Nitric oxide is a key component in inflammation-accelerated tumorigenesis - PubMed (original) (raw)

. 2008 Sep 1;68(17):7130-6.

doi: 10.1158/0008-5472.CAN-08-0410.

Peijun He, Jeffery Subleski, Lorne J Hofseth, Glenwood E Trivers, Leah Mechanic, Anne B Hofseth, Mark Bernard, Jonathan Schwank, Giang Nguyen, Ewy Mathe, Draginja Djurickovic, Diana Haines, Jonathan Weiss, Timothy Back, Eilene Gruys, Victor E Laubach, Robert H Wiltrout, Curtis C Harris

Affiliations

Nitric oxide is a key component in inflammation-accelerated tumorigenesis

S Perwez Hussain et al. Cancer Res. 2008.

Abstract

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.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Figures

Figure 1

Figure 1

Comparison of survival probability among C. _parvum_–treated and control p53-deficient mice with either WT, heterozygous, and null NOS2 status, using the Kaplan Meier survival curve. The Wilcoxon test was used to estimate the differences between survival curves of C. _parvum_–treated and control groups. •, censored animals (moribund mice that were sacrificed but did not show any tumor).

Figure 2

Figure 2

Increased NOS2 expression in C. _parvum_–treated p53-deficient mice 10 d after treatment. A and B, NOS2 expression in the spleen of C. _parvum_–treated and control p53_−/−_NOS2+/+ mice as determined by IHC. C, Western blot analysis of NOS2 in the spleen of C. _parvum_–treated and control p53_−/−_NOS2+/+ mice. Pos cont, positive control.

Figure 3

Figure 3

TUNEL assay and immunohistochemistry showing an increased number of apoptotic cells, as determined by staining with antidigoxigenin peroxidase (A), and increased expression of Ki-67 (B) and CD95-L (C) in the spleen and thymus of C. _parvum_–treated p53-deficient mice with WT NOS2, 10 d after the treatment.

Figure 4

Figure 4

Western blot analysis showing an increased expression of pAkt-Ser473 in the spleen of C. _parvum_–treated p53_−/−_NOS2+/+ mice, 10 d after the treatment.

Figure 5

Figure 5

The quantitation of cytokines in serum and in supernatant from cultured splenocytes and thymocytes of C. _parvum_–treated and control p53_−/−_NOS2+/+ and p53_−/−_NOS2_−/_− mice using the CBA on a FACScan flow cytometer, 10 d after the treatment. A single-cell suspension of the spleen and thymus was cultured for 48 h before the supernatant was used for analysis.

Figure 6

Figure 6

Total number of splenocytes and spleen FoxP3(+) T-reg cells in C. _parvum_–treated and control p53_−/−_NOS2+/+ and p53_−/−_NOS2_−/_− mice by flow cytometric analysis, 10 d after the treatment, as described in Materials and Methods.

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