Interleukin-1 and cancer progression: the emerging role of interleukin-1 receptor antagonist as a novel therapeutic agent in cancer treatment

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 (IL1ra) 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.

The Interleukin (IL)-1R1 pathway is a critical negative regulator of PyMT-mediated mammary tumorigenesis and pulmonary metastasis

“…IL-1 signaling can play an important role in immune or stromal cells as well as within the cancer cells themselves. 27 In the current study, we did not pinpoint the location of either the cytokine or the receptor within the host. Future studies would be required to understand in which cell type IL-1a and IL-1R1 are important and whether IL-1a acts in an autocrine or paracrine fashion.…”

“…24 These and other studies 25,26 have led to the proposal that IL-1R1 blockade might constitute a potential cancer therapeutic. 9,10,27 However, although IL-1b signaling has been reported to drive carcinogenesis, many studies have shown an antitumorigenic role for IL-1a. 7,21,[28][29][30][31] For instance, NIH3T3 fibrosarcoma cells transfected with IL-1a failed to grow in vivo following i.v.…”

Chronic Inflammation in Cancer Development

“…Overall, patients harboring IL-1-positive tumors have markedly worse prognoses (Lewis et al, 2006). Due to its pleiotropic nature, IL-1 promotes tumor growth and metastasis in an autocrine/paracrine manner.…”

Constitutively Active Inflammasome in Human Melanoma Cells Mediating Autoinflammation via Caspase-1 Processing and Secretion of Interleukin-1β

“…Interleukin-1␤ (IL-1␤) 3 is a pleiotropic pro-inflammatory cytokine involved in cell growth, differentiation, tissue repair, and regulation of immune response (4). IL-1␤ is often detected in human cancer tissues including breast cancer, pancreatic cancer, glioblastoma, and melanoma (5)(6)(7)(8)(9)(10)(11)(12)(13), where the expression levels of the IL-1␤ protein or gene are associated with the invasiveness and metastasis of cancers. Experiments using exogenously administered IL-1 or IL-1 knock-out mice suggest that stromal-derived IL-1 plays an important role in the progression of murine tumors (14 -19), whereas recent reports have shown that tumor-derived IL-1␤ is associated with tumor growth, immunosuppression, and chemoresistance (7,8,13,15).…”