Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma

Interaction between tumor cells and stromal cells plays an important role in the growth and metastasis of colon cancer. We previously found that carcinoma‐associated fibroblasts ( CAF s) expressed platelet‐derived growth factor receptor‐β ( PDGFR ‐β) and that PDGFR targeted therapy using imatinib or nilotinib inhibited stromal reaction. Bone marrow‐derived mesenchymal stem cells ( MSC s) migrate to tumor stroma and differentiate into CAF s. A novel oral multikinase inhibitor regorafenib inhibits receptor tyrosine kinases expressed on stromal cells (vascular endothelial growth factor receptor 1–3, TIE 2, PDGFR ‐β, and fibroblast growth factors) and tumor cells (c‐ KIT , RET , and BRAF ). These molecules are involved in tumor growth, angiogenesis, lymphangiogenesis, and stromal activation. Therefore, we examined whether regorafenib impaired the tumor‐promoting effect of CAF s/ MSC s. KM 12 SM human colon cancer cells alone or KM 12 SM cells with MSC s were transplanted into the cecal wall of nude mice. Co‐implantation of KM 12 SM cells with MSC s into the cecal wall of nude mice produced tumors with abundant stromal component and promoted tumor growth and lymph node metastasis. Single treatment with regorafenib inhibited tumor growth and metastasis by inhibiting both tumor cells and stromal reaction. This tumor‐inhibitory effect of regorafenib was more obvious in tumors developed by co‐implanting KM 12 SM cells with MSC s. Our data suggested that targeting of the tumor microenvironment with regorafenib affected tumor cell– MSC interaction, which in turn inhibited the growth and metastasis of colon cancer.