Osteosarcoma is an extremely aggressive
bone cancer with poor prognosis. Nε-(1-Carboxymethyl)-L-lysine (CML), an
advanced glycation end product (AGE), can link to
cancer progression,
tumorigenesis and
metastasis, although the underlying mechanism remains unclear. The role of CML in
osteosarcoma progression is still unclear. We hypothesized that CML could promote migration, invasion, and stemness in
osteosarcoma cells. CML and its receptor (RAGE; receptor for AGE) were higher expressed at advanced stages in human
osteosarcoma tissues. In mouse models, which
streptozotocin was administered to induce CML accumulation in the body, the subcutaneous
tumor growth was not affected, but the
tumor metastasis using tail vein injection model was enhanced. In cell models (MG63 and U2OS cells), CML enhanced
tumor sphere formation and acquisition of cancer stem cell characteristics, induced migration and invasion abilities, as well as triggered the epithelial-mesenchymal transition process, which were associated with RAGE expression and activation of downstream signaling pathways, especially the ERK/NFκB pathway. RAGE inhibition elicited CML-induced cell migration, invasion, and stemness through RAGE-mediated ERK/NFκB pathway. These results revealed a crucial role for CML in driving stemness and
metastasis in
osteosarcoma. These findings uncover a potential CML/RAGE connection and mechanism to
osteosarcoma progression and set the stage for further investigation.