Abstract
Simple SummaryBone metastasis is a leading cause of breast cancer-related deaths. The interaction between metastatic cancer cells and bone-resident cells promotes tumor growth and bone loss. Metastatic tumors within the bone can contribute to complications including pathological fracture, hypercalcemia, spinal cord compression, and pain. The underlying molecular mechanisms that regulate these interactions in the bone microenvironment are not completely understood. Multiple cell signaling pathways, transcription factors, miRNAs, and secretory factors have been shown to promote bone metastasis. Here, we review the mechanisms by which tumor-derived and tumor-microenvironment-derived factors contribute to bone metastasis. We discuss recent findings highlighting the role of cell signaling and the autophagy pathway in bone metastasis. Furthermore, we discuss the clinical management, treatment options, current challenges, and potential novel targeting strategies of metastatic bone disease.Bone metastasis is a frequent complication of breast cancer with nearly 70% of metastatic breast cancer patients developing bone metastasis during the course of their disease. The bone represents a dynamic microenvironment which provides a fertile soil for disseminated tumor cells, however, the mechanisms which regulate the interactions between a metastatic tumor and the bone microenvironment remain poorly understood. Recent studies indicate that during the metastatic process a bidirectional relationship between metastatic tumor cells and the bone microenvironment begins to develop. Metastatic cells display aberrant expression of genes typically reserved for skeletal development and alter the activity of resident cells within the bone microenvironment to promote tumor development, resulting in the severe bone loss. While transcriptional regulation of the metastatic process has been well established, recent findings from our and other research groups highlight the role of the autophagy and secretory pathways in interactions between resident and tumor cells during bone metastatic tumor growth. These reports show high levels of autophagy-related markers, regulatory factors of the autophagy pathway, and autophagy-mediated secretion of matrix metalloproteinases (MMP’s), receptor activator of nuclear factor kappa B ligand (RANKL), parathyroid hormone related protein (PTHrP), as well as WNT5A in bone metastatic breast cancer cells. In this review, we discuss the recently elucidated mechanisms and their crosstalk with signaling pathways, and potential therapeutic targets for bone metastatic disease.
Highlights
Metastatic Potential and Organ TropismThe metastatic process can be divided into three stages consisting of (1) detachment of cells from the primary tumor, (2) invasion and migration, and (3) the subsequent extravasation from the vasculature and adhesion within the metastatic site to the development of a secondary tumor
Introduction distributed under the terms andMetastatic bone disease (MBD) is a significant cause of patient mortality and poses a substantial challenge to clinicians
While the initial shift is often induced by factors secreted by tumor cells such as RANKL and parathyroid hormone related protein (PTHrP), the resulting degradation of bone releases a substantial supply of insulin like growth factors I and II (IGF-I, IGF-II), TGF-β, platelet derived growth factor (PDGF), and fibroblast growth factor (FGF) along with bone morphogenetic proteins (BMP) and other factors from the extracellular matrix (ECM) which in turn promote tumor growth and development
Summary
The metastatic process can be divided into three stages consisting of (1) detachment of cells from the primary tumor, (2) invasion and migration, and (3) the subsequent extravasation from the vasculature and adhesion within the metastatic site to the development of a secondary tumor. Several animal studies have shown that within 24 h of entry to the circulation only 0.01% of cells are able to complete this process and produce metastatic tumors. It has been suggested that a tumor is composed of a heterogeneous population of cells with varying metastatic potentials, with only a specific subset capable of surviving the three stages mentioned. While the development of specific organotropic clones has helped to elucidate the mechanisms of metastasis, the dynamic nature of tumor cells such as the acquisition of mutations and the genetic instability can shift the behavior of tumor cells leading to potential metastasis [23]
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