title: TSPAN12 is a critical factor for cancer-fibroblast cell contact-mediated cancer invasion.
abstract: Communication between cancer cells and their microenvironment controls cancer progression. Although the tumor suppressor p53 functions in a cell-autonomous manner, it has also recently been shown to function in a non-cell-autonomous fashion. Although functional defects have been reported in p53 in stromal cells surrounding cancer, including mutations in the p53 gene and decreased p53 expression, the role of p53 in stromal cells during cancer progression remains unclear. We herein show that the expression of α-smooth muscle actin (α-SMA), a marker of cancer-associated fibroblasts (CAFs), was increased by the ablation of p53 in lung fibroblasts. CAFs enhanced the invasion and proliferation of lung cancer cells when cocultured with p53-depleted fibroblasts and required contact between cancer and stromal cells. A comprehensive analysis using a DNA chip revealed that tetraspanin 12 (TSPAN12), which belongs to the tetraspanin protein family, was derepressed by p53 knockdown. TSPAN12 knockdown in p53-depleted fibroblasts inhibited cancer cell proliferation and invasion elicited by coculturing with p53-depleted fibroblasts in vitro, and inhibited tumor growth in vivo. It also decreased CXC chemokine ligand 6 (CXCL6) secretion through the β-catenin signaling pathway, suggesting that cancer cell contact with TSPAN12 in fibroblasts transduced β-catenin signaling into fibroblasts, leading to the secretion of CXCL6 to efficiently promote invasion. These results suggest that stroma-derived p53 plays a pivotal role in epithelial cancer progression and that TSPAN12 and CXCL6 are potential targets for lung cancer therapy.
authors.affiliation: Division of Refractory Cancer Research, Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan;
authors.forename: Ryo
authors.initials: R
authors.lastname: Otomo
authors.affiliation: Graduate School of Medicine, Kobe University, Chuo-ku, Kobe, Hyogo 650-0017, Japan;
authors.forename: Chihiro
authors.initials: C
authors.lastname: Otsubo
authors.affiliation: Division of Refractory Cancer Research.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Matsushima-Hibiya
authors.affiliation: Division of Refractory Cancer Research, Department of Medical Genome Sciences, Laboratory of Tumor Cell Biology, Graduate School of Frontier Sciences, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; and.
authors.forename: Makoto
authors.initials: M
authors.lastname: Miyazaki
authors.affiliation: Department of Biological Science and Technology, Faculty of Industrial Science and Technology, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan;
authors.forename: Fumio
authors.initials: F
authors.lastname: Tashiro
authors.affiliation: Division of Genetics.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ichikawa
authors.affiliation: Division of Genome Biology.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Division of Molecular and Cellular Medicine, and.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
authors.affiliation: Division of Genome Biology.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
authors.affiliation: Division of Cancer Development System, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan;
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Nakagama
authors.affiliation: Cancer Science Institute of Singapore, Centre for Life Sciences, National University of Singapore, 02-07, Singapore 117456.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.affiliation: Division of Refractory Cancer Research, menari@ncc.go.jp.
authors.forename: Masato
authors.initials: M
authors.lastname: Enari
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D054427:Chemokine CXCL6 / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D059470:Tetraspanins / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C515503:CXCL6 protein, human; D054427:Chemokine CXCL6; C495901:TP53 protein, human; C545100:TSPAN12 protein, human; D059470:Tetraspanins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin
keywords: cancer invasion; cancer-associated fibroblasts; cancer–stromal cell interaction; p53; tetraspanin family