Interleukin-6 in bone metastasis and cancer progression

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.

Figure 1. IL-6-mediated signaling, gene expression, and its cellular effects

IL-6 activates three pathways, STAT-3, Erk1/2, and PkB/Akt. This results in the upregulation of a number of genes that affect survival, proliferation, differentiation, osteogenesis/osteolysis, angiogenesis, and immune modulation, in a variety of target cells. The expression of these genes has several pro-tumorigenic effects.

Figure 2. Paracrine effects of IL-6 in the bone marrow microenvironment

(1) Tumor cells induce the production of IL-6 in BMMCs and myeloid cells in the bone marrow microenvironment, (2) IL-6 stimulates the proliferation and enhances the survival of tumor cells, (3) IL-6 increases the production of PTHrP and DKK-1 by tumor cells, (4) IL-6 promotes the degradation of the bone matrix by inducing the expression of RANKL in osteoblasts, (5) IL-6 activates osteoclasts, (6) IL-6 stimulates endothelial cells and endothelial progenitor cells, promoting angiogenesis and vasculogenesis, (7) IL-6 inhibits the maturation of APC and dendritic cells, (8) myeloid cells produce sIL-6R, which potentiates the effect of IL-6, (9) growth factors like TGF-β, IGF-1, and BMP are released from degraded bone, and enhance IL-6 production, contributing to the vicious circle of bone metastasis.