TY - JOUR
T1 - P53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation
AU - Huang, Y.
AU - Yu, P.
AU - Li, W.
AU - Ren, G.
AU - Roberts, A. I.
AU - Cao, W.
AU - Zhang, X.
AU - Su, J.
AU - Chen, X.
AU - Chen, Q.
AU - Shou, P.
AU - Xu, C.
AU - Du, L.
AU - Lin, L.
AU - Xie, N.
AU - Zhang, L.
AU - Wang, Y.
AU - Shi, Y.
N1 - Funding Information:
This work was supported by grants from the Ministry of Science and Technology of China (2010CB945600 and 2011DFA30630), Scientific Innovation Project of the Chinese Academy of Sciences (XDA01040107 and KSCX1-YW-22-04) and International Cooperation and Exchanges NSFC (31010103908). We are also grateful to Yikun Yao (IHS, CAS) for his assistance and suggestions.
PY - 2014/7/17
Y1 - 2014/7/17
N2 - 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.
AB - 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.
KW - iNOS
KW - immunomodulation
KW - mesenchymal stem cells
KW - p53
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U2 - 10.1038/onc.2013.355
DO - 10.1038/onc.2013.355
M3 - Article
C2 - 23975435
AN - SCOPUS:84904630964
SN - 0950-9232
VL - 33
SP - 3830
EP - 3838
JO - Oncogene
JF - Oncogene
IS - 29
ER -