Identification of Pancreatic Cancer Stem Cells

Cancer Research - Tập 67 Số 3 - Trang 1030-1037 - 2007
Chenwei Li1, David G. Heidt1, Piero Dalerba2, Charles Burant3,4, Lanjing Zhang4, Volkan Adsay2, Max S. Wicha4, Michael F. Clarke5, Diane M. Simeone1,3
11Surgery, Departments of
24Department of Pathology, Karmanos Cancer Center, Detroit, Michigan; and
32Molecular and Integrative Physiology, and
43Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan;
55Department of Internal Medicine, Stanford University School of Medicine, Palo Alto, California

Tóm tắt

Abstract Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells within a tumor, termed cancer stem cells. Although data have been provided to support this theory in human blood, brain, and breast cancers, the identity of pancreatic cancer stem cells has not been determined. Using a xenograft model in which primary human pancreatic adenocarcinomas were grown in immunocompromised mice, we identified a highly tumorigenic subpopulation of pancreatic cancer cells expressing the cell surface markers CD44, CD24, and epithelial-specific antigen (ESA). Pancreatic cancer cells with the CD44+CD24+ESA+ phenotype (0.2–0.8% of pancreatic cancer cells) had a 100-fold increased tumorigenic potential compared with nontumorigenic cancer cells, with 50% of animals injected with as few as 100 CD44+CD24+ESA+ cells forming tumors that were histologically indistinguishable from the human tumors from which they originated. The enhanced ability of CD44+CD24+ESA+ pancreatic cancer cells to form tumors was confirmed in an orthotopic pancreatic tail injection model. The CD44+CD24+ESA+ pancreatic cancer cells showed the stem cell properties of self-renewal, the ability to produce differentiated progeny, and increased expression of the developmental signaling molecule sonic hedgehog. Identification of pancreatic cancer stem cells and further elucidation of the signaling pathways that regulate their growth and survival may provide novel therapeutic approaches to treat pancreatic cancer, which is notoriously resistant to standard chemotherapy and radiation. [Cancer Res 2007;67(3):1030–7]

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Tài liệu tham khảo

Hoyert DL, Heron MP, Murphy SL, Kung HC. Deaths: final data for 2003. Natl Vital Stat Rep 2006; 19: 1–120.

Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature 2001; 414: 105–11.

Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–7.

Lapidot T, Sirard C, Vormoor J, et al. A cell initiating human acute myeloid leukemia after transplantation into SCID mice. Nature 1994; 17: 645–8.

Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci U S A 2003; 100: 3983–8.

Singh SK, Hawkins C, Clarke ID, et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.

Galli R, Binda E, Orfanelli U, et al. Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma. Cancer Res 2004; 64: 7011–21.

Hemmati HD, Nakano I, Lazareff JA, et al. Cancerous stem cells arise from pediatric brain tumors. Proc Natl Acad Sci U S A 2003; 100: 15178–83.

Patrawala L, Calhoun T, Schneider-Broussard R, et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006; 25: 1696–708.

Szotek PP, Pieretti-Vanmarcke R, Masiakos PT, et al. Ovarian cancer side population defines cells with stem cell-like characteristics and Mullerian inhibiting substance responsiveness. Proc Natl Acad Sci U S A 2006; 103: 11154–9.

Costello RT, Mallet F, Gaugler B, et al. Human acute myeloid leukemia CD34+/CD38− progenitor cells have decreased sensitivity to chemotherapy and Fas induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities. Cancer Res 2000; 60: 4403–11.

Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5: 274–84.

Guzman ML, Swiderski CF, Howard DS, et al. Preferential induction of apoptosis for primary human leukemic stem cells. Proc Natl Acad Sci U S A 2002; 99: 16220–5.

Arumugam T, Simeone DM, Van Golen K, Logsdon CD. S100P promotes pancreatic cancer growth, survival, and invasion. Clin Cancer Res 2005; 11: 5356–64.

Logsdon CD, Simeone DM, Binkley C, et al. Molecular profiling of pancreatic adenocarcinoma and chronic pancreatitis identifies multiple genes differentially regulated in pancreatic cancer. Cancer Res 2003; 63: 2649–57.

Hahn SA, Seymour AB, Hoque AT, et al. Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res 1995; 55: 4670–5.

Litvinov SV, Velders MP, Bakker HA, Fleuren GJ, Warnaar SO. Ep-CAM: a human epithelial antigen is a homophilic cell-cell adhesion molecule. J Cell Biol 1994; 125: 437–46.

Ponta H, Sherman L, Herrlich PA. CD44: from adhesion molecules to signalling regulators. Nat Rev Mol Cell 2003; 4: 33–45.

Weichert W, Denkert C, Burkhardt M, et al. Cytoplasmic CD24 expression in colorectal cancer independently correlates with shortened patient survival. Clin Cancer Res 2005; 11: 6574–81.

Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res 2006; 66: 4553–7.

Liu S, Dontu G, Mantle ID, et al. Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 2006; 66: 6063–71.

Park I-K, Morrison SJ, Clarke MF. Bmi1, stem cells, and senescence regulation. J Clin Invest 2004; 113: 175–9.

Androutsellis-Theotokis A, Leker RR, Soldner F, et al. Notch signaling regulates stem cell numbers in vitro and in vivo. Nature 2006; 442: 823–6.

Lie DC, Colamarino SA, Song HJ, et al. Wnt signaling regulates adult hippocampal neurogenesis. Nature 2005; 437: 1370–5.

Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes hematopoietic stem cells from leukemia-initiating cells. Nature 2006;441:475–82.

Ayyanan A, Civenni G, Ciarloni L, et al. Increased Wnt signaling triggers oncogenic conversion of human breast epithelial cells by a Notch dependent mechanism. Proc Natl Acad Sci U S A 2006; 103: 3799–804.

Pasca di Magliano M, Hebrok M. Hedgehog signaling in cancer formation and maintenance. Nat Rev Cancer 2003; 3: 903–11.

Thayer SP, Pasca di Magliano M, Heiser PW, et al. Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003; 425: 851–6.

Berman DM, Karhadkar SS, Maitra A, et al. Widespread requirement for hedgehog ligand stimulation in growth of digestive tract tumours. Nature 2003; 425: 846–51.

Singh SK, Clarke ID, Terasaki M, et al. Identification of a cancer stem cell in human brain tumors. Cancer Res 2003; 63: 5821–8.

Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins, AT. CD133, a novel marker for human prostate epithelial stem cells. J Cell Sci 2004; 117: 3539–45.

Fang D, Nguyen TK, Leishear K, et al. A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 2005; 65: 9328–37.

Matsui W, Huff CA, Wang Q, et al. Characterization of clonagenic multiple myeloma cells. Blood 2004; 103: 2332–6.

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Thông tin xuất bản

Cancer Research

Tập 67 Số 3

1030-1037

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