A BENIGN CULTURED COLON ADENOMA BEARS 3 GENETICALLY ALTERED COLON-CANCER ONCOGENES, BUT PROGRESSES TO TUMORIGENICITY AND TRANSFORMING GROWTH-FACTOR-BETA INDEPENDENCE WITHOUT INACTIVATING THE P53 TUMOR-SUPPRESSOR GENE
A BENIGN CULTURED COLON ADENOMA BEARS 3 GENETICALLY ALTERED COLON-CANCER ONCOGENES, BUT PROGRESSES TO TUMORIGENICITY AND TRANSFORMING GROWTH-FACTOR-BETA INDEPENDENCE WITHOUT INACTIVATING THE P53 TUMOR-SUPPRESSOR GENE
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DOI：
10.1172/jci117048
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发表时间：
1994-03-01
影响因子：
15.9
通讯作者：
WILLSON, JKV
中科院分区：
文献类型：
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作者：
MARKOWITZ, SD;MYEROFF, L;WILLSON, JKV
我们描述了一个结肠腺瘤细胞系的自发进展到致瘤性和生长因子独立性。该系统允许直接比较结肠癌抑制基因和癌基因改变的恶性进展的生物学阶段。VACO-235是一种人结肠腺瘤细胞系，在裸鼠中早期传代无致瘤性，不能在软琼脂中生长，血清和EGF刺激其生长，tgf - β抑制其生长。VACO-235子代93及更高代在培养中自发发展为弱致瘤性，但保留了VACO-235早期代的所有其他生长特征。小鼠晚期VACO-235的异种移植物在培养中被重建为孙女细胞系VACO-411。VACO-411是高度致瘤性的，在软琼脂中克隆，对血清、EGF和tgf - β无反应。早期传代VACO-235携带突变型K-ras等位基因，只携带突变型APC等位基因，不表达DCC转录物，只表达野生型p53转录物。VACO-411保留了相同的基因型，仍然只表达野生型p53。ras突变、APC突变和DCC失活后的结肠细胞仍然是非致瘤性和生长因子依赖性的。恶性进展涉及至少两个额外的步骤，并且在VACO-411中可以通过不需要p53失活的新途径进行。
We describe the spontaneous progression of a colon adenoma cell line to tumorigenicity and growth factor independence. This system allows direct comparison of biologic stages of malignant progression with alterations of colon cancer suppressor genes and oncogenes. VACO-235, a human colon adenoma cell line, is at early passages nontumorigenic in the nude mouse, unable to grow in soft agar, growth stimulated by serum and EGF, and growth inhibited by TGF-beta. VACO-235 daughter passages 93 and higher have in culture spontaneously progressed to being weakly tumorigenic, but retain all other growth characteristics of VACO-235 early passages. A mouse xenograft from late passage VACO-235 was reestablished in culture as the granddaughter cell line, VACO-411. VACO-411 is highly tumorigenic, clones in soft agar, and is unresponsive to serum, EGF, and TGF-beta. Early passage VACO-235 bears a mutant K-ras allele, bears only mutant APC alleles, expresses no DCC transcripts, and expresses only wild type p53 transcripts. VACO-411 retains the identical genotype, still expressing only wild type p53. Colonic cells after ras mutation, APC mutation, and DCC inactivation remain nontumorigenic and growth factor dependent. Malignant progression involves at least two additional steps, and in VACO-411 can proceed by a novel pathway not requiring p53 inactivation.