Arends M J, McGregor A H, Wyllie A H
Department of Pathology, University Medical School, Edinburgh, United Kingdom.
Am J Pathol. 1994 May;144(5):1045-57.
Immortalized rat fibroblasts were transfected with expression plasmids containing a mutated human Ha-ras (T24) oncogene, human c-myc, HPV 16 or 18 genomes, or combinations of these. Cell proliferation rates in vitro of the resulting 13 transformed lines were closely similar but apoptotic rates in vitro varied over a 60-fold range and correlated inversely with rates of population expansion in culture. To determine whether such differences in susceptibility to apoptosis affected the pattern of tumor growth in vivo, the transfected lines were injected subcutaneously into immunesuppressed mice producing fibrosarcomas in which prevalence of apoptosis and mitosis, extent of necrosis, and net growth rate were measured. Cell lines with high apoptotic rates in vitro tended to generate slowly growing tumors with high ratios of apoptosis to mitosis and little necrosis. The three most extreme examples of this phenotype all resulted from single transfections with c-myc. Lines with low apoptotic rates in vitro generated rapidly expanding tumors with high mitotic rates, extensive necrosis, and little apoptosis relative to mitosis, even in the compromised zone at the edge of necrotic regions. The four fastest-growing tumors all contained a T24-ras oncogene. The results suggest that oncogene expression determines intrinsic apoptotic rates and in this way may significantly influence the net growth rate and extent of necrosis in tumors.
将含有突变型人Ha-ras（T24）癌基因、人c-myc、HPV 16或18基因组或这些基因组合的表达质粒转染永生化大鼠成纤维细胞。所得13个转化细胞系的体外细胞增殖率非常相似，但体外凋亡率在60倍范围内变化，且与培养物中群体扩增率呈负相关。为了确定这种对凋亡敏感性的差异是否影响体内肿瘤生长模式，将转染细胞系皮下注射到免疫抑制小鼠中，形成纤维肉瘤，测量其中凋亡和有丝分裂的发生率、坏死程度和净生长率。体外凋亡率高的细胞系倾向于产生生长缓慢的肿瘤，凋亡与有丝分裂的比例高，坏死少。这种表型的三个最极端例子均来自用c-myc进行的单次转染。体外凋亡率低的细胞系产生快速生长的肿瘤，有丝分裂率高，坏死广泛，相对于有丝分裂凋亡少，即使在坏死区域边缘的受损区域也是如此。四个生长最快的肿瘤均含有T24-ras癌基因。结果表明，癌基因表达决定内在凋亡率，从而可能显著影响肿瘤的净生长率和坏死程度。
