Bell C, Frost P, Kerbel R S
M.D. Anderson Hospital and Tumor Institute, Houston, Texas.
Cancer Genet Cytogenet. 1991 Jul 15;54(2):153-61. doi: 10.1016/0165-4608(91)90203-7.
Examination of tumors usually shows them to consist of phenotypically and clonally heterogeneous cell subpopulations. On the other hand, previous studies from our laboratory have provided compelling evidence for the rapid evolution, or overgrowth, of single "dominant" clones during the course of primary tumor growth. Thus in one such study, syngeneic CBA mice were injected with a mixture of 50-100 different genetically tagged clones of a mouse mammary carcinoma called SP1. The vast majority of these clones were non-metastatic. The different clones were tagged by random integrations of foreign DNA using calcium phosphate-mediated transfection of the plasmid pSV2neo, the resultant primary tumors were found to consist of a single dominant clone, called B5, which was also shown to be metastatically competent. The detection of single dominant clones such as B5 in primary tumors can be reconciled with the concept of tumor cell heterogeneity if it could be shown that the dominant clone was in fact heterogeneous for other genetic or phenotypic markers, i.e., was homogeneous only for the plasmid-based genetic marker used for its detection. To study this question, we examined the karyotypes of several sublines of B5, two derived from a primary advanced tumor and one from a spontaneous lung metastasis. We indeed found evidence to support the existence of marked cellular heterogeneity within and between the three sublines examined. Thus, while all three retained common cytogenetic markers, each also expressed unique markers. Moreover, karyotypic heterogeneity within a given subline was observed. Thus the concept of clonal dominance of primary tumors by metastatically competent cell subpopulations is not incompatible with the concept of the cellular heterogeneity of tumors. The implications of the results are discussed.
对肿瘤的检查通常显示它们由表型和克隆性均异的细胞亚群组成。另一方面，我们实验室之前的研究提供了令人信服的证据，证明在原发性肿瘤生长过程中单个“优势”克隆会快速进化或过度生长。因此，在一项此类研究中，将50 - 100个不同的、带有基因标记的小鼠乳腺癌克隆（称为SP1）的混合物注射到同基因的CBA小鼠体内。这些克隆中的绝大多数是非转移性的。通过使用磷酸钙介导的质粒pSV2neo转染将外源DNA随机整合来标记不同的克隆，结果发现原发性肿瘤由单个优势克隆组成，称为B5，它也被证明具有转移能力。如果能够证明优势克隆实际上在其他遗传或表型标记方面是异质的，即仅在用于检测的基于质粒的遗传标记方面是同质的，那么在原发性肿瘤中检测到诸如B5这样的单个优势克隆就可以与肿瘤细胞异质性的概念相协调。为了研究这个问题，我们检查了B5的几个亚系的核型，其中两个亚系源自原发性晚期肿瘤，一个源自自发性肺转移瘤。我们确实发现了证据支持在所检查的三个亚系内部和之间存在明显的细胞异质性。因此，虽然所有三个亚系都保留了共同的细胞遗传学标记，但每个亚系也都表达独特的标记。此外，在给定的亚系内也观察到了核型异质性。因此，具有转移能力的细胞亚群对原发性肿瘤的克隆优势概念与肿瘤细胞异质性概念并非不相容。本文讨论了这些结果的意义。
