Cutting to the core: Proteases in the tumor-bone interface and metastatic progression

Proteases are critical modulators of cancer progression, with matrix metalloproteinases (MMPs) and cathepsins playing central roles in the development and metastasis of breast and prostate cancers. These enzymes degrade and remodel the extracellular matrix, facilitating tumor-stromal interactions and promoting epithelial-to-mesenchymal transition, thereby enhancing tumor invasiveness. Beyond the primary tumor site, proteases contribute to multiple steps of the metastatic cascade, including intravasation, immune evasion, and extravasation. Importantly, MMPs and cathepsins also drive osteolytic activity that supports tumor colonization and growth in the bone microenvironment by activating osteoclasts, releasing matrix-bound growth factors, and perpetuating a vicious cycle of bone destruction. Given their multifaceted roles, MMPs and cathepsins represent promising therapeutic targets in bone-metastatic breast and prostate cancers.