Leptin was previously demonstrated to exert potent immune modulatory properties in several immune mediated disorders. The aim of the study was to determine
leptin's anti-tumor effect in a
murine model of human
hepatocellular carcinoma (HCC).
In vivo, Athymic
T cell deficient (nude) mice transplanted with 1×106 human Hep3B cells, followed by administration of two daily intraperitoneal doses of 0.5 mg /
gram leptin for 6 weeks.
Leptin administration induced a significant reduction in
tumor size and
improved survival in nude mice. Histologically, tumors of
leptin-administered mice featured increased inflammatory
exudate in
interphase areas.
Leptin-induced tumor suppression was associated with a significant increase in
peripheral natural killer (NK)
cell number. Splenocytes from leptin-treated mice featured decreased expression of CIS mRNA. To determine which
lymphocyte subset is a prerequisite for the anti tumor effect of leptin, T&
B cell deficient (Scid) mice and T,B& NK deficient (Scid-Beige) mice were subcutaneously implanted with Hep3B
tumor cells, with and without the daily intraperitoneal administration of 0.5 mg /
gram leptin for 6 weeks.
SCID mice featured leptin-associated tumor suppression similar to those of nude mice. In contrast, NK-deficient SCID-Beige mice developed larger tumors. To further establish
natural killer cell's central role in mediation of leptin's anti-tumor effect, NK cells were incubated
in vitro with increasing doses of leptin, demonstrating a
dose-dependent increase in cytotoxic activity. Incubation of leptin with
hepatoma cell line was found to induce a
dose-dependent reduction in
hepatoma cell proliferation, suggesting an additive direct anti-tumor effect. Further synergism in inhibition of
hepatoma cell proliferation
in vitro was achieved following addition of natural killer cells. HCC cells expressed
leptin receptor mRNA, while addition of leptin induced increased mRMA expression of STAT2 and SOCS1 on tumor
cell lines. Leptin administration induces a significant suppression of human HCC. This effect is mediated by induction of
natural killer cell proliferation and activation, and by direct inhibition of
tumor growth. Decreased
natural killer cell expression of inhibitory CIS
protein and
over expression of the anti-proliferative STAT2 and SOCS1 proteins in HCC lines may
underline both anti cancerous effects of leptin.