Abstract
The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells which produce cytokines, growth factors, and adhesion molecules that promote tumor progression and metastasis. Of particular interest in this setting is interleukin-1 (IL-1), a pleiotropic cytokine with numerous roles in both physiological and pathological states. It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors. A number of studies have reported that high IL-1 concentrations within the tumor microenvironment are associated with a more virulent tumor phenotype. Solid tumors in which IL-1 has been shown to be up regulated include breast, colon, lung, head and neck cancers, and melanomas, and patients with IL-1 producing tumors have generally bad prognoses. The exact mechanisms by which IL-1 promotes tumor growth remain unclear, though the protein is believed to act via induction of pro-metastatic genes such as matrix metalloproteinases and through the stimulation of adjacent cells to produce angiogenic proteins and growth factors such as VEGF, IL-8, IL-6, TNFα, and TGFβ. The IL-1 receptor antagonist (IL-1ra) is a naturally occurring inhibitor to IL-1 and acts by binding to the IL-1 receptor without activating it. The protein has been shown to decrease tumor growth, angiogenesis, and metastases in murine xenograft models. Our focus in this review is to summarize the known data on the role of IL-1 in tumor progression and metastasis and the use of IL-1 inhibition as a novel therapeutic approach in the treatment of solid organ malignancies.
Highlights
The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells all of which produce cytokines, growth factors, and adhesion molecules that may promote tumor progression and metastases
Chronic pathological inflammation is mediated via the continuing presence of a persistent stimulus, such as tumor cells, and the resulting prolonged inflammatory cytokine exposure has the potential to promote tumor growth through the induction of angiogenesis, DNA damage, and other events favorable to tumor invasion and metastases, as reviewed in reference [2]
It is known to be up regulated in many tumor types and has been implicated as a factor in tumor progression via the expression of metastatic and angiogenic genes and growth factors
Summary
The tumor microenvironment consists of tumor, immune, stromal, and inflammatory cells all of which produce cytokines, growth factors, and adhesion molecules that may promote tumor progression and metastases. There are other agents that are capable of inhibiting the inflammatory and tumor promoting effects of IL-1 such as anti-interleukin-1 monoclonal antibodies, the soluble IL-1 receptor type II, interleukin-1β-converting enzyme inhibitors, and IL-1 cytokine traps Such potential therapeutic agents are currently being applied to the treatment of rheumatoid arthritis, but additional studies are necessary to determine their ability as novel therapy in cancer treatment. IL1ra consistently resulted in a statistically significant decrease in growth rate of all three IL-1-producing tumors tested but had no effect on two non-IL-1-producing tumors Both in vitro and in vivo studies demonstrated that IL-1RIItransduced cells failed to respond to IL-1 [35,36]. IL1 traps appeared to be safe, well-tolerated, and elicited no abnormal clinical laboratory values or evidence of increased number of infections, supporting further investigations of this protein
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