There are two non-immune mechanisms by which MSCs promote osteosarcoma cell proliferation and metastasis: first, the interaction between osteosarcoma cells and MSCs involving IL8 and aquaporin 1; second, abnormal gene expression, such as Rb, C-MYC, TP53, K-Ras, and IHH promote the transformation of MSCs into osteosarcoma cells (120–125). Here, IHH is linked to osteosarcoma.