Interleukin-6 in bone metastasis and cancer progression
Section snippets
Bone marrow microenvironment and bone metastasis
It is estimated that 350,000 patients die with bone metastases annually in the United States (US).1 Considering its stiff structure and composition, it is surprising that the bone is among the most common sites for the establishment of cancer metastasis.2, 3 However, it is in part explained by the unique microenvironment provided by the bone marrow. The bone marrow is the site of niches where hematopoietic stem cells (HSCs) reside. These niches consist of osteoblasts that line the endosteal
IL-6 signaling and transsignaling
Interleukin-6 is a pleiotropic cytokine overexpressed in response to injury, inflammation, and infection.14 It was originally cloned as a B cell stimulatory factor and designated Interferon β2. It was later found to stimulate cytotoxic T cells and to induce the differentiation of osteoclast precursor cells into mature and active osteoclasts.15, 16 IL-6 is produced by many cells including osteoblasts, monocytes and macrophages, and BMMCs. Serum levels of IL-6 are low or undetectable under normal
Autocrine and paracrine mechanisms of IL-6 activity
The role of IL-6 in cancer is complex and includes autocrine and paracrine mechanisms. Many tumor cells from prostate, breast, and colon cancer produce large amounts of IL-6 and express the IL-6R/gp80 and gp130 receptor subunits, which allows them to respond to IL-6 stimulation in an autocrine manner. STAT-3 is also persistently activated in tumor cells.44, 45 However, in other cancers, in particular myeloma and neuroblastoma, most tumor cells do not produce IL-6, but express a functional IL-6
Prognostic significance of IL-6 and IL-6R levels in peripheral blood of cancer patients
Considering the pro-tumorigenic roles of IL-6, it is therefore not surprising that elevated serum levels of IL-6 and sIL-6R have been associated with poor clinical outcome in many human cancers, including in breast and prostate cancer, multiple myeloma, hepatocellular carcinoma, lymphoma, and pediatric solid tumors.73, 74, 75, 76 The levels of IL-6 typically found in the serum of cancer patients is within the picogram range (100–500 pg/ml), at which there is very little evidence in vitro that
Targeting IL-6
The abundance of evidence supporting a pro-tumorigenic effect of IL-6 in tumor progression and bone metastasis has prompted the initiation of clinical trials testing the safety and therapeutic efficacy of inhibitors of IL-6 and IL-6 signaling in cancer treatment. Currently, the strategies focus on large proteins like humanized monoclonal antibodies (mAb) and small molecules that inhibit IL-6-mediated signaling or the production of IL-6 (Table 1).
Conclusion
Over the last decade, IL-6 has emerged as an important contributor to the tumor microenvironment and inflammation contributing to pro-tumorigenic activity. IL-6 function involves multiple cell–cell interactions and signaling pathways that together promote osteolytic bone metastasis, tumor cell proliferation and survival, angiogenesis and vasculogenesis, and immune escape. As a result, inhibition of IL-6 and IL-6R-mediated signaling has been the subject of intense investigation. We are at a time
Conflict of interest statement
None declared.
Acknowledgments
The authors thank Mrs. J. Rosenberg for typing and editing the manuscript. This work was supported by Grant CA 084103 from the National Institutes of Health (Y.D.C.), and the Children’s Cancer Research Fund and Children’s Neuroblastoma Cancer Foundation (T.A.).
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