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.
Highlights
Patients with advanced breast cancer are at high risk of developing metastatic disease in the skeleton
In vitro studies have associated the expression of ILs with the metastatic capacity of breast cancer cell lines [20,37,51,52,53] and clinical studies report elevated serum IL levels in patients with bone metastasis [46,47]
The studies discussed in this review highlight the role of ILs in distinct events of the metastatic cascade—tumor cell dormancy, cancer stem cells (CSCs), migration and invasion as well as colonization of the metastatic site
Summary
Breast cancer remains the most frequently diagnosed cancer in women worldwide, survival rates for patients with primary breast cancer have steadily improved [1]. Given that the disease cannot be cured once it is progressing in bone, treatment approaches that target the early stages of disease establishment such as tumor cell colonization and escape from dormancy, would be needed to provide better prognosis and treatment outcome for patients with breast cancer bone metastasis. Upon their arrival in bone, disseminated tumor cells (DTCs) encounter a heterogeneous microenvironment that is comprised of cellular and molecular entities that vastly differ from the original environment of the primary tumor. We review and discuss the role of the best-validated ILs (IL-1β, IL-6, IL-8 and IL-11) involved in the bone cell—breast cancer cell crosstalk during the early events of breast cancer bone metastasis
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