title: Antitumor activity of the MEK inhibitor trametinib on intestinal polyp formation in Apc(Δ716) mice involves stromal COX-2.
abstract: Extracellular signal-regulated kinase is an MAPK that is most closely associated with cell proliferation, and the MEK/ERK signaling pathway is implicated in various human cancers. Although epidermal growth factor receptor, KRAS, and BRAF are considered major targets for colon cancer treatment, the precise roles of the MEK/ERK pathway, one of their major downstream effectors, during colon cancer development remain to be determined. Using Apc(Δ716) mice, a mouse model of familial adenomatous polyposis and early-stage sporadic colon cancer formation, we show that MEK/ERK signaling is activated not only in adenoma epithelial cells, but also in tumor stromal cells including fibroblasts and vascular endothelial cells. Eight-week treatment of Apc(Δ716) mice with trametinib, a small-molecule MEK inhibitor, significantly reduced the number of polyps in the large size class, accompanied by reduced angiogenesis and tumor cell proliferation. Trametinib treatment reduced the COX-2 level in Apc(Δ716) tumors in vivo and in primary culture of intestinal fibroblasts in vitro. Antibody array analysis revealed that trametinib and the COX-2 inhibitor rofecoxib both reduced the level of CCL2, a chemokine known to be essential for the growth of Apc mutant polyps, in intestinal fibroblasts in vitro. Consistently, trametinib treatment reduced the Ccl2 mRNA level in Apc(Δ716) tumors in vivo. These results suggest that MEK/ERK signaling plays key roles in intestinal adenoma formation in Apc(Δ716) mice, at least in part, through COX-2 induction in tumor stromal cells.
authors: Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors: Teruaki
authors: T
authors: Fujishita
authors: Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors: Rie
authors: R
authors: Kajino-Sakamoto
authors: Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors: Yasushi
authors: Y
authors: Kojima
authors: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors: Makoto Mark
authors: MM
authors: Taketo
authors: Division of Molecular Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
authors: Masahiro
authors: M
authors: Aoki
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000032:analysis / Q000235:genetics; D051546:Cyclooxygenase 2 / Q000032:analysis*; D004195:Disease Models, Animal; D005260:Female; D017491:Genes, APC / Q000502:physiology*; D007417:Intestinal Polyps / Q000188:drug therapy* / Q000201:enzymology; D008297:Male; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D020929:Mitogen-Activated Protein Kinase Kinases
keywords: Adenomatous polyposis coli; chemokine CCL2; colorectal neoplasms; cyclooxygenase 2; extracellular signal-regulated MAP kinases