Colorectal Cancer Progression and Bone Metastasis: Molecular Mechanisms, Tumor Microenvironment, and Tumor-Bone...

Colorectal cancer (CRC) ranks as the third most common malignancy globally and represents one of the main causes of cancer-related death. This narrative review provides a comprehensive synthesis of recent advances in the molecular mechanisms underlying CRC bone metastasis, with an emphasis on key signaling pathways, tumor microenvironment interactions, and potential therapeutic targets. Bone is a relatively uncommon metastatic site in advanced CRC (1.2-12% of patients), but it frequently coexists with hepatic or pulmonary metastases and triggers skeletal-related events (SREs) such as pathological fractures, spinal cord compression, and hypercalcemia, which severely compromise patients' quality of life and survival. Although the molecular mechanisms of CRC and its bone metastasis have been extensively studied, the exact mechanisms underlying its initiation and progression remain incompletely elucidated. Here, we review recent progress focusing on TGF-β signaling, epithelial-mesenchymal transition (EMT), the tumor microenvironment (TME), the Wnt/β-catenin pathway, chemokine regulation, and immune cell interactions within the bone niche. Unlike previous reviews, this article critically distinguishes CRC-specific evidence from data extrapolated from other cancers and provides an evidence-level table to guide clinical translation. By integrating clinical, translational, and preclinical evidence, we aim to present a theoretical basis for understanding CRC bone metastasis and for developing targeted therapeutic strategies.