title: RETRACTED: CD44 expression denotes a subpopulation of gastric cancer cells in which Hedgehog signaling promotes chemotherapy resistance.
abstract: Gastric cancers may harbor a subset of cells with cancer stem cell (CSC) properties, including chemotherapy resistance, and CD44 is a gastric CSC marker. The Hedgehog (HH) pathway is a key developmental pathway that can be subverted by CSCs during tumorigenesis. Here, we examine the role of HH signaling in CD44(+) gastric cancer cells.
  
  
  
  Gastric cancer cell lines, tumor xenografts, and patient tumors were examined.
  
  
  
  Gastric cancer cell lines AGS, MKN-45, and NCI-N87 grown as spheroids or sorted for CD44(+) were found to have upregulation of HH pathway proteins. HH inhibition using Smoothened (Smo) shRNA or vismodegib (VIS) decreased spheroid formation and colony formation. CD44(+) cells, compared with unselected cells, were also resistant to 5-fluorouracil and cisplatin chemotherapy, and this resistance was reversed in vitro and in xenografts with Smo shRNA or VIS. CD44(+) cells also had significantly more migration, invasion, and anchorage-independent growth, and these properties could all be blocked with HH inhibition. Clinical tumor samples from a phase II trial of chemotherapy with or without VIS for advanced gastric cancer were analyzed for CD44 expression. In the chemotherapy alone group, high CD44 expression was associated with decreased survival, whereas in the chemotherapy plus VIS group, high CD44 expression was associated with improved survival.
  
  
  
  HH signaling maintains CSC phenotypes and malignant transformation phenotypes in CD44(+) gastric cancer cells, and HH inhibition can reverse chemotherapy resistance in CD44(+) cells. Gastric cancer is a heterogeneous disease, and the strategy of combining chemotherapy with HH inhibition may only be effective in tumors with high CD44 levels.
authors.affiliation: Departments of Surgery and.
authors.forename: Changhwan
authors.initials: C
authors.lastname: Yoon
authors.affiliation: Departments of Surgery and.
authors.forename: Do Joong
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; and.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: Departments of Surgery and.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Thomas
authors.affiliation: Departments of Surgery and Division of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Hae-June
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Departments of Surgery and.
authors.forename: Teresa S
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Medicine, Memorial Sloan-Kettering Cancer Center;
authors.forename: Yelena Y
authors.initials: YY
authors.lastname: Janjigian
authors.affiliation: Department of Medicine, New York University Medical Center, New York, New York;
authors.forename: Deirdre J
authors.initials: DJ
authors.lastname: Cohen
authors.affiliation: Departments of Surgery and yoons@mskcc.org.
authors.forename: Sam S
authors.initials: SS
authors.lastname: Yoon
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000813:Anilides / Q000008:administration & dosage; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D019008:Drug Resistance, Neoplasm; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil / Q000008:administration & dosage; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D002955:Leucovorin / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology*; D011379:Prognosis; D011725:Pyridines / Q000008:administration & dosage; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D018874:Spheroids, Cellular / Q000187:drug effects; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D053823:Hedgehog Proteins; C538724:HhAntag691; D018960:Hyaluronan Receptors; D011725:Pyridines; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; D002945:Cisplatin; D002955:Leucovorin; D005472:Fluorouracil