SPP1 and cancer: They also secrete factors that enhance bone resorption, such as lysyl oxidase (LOX), a collagen crosslinking enzyme produced primarily by hypoxic ER− cancer cells, parathyroid hormone-related peptide (PTHrP), osteopontin (OPN) and CC-chemokine ligand (CCL)-2, directly promoting bone resorption and extracellular matrix (ECM) remodeling, making the niche more permissive to DTCs [85].