Abstract
Pancreatic cancer is a devastating disease that usually presents at a late stage that is not amenable to curative treatments. It is notoriously resistant to chemotherapy and radiation, and it is clear that new treatment strategies are needed to positively impact the dismal outcomes associated with this disease. While the initial dogma of tumor biology viewed all tumor cells as equal, recent findings in the field have lead to the discovery of heterogeneous populations of tumor cells, first in blood-borne derived cancers and now within multiple solid tumor organ systems that display a differential ability to repopulate the original tumor. Conceptualized from this finding was the stem-cell hypothesis for cancer, which suggests that only a specific subset of cancer cells within each tumor is responsible for tumor initiation and propagation, termed tumor initiating cells or cancer stem cells (CSCs). By using specific cell surface marker analysis, we have identified distinct populations of tumor cells from primary pancreatic adenocarcinomas that express the surface markers CD44, CD24, and ESA, which are responsible for the initiation of new tumor growth and exhibit characteristics that support the CSC hypothesis. The identification of these cells has opened up an exciting new paradigm on how we might view and devise new patient treatments for this devastating disease. Current investigations of these pancreatic CSCs have identified such signaling pathways as the Hedgehog and BMI-1 signaling pathways which are aberrantly regulated in this select population of cells. Further study of these CSCs and the important signaling pathways that control their function will provide us with powerful information on targeting new therapies to improve patient outcomes.
This is a preview of subscription content, log in via an institution to check access.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
REFERENCES
Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin 2007;57:43–66.
Niederhuber JE, Brennan MF, Menck HR. The National Cancer Data Base report on pancreatic cancer. Cancer 1995;76:1671–7.
Carriere C, Seeley ES, Goetze T, Longnecker DS, Korc M. The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia. Proc Natl Acad Sci USA 2007;104:4437–42.
Grippo PJ, Nowlin PS, Demeure MJ, Longnecker DS, Sandgren EP. Preinvasive pancreatic neoplasia of ductal phenotype induced by acinar cell targeting of mutant Kras in transgenic mice. Cancer Res 2003;63:2016–9.
Stanger BZ, Stiles B, Lauwers GY, et al Pten constrains centroacinar cell expansion and malignant transformation in the pancreas. Cancer Cell 2005;8:185–95.
Jensen JN, Cameron E, Garay MV, Starkey TW, Gianani R, Jensen J. Recapitulation of elements of embryonic development in adult mouse pancreatic regeneration. Gastroenterology 2005;128:728–41.
Bonner-Weir S, Taneja M, Weir GC, et al In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000;97:7999–8004.
Kleeff J, Beckhove P, Esposito I, et al Pancreatic cancer microenvironment. Int J Cancer 2007;121:699–705.
Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE. Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod Pathol 2002;15:441–7.
Hingorani SR, Petricoin EF, Maitra A, et al Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 2003;4:437–50.
Pasca di Magliano M, Hebrok M. Hedgehog signalling in cancer formation and maintenance. Nat Rev Cancer 2003;3:903–11.
Thayer SP, di Magliano MP, Heiser PW, et al Hedgehog is an early and late mediator of pancreatic cancer tumorigenesis. Nature 2003;425:851–6.
Pasca di Magliano M, Sekine S, Ermilov A, Ferris J, Dlugosz AA, Hebrok M. Hedgehog/Ras interactions regulate early stages of pancreatic cancer. Genes Dev 2006;20:3161–73.
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.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003;100:3983–8.
Li C, Heidt DG, Dalerba P, et al Identification of pancreatic cancer stem cells. Cancer Res 2007;67:1030–7.
O’Brien CA, Pollett A, Gallinger S, Dick JE. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007;445:106–10.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, et al Identification and expansion of human colon-cancer-initiating cells. Nature 2007;445:111–5.
Singh SK, Hawkins C, Clarke ID, et al Identification of human brain tumour initiating cells. Nature 2004;432:396–401.
Sugiyama T, Rodriguez RT, McLean GW, Kim SK. Conserved markers of fetal pancreatic epithelium permit prospective isolation of islet progenitor cells by FACS. Proc Natl Acad Sci USA 2007;104:175–80.
Hermann PC, Huber SL, Herrler T, et al Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 2007;1:313–23.
Fallon P, Gentry T, Balber AE, et al Mobilized peripheral blood SSCloALDHbr cells have the phenotypic and functional properties of primitive haematopoietic cells and their number correlates with engraftment following autologous transplantation. Br J Haematol 2003;122:99–108.
Corti S, Locatelli F, Papadimitriou D, et al Identification of a primitive brain-derived neural stem cell population based on aldehyde dehydrogenase activity. Stem Cells 2006;24:975–85.
Ginestier C, Hur MH, Charafe-Jauffret E, et al ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007;1:555–67.
Feldmann G, Dhara S, Fendrich V, et al Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res 2007;67:2187–96.
Yuan X, Curtin J, Xiong Y, et al Isolation of cancer stem cells from adult glioblastoma multiforme. Oncogene 2004;23:9392–400.
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.
Bhardwaj G, Murdoch B, Wu D, et al Sonic hedgehog induces the proliferation of primitive human hematopoietic cells via BMP regulation. Nat Immunol 2001;2:172–80.
Ahn S, Joyner AL. In vivo analysis of quiescent adult neural stem cells responding to Sonic hedgehog. Nature 2005;437:894–7.
Paladini RD, Saleh J, Qian C, Xu GX, Rubin LL. Modulation of hair growth with small molecule agonists of the hedgehog signaling pathway. J Invest Dermatol 2005;125:638–46.
van der Lugt NM, Domen J, Linders K, et al Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes Dev 1994;8:757–69.
Molofsky AV, Pardal R, Iwashita T, Park IK, Clarke MF, Morrison SJ. BMI-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 2003;425:962–7.
Yang J, Mani SA, Donaher JL, et al Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 2004;117:927–39.
Barbera MJ, Puig I, Dominguez D, et al Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells. Oncogene 2004;23:7345–54.
Hajra KM, Chen DY, Fearon ER. The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Res 2002;62:1613–8.
Mani SA, Guo W, Liao MJ, et al The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008;133:704–15.
Ishikawa F, Yoshida S, Saito Y, et al Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007;25:1315–21.
Singh SK, Clarke ID, Terasaki M, et al Identification of a cancer stem cell in human brain tumors. Cancer Res 2003;63:5821–8.
Bao S, Wu Q, McLendon RE, et al Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 2006;444:756–60.
Tuxhorn JA, Ayala GE, Rowley DR. Reactive stroma in prostate cancer progression. J Urol 2001;166:2472–83.
Garber K. Notch emerges as new cancer drug target. J Natl Cancer Inst 2007;99:1284–5.
Balic M, Lin H, Young L, et al Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin Cancer Res 2006;12:5615–21.
Zheng S, Lin H, Liu J Q, et al Membrane microfilter device for selective capture, electrolysis and genomic analysis of human circulating tumor cells. J Chromatogr A 2007;1162:154–61.
Nagrath S, Sequist LV, Maheswaran S, et al Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 2007;450:1235–9.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Humana Press, a part of Springer Science+Business Media, LLC
About this chapter
Cite this chapter
Dosch, J., Lee, C.J., Simeone, D.M. (2009). Cancer Stem Cells: Pancreatic Cancer. In: Teicher, B., Bagley, R. (eds) Stem Cells and Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-60327-933-8_15
Download citation
DOI: https://doi.org/10.1007/978-1-60327-933-8_15
Published:
Publisher Name: Humana Press
Print ISBN: 978-1-60327-932-1
Online ISBN: 978-1-60327-933-8
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)