Mechanisms of bone metastases of breast cancer

Abstract

Cancer development is a multi-step process driven by genetic alterations that elicit the progressive transformation of normal human cells into highly malignant derivatives. The altered cell proliferation phenotype of cancer involves a poorly characterized sequence of molecular events, which often result in the development of distant metastasis. In the case of breast cancer, the skeleton is among the most common of metastatic sites. In spite of its clinical importance, the underlying cellular and molecular mechanisms driving bone metastasis remain elusive. Despite advances in our understanding of the phenotype of cancer cells, the increased focus on the contribution of the tumor microenvironment and the recent revival of interest in the role of tumor-propagating cells (so called cancer stem cells) that may originate or be related to normal stem cells produced in the bone marrow, many important questions remain unanswered. As such, a more complete understanding of the influences of both the microenvironment and the tumor phenotype, which impact the entire multi-step metastatic cascade, is required. In this review, the importance of tumor heterogeneity, tumor-propagating cells, the microenvironment of breast cancer metastasis to bone as well as many current endocrine therapies for the prevention and treatment of metastatic breast cancer is discussed.

Figure 1

Schematic representation of tumor-bone marrow microenvironment interactions. Invading tumor cells secrete osteolytic factors that can directly and indirectly stimulate osteoclastic bone resorption, by multinucleated osteoclasts (shown as green cells). Indirect stimulation is primarily by up-regulation of RANK-RANKL signaling by osteoblasts (shown as cuboidal pale blue cells on bone surface) or by stimulation of host immune cells that can increase RANK-RANKL signaling and also negatively regulate tumor cells. Tumor cells also secrete factors that can activate other receptors on the osteoblast, leading to increased osteolysis. Tumors also secrete agents such as VEGF and PDGF that influence vessel formation, as well as agents that can alter platelet function, both of which support osteoclastogenesis and osteolysis. Tumor cells may also influence other bone marrow microenvironment cells, such as stromal cells, that can be induced to differentiate towards the adipogeneic lineage (white cell; red nuclei) or that can become osteoblasts or that can otherwise support osteoclast progression through interactions in the bone marrow niche. The overall integrated result of increased tumor burden in bone in the case of metastatic breast cancer is increased osteolysis.