Interleukins as Mediators of the Tumor Cell-Bone Cell Crosstalk during the Initiation of Breast Cancer Bone Metastasis

Abstract

Patients with advanced breast cancer are at high risk of developing bone metastasis. Despite treatment advances for primary breast cancer, metastatic bone disease remains incurable with a low relative survival. Hence, new therapeutic approaches are required to improve survival and treatment outcome for these patients. Bone is among the most frequent sites of metastasis in breast cancer. Once in the bone, disseminated tumor cells can acquire a dormant state and remain quiescent until they resume growth, resulting in overt metastasis. At this stage the disease is characterized by excessive, osteoclast-mediated osteolysis. Cells of the bone microenvironment including osteoclasts, osteoblasts and endothelial cells contribute to the initiation and progression of breast cancer bone metastasis. Direct cell-to-cell contact as well as soluble factors regulate the crosstalk between disseminated breast cancer cells and bone cells. In this complex signaling network interleukins (ILs) have been identified as key regulators since both, cancer cells and bone cells secrete ILs and express corresponding receptors. ILs regulate differentiation and function of bone cells, with several ILs being reported to act pro-osteoclastogenic. Consistently, the expression level of ILs (e.g., in serum) has been associated with poor prognosis in breast cancer. In this review we discuss the role of the most extensively investigated ILs during the establishment of breast cancer bone metastasis and highlight their potential as therapeutic targets in preventing metastatic outgrowth in bone.

Keywords: bone metastasis; bone microenvironment; breast cancer; disseminated tumor cell; dormancy; interleukin.

Figure 1

Interleukins during the progression of breast cancer bone metastasis. Interleukins (ILs) play pivotal roles in mediating several steps of the metastatic cascade in breast cancer. Dynamic changes in circulating tumor cell (CTC) levels in combination with corresponding alterations in serum IL levels might serve as prognostic markers for the progression of breast cancer. Furthermore, ILs are suggested to regulate the attraction of disseminated tumor cells (DTCs) to the metastatic site, facilitate extravasation from the circulation, adhesion and migration in the secondary organ. Once in the secondary organ, DTCs receive interleukin signals from adjacent, tissue-resident cells that regulate their fate in the secondary organ. Cells of the bone microenvironment secrete ILs that control tumor cell dormancy. In turn, proliferating tumor cells secrete ILs that stimulate osteoclastic bone resorption and consequently osteolysis. Factors released during osteolysis (e.g., Transforming growth factor β (TGF-β)) then fuel the vicious cycle of bone metastasis. Stromal-derived ILs can also regulate tumor growth via affecting vascular endothelial cells, thus promoting vascularization and metastatic growth.