Dive into the bone: new insights into molecular mechanisms of cancer bone invasion

Cancer-bone interactions have been investigated primarily in the context of bone metastasis. However, hematogenous spread is not the only route by which cancer cells enter the bone. Certain types of cancer, including head and neck squamous cell carcinoma (HNSCC), directly invade the bone tissue because of the close anatomical relationship between the bone and primary lesions. This type of invasion significantly worsens prognosis and quality of life; however, comparatively less attention has been paid to the mechanisms of primary tumor-related bone invasion. A recent study demonstrated that the periosteum thickens in response to the proximity of tumors and functions as a physical barrier against tumor progression. Periosteum thickening occurs at the pre-invasive stage, a key time point that has been overlooked in previous studies, and critically contributes to the inhibition of cancer invasion into the bone. This study provides insights into the mechanisms of localized bone invasion by cancer, highlights the anti-tumor effects of non-immune stromal cells, and offers a new concept of "stromal defense against cancer," extending the horizon of cancer biology. Here, I discuss the tumor-host interactions during multiple steps of cancer invasion into the bone and how the emerging concepts from bone research contribute to the understanding of the pathogenesis and development of new therapeutic strategies for malignancies in the bone and beyond.