Deng J, Xia W, Hung M C
Department of Tumor Biology, The University of Texas MD Anderson Cancer Center, Houston 77030, USA.
Oncogene. 1998 Oct 29;17(17):2167-75. doi: 10.1038/sj.onc.1202148.
Disruption of apoptotic pathways is a major factor in the multistep process of tumorigenesis, whereas induction of apoptosis can be important for tumor suppression and cancer therapy. The adenovirus type 5 E1A gene provides a useful tool to study the function of tumor suppression and apoptosis. E1A has been shown to induce apoptosis in different systems in vitro. However, this activity has not been well characterized in vivo. Therefore, the effect of this activity and the link to the in vivo biological function are not clear. To answer these questions, we introduced E1A into murine melanoma cells and characterized the biological features both in vitro and in vivo. Expression of the E1A gene does not affect the proliferation rate of tumor cells in vitro, but inhibits tumor growth in vivo. The in vitro analysis indicated that the E1A-expressing tumor cells are sensitive to serum depletion-induced apoptosis. Importantly, E1A-mediated apoptosis was also identified in vivo, suggesting this activity contributed to the tumor suppressive function. The in vivo apoptotic pattern was unique: most of the apoptotic cells were around the periphery of the tumors, implicating the interaction of these cells with stress stimuli in vivo. In addition, E1A also rendered the tumor cells susceptible to the cytotoxicity of other anticancer agents, a feature useful for improving the efficacy of cancer therapy. The results provide a functional link between in vitro activity and in vivo effects.
凋亡途径的破坏是肿瘤发生多步骤过程中的一个主要因素，而诱导凋亡对于肿瘤抑制和癌症治疗可能很重要。5型腺病毒E1A基因提供了一个研究肿瘤抑制和凋亡功能的有用工具。E1A已被证明在不同的体外系统中可诱导凋亡。然而，这种活性在体内尚未得到很好的表征。因此，这种活性的作用以及与体内生物学功能的联系尚不清楚。为了回答这些问题，我们将E1A导入小鼠黑色素瘤细胞，并在体外和体内对其生物学特性进行了表征。E1A基因的表达在体外不影响肿瘤细胞的增殖率，但在体内抑制肿瘤生长。体外分析表明，表达E1A的肿瘤细胞对血清饥饿诱导的凋亡敏感。重要的是，在体内也鉴定出了E1A介导的凋亡，这表明这种活性有助于肿瘤抑制功能。体内凋亡模式是独特的：大多数凋亡细胞位于肿瘤周边，这意味着这些细胞在体内与应激刺激相互作用。此外，E1A还使肿瘤细胞对其他抗癌药物的细胞毒性敏感，这一特性有助于提高癌症治疗的疗效。这些结果提供了体外活性与体内效应之间的功能联系。
