extramural, Review
ISSN1759-4774
页码81-94
期号15(2)
作者Ibiayi Dagogo-Jack, Alice T Shaw

一句话小结 ​

本综述探讨了癌症在发展过程中因细胞异质性而导致的空间和时间变化，并指出这种异质性是耐药性的关键驱动力。通过分析多区域测序、单细胞测序等新兴技术，研究强调了准确评估肿瘤异质性对个性化治疗开发的重要性。

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肿瘤异质性 · 癌症治疗 · 耐药性 · 分子特征 · 个性化治疗

摘要 ​

癌症是一种动态疾病。在疾病的发展过程中，癌症通常变得更加异质化。由于这种异质性，肿瘤的主体可能包含一组多样的细胞，这些细胞具有不同的分子特征，并对治疗的敏感性存在差异。这种异质性可能导致在疾病部位之间以及内部的遗传上不同的肿瘤细胞亚群的非均匀分布（空间异质性），或者癌细胞分子组成的时间变化（时间异质性）。异质性为耐药性提供了动力；因此，准确评估肿瘤异质性对于开发有效治疗至关重要。多区域测序、单细胞测序、尸检样本分析以及液体活检样本的纵向分析都是具有巨大潜力的新兴技术，可以解析癌症复杂的克隆结构。在本综述中，我们讨论了肿瘤内异质性的驱动因素以及当前用于应对这种异质性及其后果的方法。我们还探讨了肿瘤异质性的临床评估如何促进更有效个性化治疗的开发。

英文摘要 ​

Cancer is a dynamic disease. During the course of disease, cancers generally become more heterogeneous. As a result of this heterogeneity, the bulk tumour might include a diverse collection of cells harbouring distinct molecular signatures with differential levels of sensitivity to treatment. This heterogeneity might result in a non-uniform distribution of genetically distinct tumour-cell subpopulations across and within disease sites (spatial heterogeneity) or temporal variations in the molecular makeup of cancer cells (temporal heterogeneity). Heterogeneity provides the fuel for resistance; therefore, an accurate assessment of tumour heterogeneity is essential for the development of effective therapies. Multiregion sequencing, single-cell sequencing, analysis of autopsy samples, and longitudinal analysis of liquid biopsy samples are all emerging technologies with considerable potential to dissect the complex clonal architecture of cancers. In this Review, we discuss the driving forces behind intratumoural heterogeneity and the current approaches used to combat this heterogeneity and its consequences. We also explore how clinical assessments of tumour heterogeneity might facilitate the development of more-effective personalized therapies.

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主要研究问题 ​

  1. 肿瘤异质性在不同类型癌症中的表现有何差异？
  2. 目前有哪些新兴技术能够有效评估肿瘤异质性，并如何应用于临床？
  3. 如何通过分析肿瘤异质性来预测患者对特定癌症治疗的反应？
  4. 目前针对肿瘤异质性所采取的个性化治疗策略有哪些成功案例？
  5. 在多区域测序和单细胞测序中，哪种方法对揭示肿瘤的克隆结构更有效？

核心洞察 ​

1. 研究背景和目的 ​

癌症是一种动态发展的疾病，其在病程中通常会变得更加异质。肿瘤的异质性使得肿瘤大体内可能包含一系列具有不同分子特征的细胞，这些细胞对治疗的敏感性各不相同。因此，了解肿瘤异质性对于开发有效的癌症治疗至关重要。本研究旨在探讨肿瘤内异质性的驱动因素，以及如何通过新兴技术对肿瘤异质性进行评估，以促进个性化治疗的发展。

2. 主要方法和发现 ​

研究采用了多区域测序、单细胞测序、尸检样本分析以及液体活检样本的纵向分析等新兴技术，这些方法具有很大的潜力去解析癌症的复杂克隆结构。发现肿瘤的异质性不仅存在于空间（即不同部位的细胞组成差异），还体现在时间上（即癌细胞分子组成的随时间变化）。这种异质性成为癌症耐药的根源，因此，准确评估肿瘤异质性是开发成功治疗方案的关键。

3. 核心结论 ​

肿瘤异质性是癌症耐药的主要驱动力，理解肿瘤内的多样性能够帮助科学家们识别出不同的肿瘤细胞亚群，从而为个性化治疗提供依据。新兴技术的应用将有助于更全面地揭示肿瘤的克隆结构，进而促进对抗癌症治疗的有效性。

4. 研究意义和影响 ​

本研究强调了肿瘤异质性在癌症治疗中的重要性，指出了在临床上评估肿瘤异质性可能对个性化治疗的发展产生深远影响。随着对肿瘤异质性理解的深入，未来有望通过靶向不同肿瘤细胞亚群，实现更精准的治疗策略，提升患者的治疗效果和生存率。这也为癌症研究提供了新的思路和方法，推动了精准医学的发展。

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引用本文的文献 ​

  1. Intratumoral heterogeneity of Notch1 expression in small cell lung cancer. - Takaaki Ito - Journal of thoracic disease (2018)
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  4. Molecular imaging and molecular diagnostics: two sides of the same coin? - Marcus Hacker;Gregor Hoermann;Lukas Kenner - European journal of nuclear medicine and molecular imaging (2018)
  5. Applications of CRISPR-Cas Enzymes in Cancer Therapeutics and Detection. - Chun-Hao Huang;Ko-Chuan Lee;Jennifer A Doudna - Trends in cancer (2018)
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  7. Epithelial-to-mesenchymal transition in cancer: complexity and opportunities. - Yun Zhang;Robert A Weinberg - Frontiers of medicine (2018)
  8. Overview of precision oncology trials: challenges and opportunities. - Elena Fountzilas;Apostolia M Tsimberidou - Expert review of clinical pharmacology (2018)
  9. Global Stabilization of Boolean Networks to Control the Heterogeneity of Cellular Responses. - Jung-Min Yang;Chun-Kyung Lee;Kwang-Hyun Cho - Frontiers in physiology (2018)
  10. Genetic and epigenetic alterations of colorectal cancer. - Sung Noh Hong - Intestinal research (2018)

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