Hussain S Perwez, He Peijun, Subleski Jeffery, Hofseth Lorne J, Trivers Glenwood E, Mechanic Leah, Hofseth Anne B, Bernard Mark, Schwank Jonathan, Nguyen Giang, Mathe Ewy, Djurickovic Draginja, Haines Diana, Weiss Jonathan, Back Timothy, Gruys Eilene, Laubach Victor E, Wiltrout Robert H, Harris Curtis C
Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
Cancer Res. 2008 Sep 1;68(17):7130-6. doi: 10.1158/0008-5472.CAN-08-0410.
Nitric oxide (NO()), an important signaling molecule and a component of inflammatory response, is involved in tumorigenesis. However, the quantity of NO() and the cellular microenvironment influences the role of NO() in tumor development. We used a genetic strategy to test the hypothesis that an inflammatory microenvironment with an enhanced level of NO() accelerates spontaneous tumor development. C. parvum-induced inflammation and increased NO() synthase-2 (NOS2) expression coincided with accelerated spontaneous tumor development, mostly lymphomas, in p53-/-NOS2+/+ C57BL6 mice when compared with the controls (P = 0.001). However, p53-/-NOS2-/- mice did not show any difference in tumor latency between C. parvum-treated and control groups. In C. parvum-treated p53-/-NOS2+/+ mice, tumor development was preceded by a higher expression of NOS2 and phosphorylated Akt-Ser(473) (pAkt-Ser473) in spleen, increased cell proliferation measured by Ki-67 IHC in spleen and thymus, and a lower apoptotic index and CD95-L expression in spleen and thymus. C. parvum-treated p53-/-NOS2+/+ mice showed an increase in the number of Foxp3(+) T-reg cells, dendritic cells (DC), as well as increased CD80(+), CD86(+), CD40(+), and CD83(+) on DC in the spleen. Regulatory T-cells (T-reg) and the maturation of DC may modulate tumorigenesis. An increase in the FoxP3(+)T-reg cells in C. parvum-treated p53-/-NOS2+/+ mice indicates a role of NO() in the regulation of T-reg cells that may contribute to a protumor shift of the immune environment favoring an accelerated tumor development. These data provide genetic and mechanistic evidence that an inflammatory microenvironment and an increased level of NO(*) can accelerate tumor development.
一氧化氮（NO()）是一种重要的信号分子，也是炎症反应的一个组成部分，参与肿瘤发生。然而，NO()的量以及细胞微环境会影响NO()在肿瘤发展中的作用。我们采用基因策略来验证以下假设：具有增强水平NO()的炎症微环境会加速自发性肿瘤发展。与对照组相比，微小隐孢子虫诱导的炎症以及NO()合酶-2（NOS2）表达增加与p53-/-NOS2+/+ C57BL6小鼠自发性肿瘤发展加速同时出现，主要是淋巴瘤（P = 0.001）。然而，p53-/-NOS2-/-小鼠在微小隐孢子虫处理组和对照组之间的肿瘤潜伏期没有显示出任何差异。在微小隐孢子虫处理的p53-/-NOS2+/+小鼠中，肿瘤发展之前脾脏中NOS2和磷酸化Akt-Ser(473)（pAkt-Ser473）表达较高，通过Ki-67免疫组化检测到脾脏和胸腺中的细胞增殖增加，并且脾脏和胸腺中的凋亡指数及CD95-L表达较低。微小隐孢子虫处理的p53-/-NOS2+/+小鼠显示Foxp3(+)调节性T细胞、树突状细胞（DC）数量增加，以及脾脏中DC上的CD80(+)、CD86(+)、CD40(+)和CD83(+)增加。调节性T细胞（T-reg）和DC的成熟可能调节肿瘤发生。微小隐孢子虫处理的p53-/-NOS2+/+小鼠中FoxP3(+)T-reg细胞增加表明NO()在调节T-reg细胞中起作用，这可能有助于免疫环境向促肿瘤转变，有利于加速肿瘤发展。这些数据提供了基因和机制证据，表明炎症微环境和NO(*)水平升高可加速肿瘤发展。
