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Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis

¹ Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI and ² Howard Hughes Medical Institute, NIH, Bethesda, Maryland; ³ Laboratory of Experimental Immunology, Cancer Inflammation Program, Center for Cancer Research, NCI and ⁴ Science Applications International Corporation, Frederick Cancer Research and Development Center, Frederick, Maryland; ⁵ Department of Basic Pharmacy Science, College of Pharmacy, University of South Carolina, Columbia, South Carolina; ⁶ University of Virginia Health Science Center, Charlottesville, Virginia; and ⁷ Westat, Rockville, Maryland

Requests for reprints: Curtis C. Harris, Chief, Laboratory of Human Carcinogenesis, Building 37, Room 3068, National Cancer Institute, NIH, Bethesda, MD 20892. Phone: 301-496-2048; Fax: 301-496-0497; E-mail: harrisc{at}mail.nih.gov.

Key Words: nitric oxide • inflammation • cancer • p53 • NOS2

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-Ser⁴⁷³ (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. [Cancer Res 2008;68(17):7130–6]

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