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