Interleukin-6 in bone metastasis and cancer progression

https://doi.org/10.1016/j.ejca.2010.02.026Get rights and content

Abstract

The bone and bone marrow are among the most frequent sites of cancer metastasis. It is estimated that 350,000 patients die with bone metastases annually in the United States. The ability of tumor cells to colonize the bone marrow and invade the bone is the result of close interactions between tumor cells and the bone marrow microenvironment. In this article, we review the contribution of interleukin-6 (IL-6) produced in the bone marrow microenvironment to bone metastasis. This cytokine has a strong pro-tumorigenic activity due to its multiple effects on bone metabolism, tumor cell proliferation and survival, angiogenesis, and inflammation. These effects are mediated by several signaling pathways, in particular the Janus kinase/signal transducer and transcription activator (JAK/STAT-3), Ras/mitogen activated protein kinase (MAPK), and phosphoinositol-3 kinase (PI3K)–protein kinase B/Akt (PkB/Akt), which are activated by IL-6 and amplified in the presence of soluble IL-6 receptor (sIL-6R). Supporting the role of IL-6 in human cancer is the observation of elevated serum levels of IL-6 and sIL-6R in patients with bone metastasis and their association with a poor clinical outcome. Over the last decade several large (monoclonal antibodies) and small (inhibitors of IL-6 mediated signaling) molecules that inhibit IL-6 activity in preclinical models have been developed. Several of these inhibitors are now undergoing phases I and II clinical trials, which will determine their inclusion in the list of effective targeted agents in the fight against cancer.

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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