Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice
Thrombospondin-1 gene expression affects survival and tumor spectrum of p53-deficient mice
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DOI：
10.1016/s0002-9440(10)63042-8
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发表时间：
2001-11-01
影响因子：
6
通讯作者：
Hynes, RO
中科院分区：
文献类型：
--
作者：
Lawler, J;Miao, WM;Hynes, RO
体外和体内数据表明，血小板反应蛋白-1 (TSP1) 通过多种方式抑制肿瘤进展，包括直接影响基质中的细胞生长和凋亡。隔间。为了评估 TSP1 对体内自然产生的肿瘤进展的重要性，我们将 TSP1 缺陷小鼠与 p53 缺陷小鼠进行杂交。在 p53 缺失小鼠中，TSP1 的缺失使存活时间从 160 +/- 52 天缩短至 149 +/- 42 天。比较这两个群体的生存曲线的对数秩检验得出双侧 P 值为 0.0272。对于 p53 缺失等位基因杂合的小鼠，在 TSP1 表达存在的情况下，生存期为 500 +/- 103 天，在不存在 TSP1 表达的情况下，生存期为 426 +/- 125 天（P = 0.0058）。虽然 TSP1 表达并未导致大多数肿瘤类型的发病率发生可测量的变化，但在 TSP1 缺失的情况下，观察到骨肉瘤发病率有统计学显着性（P 小于或等于 0.05）下降。为了更直接地确定宿主 TSP1 是否抑制肿瘤生长，将 B16F10 黑色素瘤细胞和 F9 睾丸畸胎癌细胞分别植入 C57BL/6J 和 129Sv TSP1 缺失小鼠体内。 B16F10肿瘤在TSP1缺失的背景下生长速度大约是其两倍，并且表现出血管密度增加、肿瘤细胞凋亡率降低以及肿瘤细胞增殖率增加。在 129Sv 遗传背景上缺乏 TSP1 的情况下也观察到肿瘤生长增加。这些数据表明内源宿主 TSP1 作为修饰基因或景观基因发挥抑制肿瘤生长的作用。
In vitro and in vivo data indicate that thrombospondin-1 (TSP1) inhibits tumor progression in several ways including direct effects on cellular growth and apoptosis in the stromal. compartment. To evaluate the importance of TSP1 for the progression of naturally arising tumors in vivo, we have crossed TSP1-deficient mice with p53-deficient mice. In p53-null mice, the absence of TSP1 decreases survival from 160 +/- 52 days to 149 +/- 42 days. A log-rank test comparing survival curves for these two populations yields a two-sided P value of 0.0272. For mice that are heterozygous for the p53-null allele, survival is 500 +/- 103 days In the presence of TSP1 expression, and 426 +/- 125 days in its absence (P = 0.0058). Whereas TSP1 expression did not cause a measurable change in the incidence of the majority of tumor types, a statistically significant (P less than or equal to 0.05) decrease in the incidence of osteosarcomas is observed in the absence of TSP1. To determine more directly if host TSP1 inhibits tumor growth, B16F10 melanoma and F9 testicular teratocarcinoma cells have been implanted in C57BL/6J and 129Sv TSP1-null mice, respectively. The B16F10 tumors grow approximately twice as fast in the TSP1-null background and exhibit an increase in vascular density, a decrease in the rate of tumor cell apoptosis, and an increase in the rate of tumor cell proliferation. Increased tumor growth is also observed in the absence of TSP1 on the 129Sv genetic background. These data indicate that endogenous host TSP1 functions as a modifier or landscaper gene to suppress tumor growth.