**2. Mechanism of bone metastases**

During metastatic dissemination, cancer cells from the primary tumor must first undergo epithelial-to-mesenchymal transition (EMT) to invade the surrounding tissue and enter the microvasculature (intravasation) of the blood and/or lymphatic systems. Once in the bloodstream, cancer cells may disseminate to distant organs, exit from blood vessels (extravasation), and settle in the foreign microenvironment, where they enter a dormant state or proliferate to subsequently form macroscopic secondary tumors (metastases) [7].

In the skeleton, the process of metastasis development begins with colonization, when circulating tumor cells enter the bone marrow and engage in specialized microenvironments or niches. Then, the colonizing tumor cells adapt to their new microenvironment, evade the immune system, and may reside in a dormant state for a long period of time until they reactivate and develop, escaping from the dormant state to actively proliferate and form micrometastases. With uncontrollable growth, the cancer cells become independent of the microenvironment and end up modifying the bone as metastases develop.
