NORMAL GENETICALLY MOSAIC MICE PRODUCED FROM MALIGNANT TERATOCARCINOMA CELLS
NORMAL GENETICALLY MOSAIC MICE PRODUCED FROM MALIGNANT TERATOCARCINOMA CELLS
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DOI：
10.1073/pnas.72.9.3585
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发表时间：
1975-01-01
影响因子：
11.1
通讯作者：
ILLMENSEE, K
中科院分区：
文献类型：
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作者：
MINTZ, B;ILLMENSEE, K
从仅在体内作为腹水瘤生长8年的胚状体的“核心”中取出具有正常模态染色体数目的恶性小鼠畸胎癌（或胚胎癌）细胞，并将其注射到具有许多遗传标记的胚泡中，以测试核心细胞的发育能力、遗传构成和恶性的可逆性。获得了93只存活的正常产前和产后动物。在迄今为止分析的14个中，有3个是细胞遗传嵌合体，在许多发育无关的组织中具有肿瘤衍生细胞的实质性贡献，包括一些从未在移植宿主中形成的实体瘤中见过的细胞。这些组织功能正常并合成它们的特异性产物（例如，免疫球蛋白、成人血红蛋白、肝蛋白），由已知基因座上的菌株型等位基因编码。此外，一个肿瘤贡献的颜色基因，钢，以前不知道是存在于癌细胞中，检测到的外套表型。来源于癌的细胞，具有X/Y性染色体组成，也有助于生殖系，并形成具有生殖功能的精子，其中一些将steel基因传递给后代。因此，在作为高度恶性肿瘤的近200个移植世代之后，胚状体核心细胞似乎是发育全能的，并且能够在体细胞和生殖系组织的分化中以有序的顺序表达迄今为止在肿瘤起源中沉默的许多基因。这种实验系统的“循环”畸胎瘤核心细胞通过小鼠，与实验诱变这些细胞，因此，可能提供一个新的和有用的工具，生物化学，发育和遗传分析哺乳动物分化。这些结果也提供了一个明确的例子，在动物的非突变的基础上转化为恶性肿瘤和逆转为正常。这种肿瘤起源于一个混乱的胚胎，这表明其他一些更专门的干细胞的恶性肿瘤可能通过组织混乱而产生，导致基因表达的发育畸变，而不是基因结构的变化。
Malignant mouse teratocarcinoma (or embryonal carcinoma) cells with a normal modal chromosome number were taken from the "cores" of embryoid bodies grown only in vivo as an ascites tumor for 8 years, and were injected into blastocysts bearing many genetic markers, in order to test the developmental capacities, genetic constitution, and reversibility of malignancy of the core cells. Ninety-three live normal pre- and postnatal animals were obtained. Of 14 thus far analyzed, three were cellular genetic mosaics with substantial contributions of tumor-derived cells in many developmentally unrelated tissues, including some never seen in the solid tumors that form in transplant hosts. The tissues functioned normally and synthesized their specific products (e.g., immunoglobulins, adult hemoglobin, liver proteins) coded for by strain-type alleles at known loci. In addition, a tumor-contributed color gene, steel, not previously known to be present in the carcinoma cells, was detected from the coat phenotype. Cells derived from the carcinoma, which is of X/Y sex chromosome constitution, also contributed to the germ line and formed reproductively functional sperms, some of which transmitted the steel gene to the progeny. Thus, after almost 200 transplant generations as a highly malignant tumor, embryoid body core cells appear to be developmentally totipotent and able to express, in an orderly sequence in differentiation of somatic and germ-line tissues, many genes hitherto silent in the tumor of origin. This experimental system of "cycling" teratocarcinoma core cells through mice, in conjunction with experimental mutagenesis of those cells, may therefore provide a new and useful tool for biochemical, developmental, and genetic analyses of mammalian differentiation. The results also furnish an unequivocal example in animals of a non-mutational basis for transformation to malignancy and of reversal to normalcy. The origin of this tumor from a disorganized embryo suggests that malignancies of some other, more specialized, stem cells might arise comparably through tissue disorganization, leading to developmental aberrations of gene expression rather than changes in gene structure.