title: Multikinase inhibitor regorafenib inhibits the growth and metastasis of colon cancer with abundant stroma.
abstract: 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 (CAFs) 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 (MSCs) migrate to tumor stroma and differentiate into CAFs. A novel oral multikinase inhibitor regorafenib inhibits receptor tyrosine kinases expressed on stromal cells (vascular endothelial growth factor receptor 1-3, TIE2, 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 CAFs/MSCs. KM12SM human colon cancer cells alone or KM12SM cells with MSCs were transplanted into the cecal wall of nude mice. Co-implantation of KM12SM cells with MSCs 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 KM12SM cells with MSCs. 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.
authors: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors: Hidehiko
authors: H
authors: Takigawa
authors: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors: Yasuhiko
authors: Y
authors: Kitadai
authors: Department of Endoscopy, Hiroshima Prefectural Hospital, Hiroshima, Japan.
authors: Kei
authors: K
authors: Shinagawa
authors: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors: Ryo
authors: R
authors: Yuge
authors: Department of Cardiovascular Physiology and Medicine, Hiroshima University, Hiroshima, Japan.
authors: Yukihito
authors: Y
authors: Higashi
authors: Department of Endoscopy, Hiroshima University Hospital, Hiroshima, Japan.
authors: Shinji
authors: S
authors: Tanaka
authors: Department of Molecular Pathology, Hiroshima University, Hiroshima, Japan.
authors: Wataru
authors: W
authors: Yasui
authors: Department of Gastroenterology and Metabolism, Hiroshima University, Hiroshima, Japan.
authors: Kazuaki
authors: K
authors: Chayama
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D008207:Lymphatic Metastasis / Q000517:prevention & control; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010671:Phenylurea Compounds / Q000494:pharmacology* / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011725:Pyridines / Q000494:pharmacology* / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D017154:Stromal Cells / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C559147:regorafenib; D020794:Receptor Protein-Tyrosine Kinases
keywords: Colon cancer; mesenchymal stem cells; molecular target therapy; regorafenib; stroma