Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences/Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Child Health Institute of New Jersey and Department of Pharmacology, Robert Wood Johnson Medical School-University of Medicine and Dentistry of New Jersey, New Brunswick, NJ, USA.
Oncogene. 2014 Jul 17;33(29):3830-8. doi: 10.1038/onc.2013.355. Epub 2013 Aug 26.
p53 is one of the most studied genes in cancer biology, and mutations in this gene may be predictive for the development of many types of cancer in humans and in animals. However, whether p53 mutations in non-tumor stromal cells can affect tumor development has received very little attention. In this study, we show that B16F0 melanoma cells form much larger tumors in p53-deficient mice than in wild-type mice, indicating a potential role of p53 deficiency in non-tumor cells of the microenvironment. As mesenchymal stem cells (MSCs) are attracted to tumors and form a major component of the tumor microenvironment, we examined the potential role of p53 status in MSCs in tumor development. We found that larger tumors resulted when B16F0 melanoma cells were co-injected with bone marrow MSCs derived from p53-deficient mice rather than MSCs from wild-type mice. Interestingly, this tumor-promoting effect by p53-deficient MSCs was not observed in non-obese diabetic/severe combined immunodeficiency mice, indicating the immune response has a critical role. Indeed, in the presence of inflammatory cytokines, p53-deficient MSCs expressed more inducible nitric oxide synthase (iNOS) and exhibited greater immunosuppressive capacity. Importantly, tumor promotion by p53-deficient MSCs was abolished by administration of S-methylisothiourea, an iNOS inhibitor. Therefore, our data demonstrate that p53 status in tumor stromal cells has a key role in tumor development by modulating immune responses.
p53 是癌症生物学中研究最多的基因之一，该基因的突变可能可预测人类和动物许多类型癌症的发生。然而，非肿瘤基质细胞中的 p53 突变是否会影响肿瘤的发生发展，这方面的研究还很少。在这项研究中，我们发现 B16F0 黑色素瘤细胞在 p53 缺失的小鼠中比在野生型小鼠中形成的肿瘤大得多，这表明微环境中非肿瘤细胞中 p53 缺失可能发挥作用。由于间充质干细胞（MSCs）被吸引到肿瘤中并形成肿瘤微环境的主要组成部分，我们研究了 p53 状态在 MSCs 中对肿瘤发展的潜在作用。我们发现，当 B16F0 黑色素瘤细胞与源自 p53 缺失小鼠的骨髓 MSCs 而非源自野生型小鼠的 MSCs 共注射时，会导致更大的肿瘤。有趣的是，在非肥胖型糖尿病/重症联合免疫缺陷（NOD/SCID）小鼠中，p53 缺失的 MSCs 没有观察到这种促肿瘤作用，这表明免疫反应起着关键作用。事实上，在炎性细胞因子存在的情况下，p53 缺失的 MSCs 表达更多的诱导型一氧化氮合酶（iNOS），并表现出更强的免疫抑制能力。重要的是，通过给予 iNOS 抑制剂 S-甲基异硫脲，p53 缺失的 MSC 对肿瘤的促进作用被消除。因此，我们的数据表明，肿瘤基质细胞中的 p53 状态通过调节免疫反应在肿瘤发展中起着关键作用。
