Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, and Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA.
J Clin Invest. 2010 Feb;120(2):636-44. doi: 10.1172/JCI40724. Epub 2010 Jan 25.
Intratumor genetic heterogeneity is a key mechanism underlying tumor progression and therapeutic resistance. The prevailing model for explaining intratumor diversity, the clonal evolution model, has recently been challenged by proponents of the cancer stem cell hypothesis. To investigate this issue, we performed combined analyses of markers associated with cellular differentiation states and genotypic alterations in human breast carcinomas and evaluated diversity with ecological and evolutionary methods. Our analyses showed a high degree of genetic heterogeneity both within and between distinct tumor cell populations that were defined based on markers of cellular phenotypes including stem cell-like characteristics. In several tumors, stem cell-like and more-differentiated cancer cell populations were genetically distinct, leading us to question the validity of a simple differentiation hierarchy-based cancer stem cell model. The degree of diversity correlated with clinically relevant breast tumor subtypes and in some tumors was markedly different between the in situ and invasive cell populations. We also found that diversity measures were associated with clinical variables. Our findings highlight the importance of genetic diversity in intratumor heterogeneity and the value of analyzing tumors as distinct populations of cancer cells to more effectively plan treatments.
肿瘤内遗传异质性是肿瘤进展和治疗耐药的关键机制。解释肿瘤内异质性的主流模型——克隆进化模型，最近受到癌症干细胞假说支持者的挑战。为了研究这个问题，我们对人类乳腺癌中与细胞分化状态相关的标记物和基因型改变进行了联合分析，并采用生态和进化方法评估了多样性。我们的分析表明，在基于包括干细胞样特征在内的细胞表型标记物定义的不同肿瘤细胞群体中，存在高度的遗传异质性。在一些肿瘤中，干细胞样和更分化的癌细胞群体在遗传上是不同的，这使我们对基于简单分化层次的癌症干细胞模型的有效性产生了质疑。多样性的程度与临床相关的乳腺癌亚型相关，在一些肿瘤中，原位和浸润性细胞群体之间的差异非常明显。我们还发现，多样性测量与临床变量相关。我们的研究结果强调了肿瘤内遗传异质性中遗传多样性的重要性，以及将肿瘤作为不同的癌细胞群体进行分析以更有效地制定治疗方案的价值。
