title: Nitric oxide is a key component in inflammation-accelerated tumorigenesis.
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.
authors.affiliation: Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD 20892, USA.
authors.forename: S Perwez
authors.initials: SP
authors.lastname: Hussain
authors.forename: Peijun
authors.initials: P
authors.lastname: He
authors.forename: Jeffery
authors.initials: J
authors.lastname: Subleski
authors.forename: Lorne J
authors.initials: LJ
authors.lastname: Hofseth
authors.forename: Glenwood E
authors.initials: GE
authors.lastname: Trivers
authors.forename: Leah
authors.initials: L
authors.lastname: Mechanic
authors.forename: Anne B
authors.initials: AB
authors.lastname: Hofseth
authors.forename: Mark
authors.initials: M
authors.lastname: Bernard
authors.forename: Jonathan
authors.initials: J
authors.lastname: Schwank
authors.forename: Giang
authors.initials: G
authors.lastname: Nguyen
authors.forename: Ewy
authors.initials: E
authors.lastname: Mathe
authors.forename: Draginja
authors.initials: D
authors.lastname: Djurickovic
authors.forename: Diana
authors.initials: D
authors.lastname: Haines
authors.forename: Jonathan
authors.initials: J
authors.lastname: Weiss
authors.forename: Timothy
authors.initials: T
authors.lastname: Back
authors.forename: Eilene
authors.initials: E
authors.lastname: Gruys
authors.forename: Victor E
authors.initials: VE
authors.lastname: Laubach
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Curtis C
authors.initials: CC
authors.lastname: Harris