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Introduction
The mechanisms that regulate tumor cell dissemination from a primary tumor and the establishment of a metastasis are complex and poorly understood. Metastasis is the leading cause of cancer‐related deaths, but disseminated tumor cells (DTCs) encounter multiple challenges, making metastatic progression a highly inefficient process. Initially, DTCs must survive in the circulation before homing to and colonizing a foreign microenvironment in a distant organ. Upon arrival at the metastatic site, DTCs enter a dormant state for some period, often months to decades, before eventually becoming reactivated and developing into an overt metastasis. An extensive body of clinical and experimental research supports Stephen Paget's “seed and soil” hypothesis that proposed tumor cells preferentially metastasize to particular secondary sites. This nonrandom tumor cell distribution, referred to as metastatic organotropism, is likely facilitated in part by blood flow dynamics, but most prominently by the fertile “soil” at distant sites.
Metastasis to the bone occurs in approximately 60% of patients with metastatic breast or prostate cancer and to a lesser extent in other cancers, including lung and melanoma. The bone microenvironment provides a uniquely fertile soil for the homing of DTCs for several reasons. First, the bone marrow houses numerous cell types implicated in metastatic progression, including hematopoietic and mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts, and the bone matrix itself provides a rich source of growth factors and cytokines. Second, the bone marrow is the primary site for hematopoietic stem cell (HSC) maintenance and contains two specialized niches: the endosteal “osteoblastic” niche and the perivascular niche. These niches are established and maintained by systemic signals and HSC interaction with resident cells, including osteoblasts and endothelial cells. Finally, the vasculature of the bone marrow results in varying oxygen levels ranging from <1% to 6% throughout the bone marrow, making the bone a particularly hypoxic tissue. Thus, the bone marrow provides an ideal microenvironment for metastasis and ample opportunities for DTCs to co‐opt these physiological niches to promote their own survival and outgrowth.
Genetic Drivers of Bone Metastasis
Metastatic progression has traditionally been thought of as a late event that occurs following numerous genetic or epigenetic aberrations; however, recent literature suggests that dissemination can occur early in tumor progression. Currently, two fundamental models of metastatic progression exist:...