Ling Li1, Xinbao Hao2, Jun Qin3, Wenhua Tang4, Fengtian He5, Amber Smith6, Min Zhang5, Diane M Simeone7, Xiaotan T Qiao8, Zhi-Nan Chen9, Theodore S Lawrence5, Liang Xu10. 1. 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. 2. 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. 3. Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, P.R. China. 4. 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. 5. Department of Radiation Oncology, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. 6. Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, Kansas. 7. Department of Surgery, Comprehensive Cancer Center, University of Michigan Medical School, Ann Arbor, Michigan. 8. Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan. 9. 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. 10. 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.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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 humanpancreatic 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 humanpancreatic 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 humanpancreatic 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: James A McCubrey; Linda S Steelman; Stephen L Abrams; Negin Misaghian; William H Chappell; Jorg Basecke; Ferdinando Nicoletti; Massimo Libra; Giovanni Ligresti; Francac Stivala; Danijela Maksimovic-Ivanic; Sanja Mijatovic; Giuseppeo Montalto; Melchiorre Cervello; Piotr Laidler; Antonio Bonati; Camilla Evangelisti; Lucio Cocco; Alberto M Martelli Journal: Curr Pharm Des Date: 2012 Impact factor: 3.116
Authors: Monique C de Jong; Jimmy Pramana; Jacqueline E van der Wal; Martin Lacko; Carine J Peutz-Kootstra; Jos M de Jong; Robert P Takes; Johannes H Kaanders; Bernard F van der Laan; Jasper Wachters; Jeroen C Jansen; Coen R Rasch; Marie-Louise F van Velthuysen; Reidar Grénman; Frank J Hoebers; Ed Schuuring; Michiel W van den Brekel; Adrian C Begg Journal: Clin Cancer Res Date: 2010-09-13 Impact factor: 12.531
Authors: Christine A Iacobuzio-Donahue; Baojin Fu; Shinichi Yachida; Mingde Luo; Hisashi Abe; Clark M Henderson; Felip Vilardell; Zheng Wang; Jesse W Keller; Priya Banerjee; Joseph M Herman; John L Cameron; Charles J Yeo; Marc K Halushka; James R Eshleman; Marian Raben; Alison P Klein; Ralph H Hruban; Manuel Hidalgo; Daniel Laheru Journal: J Clin Oncol Date: 2009-03-09 Impact factor: 44.544
Authors: Chenwei Li; David G Heidt; Piero Dalerba; Charles F Burant; Lanjing Zhang; Volkan Adsay; Max Wicha; Michael F Clarke; Diane M Simeone Journal: Cancer Res Date: 2007-02-01 Impact factor: 12.701
Authors: Lijun Jia; Jie Yang; Xinbao Hao; Min Zheng; Hongbin He; Xiufang Xiong; Liang Xu; Yi Sun Journal: Clin Cancer Res Date: 2010-01-26 Impact factor: 12.531
Authors: Lan Lan; Carl Appelman; Amber R Smith; Jia Yu; Sarah Larsen; Rebecca T Marquez; Hao Liu; Xiaoqing Wu; Philip Gao; Anuradha Roy; Asokan Anbanandam; Ragul Gowthaman; John Karanicolas; Roberto N De Guzman; Steven Rogers; Jeffrey Aubé; Min Ji; Robert S Cohen; Kristi L Neufeld; Liang Xu Journal: Mol Oncol Date: 2015-04-10 Impact factor: 6.603
Authors: Kien Pham; Daniel Delitto; Andrea E Knowlton; Emily R Hartlage; Ricky Madhavan; David H Gonzalo; Ryan M Thomas; Kevin E Behrns; Thomas J George; Steven J Hughes; Shannon M Wallet; Chen Liu; Jose G Trevino Journal: Am J Pathol Date: 2016-04-18 Impact factor: 4.307
Authors: Denisa L Dragu; Laura G Necula; Coralia Bleotu; Carmen C Diaconu; Mihaela Chivu-Economescu Journal: World J Stem Cells Date: 2015-10-26 Impact factor: 5.326
Authors: M Kumazoe; M Takai; J Bae; S Hiroi; Y Huang; K Takamatsu; Y Won; M Yamashita; S Hidaka; S Yamashita; S Yamada; M Murata; S Tsukamoto; H Tachibana Journal: Oncogene Date: 2016-11-28 Impact factor: 9.867