title: Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice.
abstract: OBJECTIVE
  CD44s is a surface marker of tumor-initiating cells (TICs); high tumor levels correlate with metastasis and recurrence, as well as poor outcomes for patients. Monoclonal antibodies against CD44s might eliminate TICs with minimal toxicity. This strategy is unclear for treatment of pancreatic cancer, and little is known about how anti-CD44s affect pancreatic cancer initiation or recurrence after radiotherapy.
  
  
  METHODS
  One hundred ninety-two pairs of human pancreatic adenocarcinoma and adjacent nontumor pancreatic tissues were collected from patients undergoing surgery. We measured CD44s levels in tissue samples and pancreatic cancer cell lines by immunohistochemistry, real-time polymerase chain reaction, and immunoblot; levels were correlated with patient survival times. We studied the effects of anti-CD44s in mice with human pancreatic tumor xenografts and used flow cytometry to determine the effects on TICs. Changes in CD44s signaling were examined by real-time polymerase chain reaction, immunoblot, reporter assay, and in vitro tumorsphere formation assays.
  
  
  RESULTS
  Levels of CD44s were significantly higher in pancreatic cancer than adjacent nontumor tissues. Patients whose tumors expressed high levels of CD44s had a median survival of 10 months compared with >43 months for those with low levels. Anti-CD44s reduced growth, metastasis, and postradiation recurrence of pancreatic xenograft tumors in mice. The antibody reduced the number of TICs in cultured pancreatic cancer cells and xenograft tumors, as well as their tumorigenicity. In cultured pancreatic cancer cell lines, anti-CD44s down-regulated the stem cell self-renewal genes Nanog, Sox-2, and Rex-1 and inhibited signal transducer and activator of transcription 3-mediated cell proliferation and survival signaling.
  
  
  CONCLUSIONS
  The TIC marker CD44s is up-regulated in human pancreatic tumors and associated with patient survival time. CD44s is required for initiation, growth, metastasis, and postradiation recurrence of xenograft tumors in mice. Anti-CD44s eliminated bulk tumor cells as well as TICs from the tumors. Strategies to target CD44s cab be developed to block pancreatic tumor formation and post-radiotherapy recurrence in patients.
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Department of Hematology/Oncology, Hainan Medical College Hospital, Haikou, Hainan, P.R. China.
authors.forename: Xinbao
authors.initials: X
authors.lastname: Hao
authors.affiliation: Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China.
authors.forename: Jun
authors.initials: J
authors.lastname: Qin
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Tang
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
authors.affiliation: Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas.
authors.forename: Amber
authors.initials: A
authors.lastname: Smith
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Min
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Diane M
authors.initials: DM
authors.lastname: Simeone
authors.affiliation: Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan.
authors.forename: Xiaotan T
authors.initials: XT
authors.lastname: Qiao
authors.affiliation: Cell Engineering Research Centre and Department of Cell Biology, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China. Electronic address: znchen@fmmu.edu.cn.
authors.forename: Zhi-Nan
authors.initials: ZN
authors.lastname: Chen
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.affiliation: Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan; Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas. Electronic address: xul@ku.edu.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000556:secondary / Q000628:therapy*; D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D051379:Mice; D008819:Mice, Nude; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000906:Antibodies; D014408:Biomarkers, Tumor; C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D014157:Transcription Factors
keywords: Cancer Stem Cell; H4C4; Progression; Tumorigenesis