Nitric Oxide Is a Key Component in Inflammation-Accelerated Tumorigenesis

• Published in: Cancer research (Chicago, Ill.) Ill.), 2008-09, Vol.68 (17), p.7130-7136
• Main Authors: PERWEZ HUSSAIN, S, PEIJUN HE, MATHE, Ewy, DJURICKOVIC, Draginja, HAINES, Diana, WEISS, Jonathan, BACK, Timothy, GRUYS, Eilene, LAUBACH, Victor E, WILTROUT, Robert H, HARRIS, Curtis C, SUBLESKI, Jeffery, HOFSETH, Lorne J, TRIVERS, Glenwood E, MECHANIC, Leah, HOFSETH, Anne B, BERNARD, Mark, SCHWANK, Jonathan, NGUYEN, Giang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis; Biological and medical sciences; Flow Cytometry; Immunohistochemistry; Inflammation - pathology; Interferon-gamma - metabolism; Interleukin-6 - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Nitric Oxide - physiology; Pharmacology. Drug treatments; Tumor Necrosis Factor-alpha - metabolism; Tumors
• ISSN: 0008-5472; 1538-7445
• 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.