title: Sulfasalazine, a therapeutic agent for ulcerative colitis, inhibits the growth of CD44v9(+) cancer stem cells in ulcerative colitis-related cancer.
abstract: OBJECTIVE
  Sulfasalazine reduces the risk of ulcerative colitis (UC)-related cancer through its anti-inflammatory effect and induction of oxidative stress in cancer cells by inhibiting the glutamate-cystine transporter, which is closely associated with the cancer stem cell surface marker CD44v9. This study aimed to quantify the effects of sulfasalazine on CD44v9 expression and pathological factors in colorectal cancers (CRCs) arising from UC.
  
  
  METHODS
  Twenty-six patients with UC-related cancer were classified into groups according to the length of sulfasalazine treatment as follows: (1) long-term (LT) (≥ 5 years) and (2) short-term (ST) (< 5 years). Using immunohistochemistry, we compared CD44v9 and Ki-67 expression and pathological characteristics of each group's tumors. In vitro assay was performed to investigate the effect of sulfasalazine on epithelial differentiation and proliferation of CD44(+) cancer cells.
  
  
  RESULTS
  Immunohistochemical analysis revealed that CD44v9 expression tended to be lower in the LT group (LT:ST=15.4%:46.2%, P=0.20), and Ki-67/CD44v9 double-stained cells were significantly lower in the LT group (LT:ST=0%:6.9%, P=0.01). Pathologically, the frequency of well-differentiated adenocarcinomas was higher in the LT group (LT:ST=84.6%:38.5%, P=0.04). In vitro assay revealed that sulfasalazine promoted the expression of epithelial differentiation markers (E-cadherin and CDX2) and inhibited the proliferation of CD44(+) cancer cells.
  
  
  CONCLUSIONS
  Long-term sulfasalazine administration reduced proliferative CD44v9(+) cells and increased the degree of differentiation of adenocarcinomas. These findings indicate the importance of CD44v9(+) cells in UC-related cancer progression and suggest that sulfasalazine may serve as a novel therapeutic agent that targets CD44v9(+) cells.
authors.affiliation: Department of surgery, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan; Division of gene regulation, institute for advanced medical research, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Seishima
authors.affiliation: Department of surgery, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan. Electronic address: okabayashikoji@gmail.com.
authors.forename: Koji
authors.initials: K
authors.lastname: Okabayashi
authors.affiliation: Division of gene regulation, institute for advanced medical research, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Osamu
authors.initials: O
authors.lastname: Nagano
authors.affiliation: Department of surgery, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Hasegawa
authors.affiliation: Department of surgery, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Tsuruta
authors.affiliation: Department of pathology, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shimoda
authors.affiliation: Department of pathology, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Kaori
authors.initials: K
authors.lastname: Kameyama
authors.affiliation: Division of gene regulation, institute for advanced medical research, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
authors.affiliation: Department of surgery, Keio university school of medicine, 35, Shinano-machi, 1608582 Shinjuku-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000328:Adult; D000368:Aged; D000071616:CDX2 Transcription Factor / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003093:Colitis, Ulcerative / Q000188:drug therapy; D015179:Colorectal Neoplasms / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D005765:Gastrointestinal Agents / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000187:drug effects*; D012333:RNA, Messenger / Q000378:metabolism; D012189:Retrospective Studies; D012460:Sulfasalazine / Q000494:pharmacology*
chemical_list: C497483:CD44 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D015820:Cadherins; D005765:Gastrointestinal Agents; D018960:Hyaluronan Receptors; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D012460:Sulfasalazine