title: Fibroblast-led cancer cell invasion is activated by epithelial-mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma.
abstract: Cancer-associated fibroblast (CAF)-dependent local invasion is the process by which cancer cells invade the extracellular matrix using tracks that have been physically remodeled by CAFs. In the present study, we investigated the process by which the epithelial-mesenchymal transition (EMT) of cancer cells affect CAF-dependent local invasion. Using an in vitro collagen invasion assay, we showed cancer cells undergoing EMT to promote the matrix-remodeling ability of CAFs and thereby enhance CAF-dependent local cancer cell invasion. Platelet-derived growth factor (PDGF)-BB secretion was significantly elevated in cancer cells undergoing EMT, and this induced an increase in the invasion ability of both CAFs and cancer cells. Conversely, knockdown of PDGF-B expression in cancer cells undergoing EMT, or treatment with a PDGF-receptor inhibitor, decreased the invasion ability of both CAFs and cancer cells. By analyzing the gene expression profiles of 442 patients with lung adenocarcinomas, we established that high expression of PDGF-B and presentation of mesenchymal-like tumors were significantly associated with a high rate of disease recurrence and poor patient prognosis. Thus, cancer cells undergoing EMT may accelerate their own ability to invade local tissues via PDGF-BB secretion to promote CAF matrix remodeling. Therefore, targeting PDGF signaling between cancer cells undergoing EMT and CAFs is a promising therapeutic target to inhibit cancer progression and improve patient prognosis.
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan. Electronic address: nerithoracsurg@yahoo.co.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Neri
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Miyashita
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Suda
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Ishibashi
authors.affiliation: System Development Section, Development Department, Microscope Solutions Business Unit, Yokohama Plant, Nikon Corporation, 471, Nagaodai-cho, Sakae-ku, Yokohama, Kanagawa, 244-8533, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kii
authors.affiliation: System Development Section, Development Department, Microscope Solutions Business Unit, Yokohama Plant, Nikon Corporation, 471, Nagaodai-cho, Sakae-ku, Yokohama, Kanagawa, 244-8533, Japan.
authors.forename: Hirotada
authors.initials: H
authors.lastname: Watanabe
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kuwata
authors.affiliation: Division of Thoracic Surgery, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Tsuboi
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Toshi
authors.initials: T
authors.lastname: Menju
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sonobe
authors.affiliation: Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, 54 Kawaharacho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Date
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ochiai
authors.affiliation: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1 Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan; Laboratory of Cancer Biology, Department of Integrated Biosciences, Graduate School of Frontier Sciences, The University of Tokyo, 5-1-5 Kashiwanoha, Kashiwa, Chiba, 277-8561, Japan. Electronic address: gishii@east.ncc.go.jp.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
mesh_terms: D000230:Adenocarcinoma / Q000401:mortality / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D000077214:Becaplermin; D000072645:Cancer-Associated Fibroblasts / Q000502:physiology*; D002478:Cells, Cultured; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008175:Lung Neoplasms / Q000401:mortality / Q000473:pathology*; D009361:Neoplasm Invasiveness; D020574:Proto-Oncogene Proteins c-sis / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors; D015398:Signal Transduction
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D000077214:Becaplermin; D017479:Receptors, Platelet-Derived Growth Factor
keywords: Cancer-associated fibroblasts; Epithelial–mesenchymal transition; Extracellular matrix remodeling; Fibroblast-dependent cancer invasion; Platelet-derived growth factor B