Iozzo R V, Chakrani F, Perrotti D, McQuillan D J, Skorski T, Calabretta B, Eichstetter I
Department of Pathology, Anatomy, and Cell Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3092-7. doi: 10.1073/pnas.96.6.3092.
Ectopic expression of decorin in a wide variety of transformed cells results in growth arrest and the inability to generate tumors in nude mice. This process is caused by a decorin-mediated activation of the epidermal growth factor receptor, which leads to a sustained induction of endogenous p21(WAF1/CIP1) (the cyclin-dependent kinase inhibitor p21) and growth arrest. However, mice harboring a targeted disruption of the decorin gene do not develop spontaneous tumors. To test the role of decorin in tumorigenesis, we generated mice lacking both decorin and p53, an established tumor-suppressor gene. Mice lacking both genes showed a faster rate of tumor development and succumbed almost uniformly to thymic lymphomas within 6 months [mean survival age (T50) approximately 4 months]. Mice harboring one decorin allele and no p53 gene developed the same spectrum of tumors as the double knockout animals, but had a survival rate similar to the p53 null animals (T50 approximately 6 months). Ectopic expression of decorin in thymic lymphoma cells isolated from double mutant animals markedly suppressed their colony-forming ability. When these lymphoma cells were cocultured with fibroblasts derived from either wild-type or decorin null embryos, the cells grew faster in the absence of decorin. Moreover, exogenous decorin proteoglycan or its protein core significantly retarded their growth in vitro. These results indicate that the lack of decorin is permissive for lymphoma tumorigenesis in a mouse model predisposed to cancer and suggest that germ-line mutations in decorin and p53 may cooperate in the transformation of lymphocytes and ultimately lead to a more aggressive phenotype by shortening the tumor latency.
在多种转化细胞中，核心蛋白聚糖的异位表达会导致生长停滞，并且无法在裸鼠体内形成肿瘤。这个过程是由核心蛋白聚糖介导的表皮生长因子受体激活引起的，这会导致内源性 p21（WAF1/CIP1）（细胞周期蛋白依赖性激酶抑制剂 p21）的持续诱导和生长停滞。然而，携带核心蛋白聚糖基因靶向破坏的小鼠不会发生自发性肿瘤。为了测试核心蛋白聚糖在肿瘤发生中的作用，我们构建了同时缺失核心蛋白聚糖和 p53（一种已确定的肿瘤抑制基因）的小鼠。同时缺失这两种基因的小鼠肿瘤发展速度更快，几乎在 6 个月内均死于胸腺淋巴瘤[平均生存年龄（T50）约为 4 个月]。携带一个核心蛋白聚糖等位基因且无 p53 基因的小鼠发生的肿瘤谱与双敲除动物相同，但生存率与 p53 基因缺失动物相似（T50 约为 6 个月）。从双突变动物中分离出的胸腺淋巴瘤细胞中核心蛋白聚糖的异位表达显著抑制了它们的集落形成能力。当这些淋巴瘤细胞与来自野生型或核心蛋白聚糖缺失胚胎的成纤维细胞共培养时，在没有核心蛋白聚糖的情况下细胞生长得更快。此外，外源性核心蛋白聚糖蛋白聚糖或其蛋白核心显著抑制了它们在体外的生长。这些结果表明，在易患癌症的小鼠模型中，缺乏核心蛋白聚糖有利于淋巴瘤的肿瘤发生，并表明核心蛋白聚糖和 p53 的种系突变可能在淋巴细胞转化中协同作用，并最终通过缩短肿瘤潜伏期导致更具侵袭性的表型。
