Bone marrow-derived mesenchymal stem cells (BMSCs) can be recruited to tumor sites and integrate into the stroma of tumors. When co-cultured with BMSCs, otherwise weakly metastatic nasopharyngeal carcinoma cells (NPC) showed improved metastatic ability. BMSCs in the tumor environment displayed the characteristics of macrophages. Nitric oxide produced by BMSCs in tumor environment could translocate caldesmon to podosome in Ca2+/calmodulin manner and promoted metastatic ability of NPC cells through invadopodia formation, with which the NPC cells degrade the extracellular matrix. Thus, we concluded that the BMSCs promoted cell migration and invasion through nitric oxide-induced paracrine signals.