title: Cancer cell invasion driven by extracellular matrix remodeling is dependent on the properties of cancer-associated fibroblasts.
abstract: OBJECTIVE
  As one form of tumor invasion, cancer cells can invade the extracellular matrix (ECM) through tracks that have been physically remodeled by cancer-associated fibroblasts (CAFs). However, CAFs are a heterogeneous population with diverse matrix-remodeling capacities. The purpose of this study was to investigate how CAFs with various matrix-remodeling capacities influence cancer cell invasion.
  
  
  METHODS
  We established single-cell-derived clones from three primary cultures of CAFs from lung adenocarcinoma patients (Case 1, 5 clones; Case 2, 5 clones; and Case 3, 7 clones). Using a co-culture model, we evaluated the correlations between the number of invaded cancer cells and the remodeling areas generated by CAF clones in each case.
  
  
  RESULTS
  When A549 lung adenocarcinoma cells and CAF clones were co-cultured, both the numbers of invaded cancer cells and the remodeling areas generated by the CAF clones varied greatly. The number of invaded cancer cells was moderately and strongly correlated with the remodeling areas generated by each CAF clone originating from Cases 1 and 2 (R(2) value = 0.53 and 0.68, respectively), suggesting that the remodeling areas in the ECM may determine the number of invaded cancer cells. In contrast, the number of invaded cancer cells was not correlated with the remodeling areas generated by CAF clones originating from Case 3, suggesting that factors other than the remodeling areas might determine the number of invading cancer cells.
  
  
  CONCLUSIONS
  These findings showed two types of fibroblast-dependent cancer cell invasion that are dependent on and independent of the remodeling areas generated by CAFs.
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.|Division of Thoracic Oncology, National Cancer Center Hospital East, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, Japan.
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.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hashimoto
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 Cancer Stem Cell, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Kenkichi
authors.initials: K
authors.lastname: Masutomi
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: 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 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: Division of Pathology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, 6-5-1, Kashiwanoha, Kashiwa, Chiba, 277-8577, 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. gishii@east.ncc.go.jp.
authors.forename: Genichiro
authors.initials: G
authors.lastname: Ishii
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology*; D000077192:Adenocarcinoma of Lung; D002450:Cell Communication / Q000502:physiology*; D045744:Cell Line, Tumor; D002999:Clone Cells; D018920:Coculture Techniques; D005109:Extracellular Matrix / Q000473:pathology*; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness; D019098:Telomerase / Q000235:genetics
chemical_list: C509186:TERT protein, human; D019098:Telomerase
keywords: Cancer-associated fibroblasts; Extracellular matrix remodeling; Fibroblast-dependent cancer invasion; Single-cell-derived clones