Kyoko Yamaguchi1, Tomoyasu Yoshihiro1, Hiroshi Ariyama2, Mamoru Ito1, Michitaka Nakano1, Yuichiro Semba1, Jumpei Nogami1, Kenji Tsuchihashi1, Takuji Yamauchi1, Shohei Ueno1, Taichi Isobe3, Koji Shindo4, Taiki Moriyama4, Kenoki Ohuchida4, Masafumi Nakamura4, Yoshihiro Nagao5,6, Tetsuo Ikeda5, Makoto Hashizume5, Hiroyuki Konomi7, Takehiro Torisu8, Takanari Kitazono8, Tomohiro Kanayama9, Hiroyuki Tomita9, Yoshinao Oda10, Hitoshi Kusaba1, Takahiro Maeda1, Koichi Akashi1, Eishi Baba3. 1. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 2. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. ariyama.hiroshi.915@m.kyushu-u.ac.jp. 3. Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 4. Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 5. Department of Advanced Medicine and Innovative Technology, Kyushu University Hospital, Fukuoka, Japan. 6. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 7. Department of Surgery, Hamanomachi Hospital, Fukuoka, Japan. 8. Department of Medicine and Clinical Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 9. Department of Tumor Pathology, Graduate School of Medicine, Gifu University, Gifu, Japan. 10. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract
BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.
BACKGROUND: Loss of E-cadherin expression is frequently observed in signet ring carcinoma (SRCC). People with germline mutations in CDH1, which encodes E-cadherin, develop diffuse gastric cancer at a higher rate. Loss of E-cadherin expression is thus assumed to trigger oncogenic development. METHODS: To investigate novel therapeutic targets for gastric SRCC, we engineered an E-cadherin-deficient SRCC model in vitro using a human gastric organoid (hGO) with CDH1 knockout (KO). RESULTS: CDH1 KO hGO cells demonstrated distinctive morphological changes similar to SRCC and high cell motility. RNA-sequencing revealed up-regulation of matrix metalloproteinase (MMP) genes in CDH1 KO hGO cells compared to wild type. MMP inhibitors suppressed cell motility of CDH1 KO hGO cells and SRCC cell lines in vitro. Immunofluorescent analysis with 95 clinical gastric cancer tissues revealed that MMP-3 was specifically abundant in E-cadherin-aberrant SRCC. In addition, CXCR4 molecules translocated onto the cell membrane after CDH1 KO. Addition of CXCL12, a ligand of CXCR4, to the culture medium prolonged cell survival of CDH1 KO hGO cells and was abolished by the inhibitor, AMD3100. In clinical SRCC samples, CXCL12-secreting fibroblasts showed marked infiltration into the cancer area. CONCLUSIONS: E-cadherin deficient SRCCs might gain cell motility through upregulation of MMPs. CXCL12-positive cancer-associated fibroblasts could serve to maintain cancer-cell survival as a niche. MMPs and the CXCL12/CXCR4 axis represent promising candidates as novel therapeutic targets for E-cadherin-deficient SRCC.
Authors: Eric Van Cutsem; Vladimir M Moiseyenko; Sergei Tjulandin; Alejandro Majlis; Manuel Constenla; Corrado Boni; Adriano Rodrigues; Miguel Fodor; Yee Chao; Edouard Voznyi; Marie-Laure Risse; Jaffer A Ajani Journal: J Clin Oncol Date: 2006-11-01 Impact factor: 44.544
Authors: William M Rogers; Erika Dobo; Jeffrey A Norton; Jacques Van Dam; R Brooke Jeffrey; David G Huntsman; Kerry Kingham; Nicki Chun; James M Ford; Teri A Longacre Journal: Am J Surg Pathol Date: 2008-06 Impact factor: 6.394
Authors: C Mariette; F Carneiro; H I Grabsch; R S van der Post; W Allum; Giovanni de Manzoni Journal: Gastric Cancer Date: 2018-08-25 Impact factor: 7.370