Tumor necrosis factor (TNF) is a multifunctional
cytokine that plays important roles in diverse cellular events such as cell survival, proliferation, differentiation, and death. As a pro-inflammatory
cytokine, TNF is secreted by inflammatory cells, which may be involved in
inflammation-associated
carcinogenesis. TNF exerts its biological functions through activating distinct signaling pathways such as
nuclear factor-kappaB (
NF-kappaB) and
c-Jun N-terminal kinase (JNK).
NF-kappaB is a major cell survival signal that is anti-apoptotic, whereas sustained JNK activation contributes to cell death. The crosstalk between the
NF-kappaB and JNK is involved in determining cellular outcomes in response to TNF. In regard to
cancer, TNF is a double-dealer. On one hand, TNF could be an endogenous
tumor promoter, because TNF stimulates the growth, proliferation, invasion and
metastasis, and
tumor angiogenesis of
cancer cells. On the other hand, TNF could be a
cancer killer. The property of TNF in inducing
cancer cell death renders it a potential
cancer therapeutic, although much work is needed to reduce its toxicity for systematic TNF administration. Recent studies have focused on sensitizing
cancer cells to TNF-induced apoptosis through inhibiting survival signals such as
NF-kappaB, by combined
therapy. In this article we provide an overview of the roles of TNF-induced signaling pathways in
cancer biology with specific emphasis on
carcinogenesis and
cancer therapy.