Given the unique physicochemical properties and cytokine milieu of the bone and bone marrow microenvironment—characterized by hypoxia [26], high extracellular calcium levels [27], abundant matrix proteins such as collagen [28] and osteopontin [29], and soluble factors like TGF-β, CXCL12, and RANKL [8]—in vivo circulation selection enables effective isolation and enrichment of tumor subpopulations with a propensity for bone metastasis. The gene discussed is SPP1; the disease is neoplasm.