Pancreatic cancer (PC) is one of the most lethal malignant tumors, which often result from diagnoses of advanced stages and ineffective therapies. A main reason for this extremely poor prognosis is the cancer’s tendency to invade adjacent tissues and metastasize to regional lymph at a relatively early stage. Nowadays, the resistance to conventional chemotherapy is becoming crucial in poor clinical outcomes of PC. In order to improve the prognosis and clinical outcomes of PC, there is a pressing need to develop new therapeutic strategies not only aimed at preventing invasion and metastasis, but also improving the resistance of chemotherapies. The resistance to conventional therapeutic agents in cancer may be sustained by a fraction of cancer cells within the tumor, which is called the cancer stem cells (CSCs). Combined therapies targeting CSCs and their progenies may represent the most promising approach for the future treatment of patients with PC.
Bethesda, M.D. SEER Cancer Statistics Factsheets: Pancreas Cancer. National Cancer Institute. http://seer.cancer.gov/statfacts/html/pancreas.html
Vincent, A., Herman, J., Schulick, R., et al. (2011) Pancreatic Cancer. The Lancet, 378, 607-620. http://dx.doi.org/10.1016/S0140-6736(10)62307-0
Conroy, T., Gavoille, C. and Adenis, A. (2011) Metastatic Pancreatic Cancer: Old Drugs, New Paradigms. Current Opinion in Oncology, 23, 390-395. http://dx.doi.org/10.1097/CCO.0b013e3283473610
Chen, W.Q., Zheng, R.S., Zhang, S.W., et al. (2014) The Incidences and Mortalities of Major Cancers in China, 2010. Chinese Journal of Cancer, 33, 402-405.
Lee, C.J., Dosch, J. and Simeone, D.M. (2008) Pancreatic Cancer Stem Cells. Journal of Clinical Oncology, 26, 2806-2812. http://dx.doi.org/10.1200/JCO.2008.16.6702
Hermann, P.C., Mueller, M.T. and Heeschen, C. (2009) Pancreatic Cancer Stem Cells—Insights and Perspectives. Expert Opinion on Biological Therapy, 9, 1271-1278. http://dx.doi.org/10.1517/14712590903246362
Ischenko, I., Seeliger, H., Kleespies, A., et al. (2010) Pancreatic Cancer Stem Cells: New Understanding of Tumorigenesis, Clinical Implications. Langenbeck’s Archives of Surgery, 395, 1-10. http://dx.doi.org/10.1007/s00423-009-0502-z
Chuthapisith, S., Eremin, J., El-Sheemey, M., et al. (2010) Breast Cancer Chemoresistance: Emerging Importance of Cancer Stem Cells. Surgical Oncology, 19, 27-32. http://dx.doi.org/10.1016/j.suronc.2009.01.004
Lonardo, E., Hermann, P.C. and Heeschen, C. (2010) Pancreatic Cancer Stem Cells—Update and Future Perspectives. Molecular Oncology, 4, 431-442. http://dx.doi.org/10.1016/j.molonc.2010.06.002
Hermann, P.C., Bhaskar, S., Cioffi, M., et al. (2010) Cancer Stem Cells in Solid Tumors. Seminars in Cancer Biology, 20, 77-84. http://dx.doi.org/10.1016/j.semcancer.2010.03.004
Clarke, M.F., Dick, J.E., Dirks, P.B., Eaves, C.J., Jamieson, C.H.M., Leanne Jones, D., et al. (2006) Cancer Stem Cells—Perspectives on Current Status and Future Directions: AACR Workshop on Cancer Stem Cells. Cancer Research, 66, 9339-9344. http://dx.doi.org/10.1158/0008-5472.CAN-06-3126
Reya, T., Morrison, S.J., Clarke, M.F. and Weissman, I.L. (2001) Stem Cells, Cancer, and Cancer Stem Cells. Nature, 414, 105-111. http://dx.doi.org/10.1038/35102167
Shigdar, S., Li, Y., Bhattacharya, S., O’Connor, M., Pu, C.W., Lin, J., et al. (2014) Inflammation and Cancer Stem Cells. Cancer Letters, 345, 271-278. http://dx.doi.org/10.1016/j.canlet.2013.07.031
Marchesi, V. (2013) Breast Cancer: Mutations in Breast Cancer Stem Cells Correlate with Metastases. Nature Reviews Clinical Oncology, 10, 546. http://dx.doi.org/10.1038/nrclinonc.2013.146
Bonnet, D. and Dick, J.E. (1997) Human Acute Myeloid Leukemia Is Organized as a Hierarchy that Originates from a Primitive Hematopoietic Cell. Nature Medicine, 3, 730-737. http://dx.doi.org/10.1038/nm0797-730
Al-Hajj, M., Wicha, M.S., Benito-Hernandez, A., Morrison, S.J. and Clarke, M.F. (2003) Prospective Identification of Tumorigenic Breast Cancer Cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983-3988. http://dx.doi.org/10.1073/pnas.0530291100
Ignatova, T.N., Kukekov, V.G., Laywell, E.D., Suslov, O.N., Vrionis, F.D. and Steindler, D.A. (2002) Human Cortical Glial Tumors Contain Neural Stem-Like Cells Expressing Astroglial and Neuronal Markers in Vitro. Glia, 39, 193-206. http://dx.doi.org/10.1002/glia.10094
Kim, Y., Wu, Q., Hamerlik, P., Hitomi, M., Sloan, A.E., Barnett, G.H., et al. (2013) Aptamer Identification of Brain Tumor-Initiating Cells. Cancer Research, 73, 4923-4936. http://dx.doi.org/10.1158/0008-5472.CAN-12-4556
Matsui, W., Borrello, I. and Mitsiades, C. (2012) Autologous Stem Cell Transplantation and Multiple Myeloma Cancer Stem Cells. Biology of Blood and Marrow Transplant, 18, S27-S32. http://dx.doi.org/10.1016/j.bbmt.2011.10.036
Li, C., Lee, C.J. and Simeone, D.M. (2009) Identification of Human Pancreatic Cancer Stem Cells. Methods Mol Biol, Volume 568, 161-173. http://dx.doi.org/10.1007/978-1-59745-280-9_10
O’Brien, C.A., Pollett, A., Gallinger, S. and Dick, J.E. (2007) A Human Colon Cancer Cell Capable of Initiating Tumour Growth in Immunodeficient Mice. Nature, 445, 106-110. http://dx.doi.org/10.1038/nature05372
Yang, Z.F., Ho, D.W., Ng, M.N., Lau, C.K., Yu, W.C., Ngai, P., et al. (2008) Significance of CD90+ Cancer Stem Cells in Human Liver Cancer. Cancer Cell, 13, 153-166. http://dx.doi.org/10.1016/j.ccr.2008.01.013
Mateo, F., Fernandez, P.L. and Thomson, T.M. (2013) Stem Cells in Prostate Cancer. Archivos Espa?oles de Urología, 66, 475-486.
Prince, M.E., Sivanandan, R., Kaczorowski, A., Wolf, G.T., Kaplan, M.J., Dalerba, P., et al. (2007) Identification of a Subpopulation of Cells with Cancer Stem Cell Properties in Head and Neck Squamous Cell Carcinoma. Proceedings of the National Academy of Sciences of the United States of America, 104, 973-978. http://dx.doi.org/10.1073/pnas.0610117104
Fang, D., Nguyen, T.K., Leishear, K., Finko, R., Kulp, A.N., Hotz, S., et al. (2005) A Tumorigenic Subpopulation with Stem Cell Properties in Melanomas. Cancer Research, 65, 9328-9337. http://dx.doi.org/10.1158/0008-5472.CAN-05-1343
Szotek, P.P., Pieretti-Vanmarcke, R., Masiakos, P.T., Dinulescu, D.M., Connolly, D., Foster, R., et al. (2006) Ovarian Cancer Side Population Defines Cells with Stem Cell-Like Characteristics and Mullerian Inhibiting Substance Responsiveness. Proceedings of the National Academy of Sciences of the United States of America, 103, 11154-11159. http://dx.doi.org/10.1073/pnas.0603672103
Yasuda, H., Soejima, K., Watanabe, H., Kawada, I., Nakachi, I., Yoda, S., et al. (2010) Distinct Epigenetic Regulation of Tumor Suppressor Genes in Putative Cancer Stem Cells of Solid Tumors. International Journal of Oncology, 37, 1537-1546.
Garner, J.M., Fan, M., Yang, C.H., Du, Z.Y., Sims, M., Davidoff, A.M. and Pfeffer, L.M. (2013) Constitutive Activation of Signal Transducer and Activator of Transcription 3 (STAT3) and Nuclear Factor κB Signaling in Glioblastoma Cancer Stem Cells Regulates the Notch Pathway. Journal of Biological Chemistry, 288, 26167-26176. http://dx.doi.org/10.1074/jbc.M113.477950
Norris, L., Karmokar, A., Howells, L., Steward, W.P., Gescher, A. and Brown, K. (2013) The Role of Cancer Stem Cells in the Anti-Carcinogenicity of Curcumin. Molecular Nutrition & Food Research, 57, 1630-1637. http://dx.doi.org/10.1002/mnfr.201300120
Lobo, N.A., Shimono, Y., Qian, D. and Clarke, M.F. (2007) The Biology of Cancer Stem Cells. Annual Review of Cell and Developmental Biology, 23, 675-699. http://dx.doi.org/10.1146/annurev.cellbio.22.010305.104154
Li, C.W., Heidt, D.G., Dalerba, P., Burant, C.F., Zhang, L.J., Adsay, V., et al. (2007) Identification of Pancreatic Cancer Stem Cells. Cancer Research, 67, 1030-1037. http://dx.doi.org/10.1158/0008-5472.CAN-06-2030
Abel, E.V. and Simeone, D.M. (2013) Biology and Clinical Applications of Pancreatic Cancer Stem Cells. Gastroenterology, 144, 1241-1248. http://dx.doi.org/10.1053/j.gastro.2013.01.072
Singh, S.K., Clarke, I.D., Terasaki, M., Bonn, V.E., Hawkins, C., Squire, J. and Dirks, P.B. (2003) Identification of a Cancer Stem Cell in Human Brain Tumors. Cancer Research, 63, 5821-5828.
Miki, J., Furusato, B., Li, H.Z., Gu, Y.P., Takahashi, H., Egawa, S., et al. (2007) Identification of Putative Stem Cell Markers, CD133 and CXCR4, in hTERT-Immortalized Primary Nonmalignant and Malignant Tumor-Derived Human Prostate Epithelial Cell Lines and in Prostate Cancer Specimens. Cancer Research, 67, 3153-3161. http://dx.doi.org/10.1158/0008-5472.CAN-06-4429
Hermann, P.C., Huber, S.L., Herrler, T., Aicher, A., Ellwart, J.W., Guba, M., Bruns, C.J. and Heeschen, C. (2007) Distinct Populations of Cancer Stem Cells Determine Tumor Growth and Metastatic Activity in Human Pancreatic Cancer. Cell Stem Cell, 1, 313-323. http://dx.doi.org/10.1016/j.stem.2007.06.002
Lee, H.J., You, D.D., Choi, D.W., Choi, Y.S., Kim, S.J., Won, Y.S. and Moon, H.J. (2011) Significance of CD133 as a Cancer Stem Cell Markers Focusing on the Tumorigenicity of Pancreatic Cancer Cell Lines. Journal of the Korean Surgical Society, 81, 263-270.
Michieli, P., Mazzone, M., Basilico, C., Cavassa, S., Sottile, A., Naldini, L. and Comoglio, P.M. (2004) Targeting the Tumor and Its Microenvironment by a Dual-Function Decoy Met Receptor. Cancer Cell, 6, 61-73. http://dx.doi.org/10.1016/j.ccr.2004.05.032
Li, C.W., Wu, J.J., Hynes, M., Dosch, J., Sarkar, B., Welling, T.H., di Magliano, M.P. and Simeone, D.M. (2011) c-Met Is a Marker of Pancreatic Cancer Stem Cells and Therapeutic Target. Gastroenterology, 141, 2218-2227. http://dx.doi.org/10.1053/j.gastro.2011.08.009
Herreros-Villanueva, M., Zubia-Olascoaga, A. and Bujanda, L. (2012) c-Met in Pancreatic Cancer Stem Cells: Therapeutic Implications. World Journal of Gastroenterology, 18, 5321-5323. http://dx.doi.org/10.3748/wjg.v18.i38.5321
Ginestier, C., Hur, M.H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., et al. (2007) ALDH1 Is a Marker of Normal and Malignant Human Mammary Stem Cells and a Predictor of Poor Clinical Outcome. Cell Stem Cell, 1, 555-567. http://dx.doi.org/10.1016/j.stem.2007.08.014
Jiang, F., Qiu, Q., Khanna, A., Todd, N.W., Deepak, J., Xing, L.X., et al. (2009) Aldehyde Dehydrogenase 1 Is a Tumor Stem Cell-Associated Marker in Lung Cancer. Molecular Cancer Research: MCR, 7, 330-338. http://dx.doi.org/10.1158/1541-7786.MCR-08-0393
Kim, M.P., Fleming, J.B., Wang, H., Abbruzzese, J.L., Choi, W., Kopetz, S., McConkey, D.J., Evans, D.B. and Gallick, G.E. (2011) ALDH Activity Selectively Defines an Enhanced Tumor-Initiating Cell Population Relative to CD133 Expression in Human Pancreatic Adenocarcinoma. PLoS ONE, 6, e20636. http://dx.doi.org/10.1371/journal.pone.0020636
Rasheed, Z.A., Yang, J., Wang, Q., Kowalski, J., Freed, I., Murter, C., et al. (2010) Prognostic Significance of Tumorigenic Cells with Mesenchymal Features in Pancreatic Adenocarcinoma. Journal of the National Cancer Institute, 102, 340-351. http://dx.doi.org/10.1093/jnci/djp535
Duong, H.Q., Hwang, J.S., Kim, H.J., Kang, H.J., Seong, Y.S. and Bae, I. (2012) Aldehyde Dehydrogenase 1A1 Confers Intrinsic and Acquired Resistance to Gemcitabine in Human Pancreatic Adenocarcinoma MIA PaCa-2 Cells. International Journal of Oncology, 41, 855-861.
Jimeno, A., Feldmann, G., Suarez-Gauthier, A., Rasheed, Z., Solomon, A., Zou, G.M., et al. (2009) A Direct Pancreatic Cancer Xenograft Model as a Platform for Cancer Stem Cell Therapeutic Development. Molecular Cancer Therapeutics, 8, 310-314. http://dx.doi.org/10.1158/1535-7163.MCT-08-0924
Wang, Z.W., Li, Y., Ahmad, A., Banerjee, S., Azmi, A.S., Kong, D. and Sarkar, F.H. (2011) Pancreatic Cancer: Understanding and Overcoming Chemoresistance. Nature Reviews Gastroenterology and Hepatology, 8, 27-33. http://dx.doi.org/10.1038/nrgastro.2010.188
Sarkar, F.H., Li, Y., Wang, Z. and Kong, D. (2009) Pancreatic Cancer Stem Cells and EMT in Drug Resistance and Metastasis. Minerva Chirurgica, 64, 489-500.
Wang, Z., Li, Y., Ahmad, A., Azmi, A.S., Kong, D., Banerjee, S. and Sarkar, F.H. (2010) Targeting miRNAs Involved in Cancer Stem Cell and EMT Regulation: An Emerging Concept in Overcoming Drug Resistance. Drug Resistance Updates, 13, 109-118. http://dx.doi.org/10.1016/j.drup.2010.07.001
Zhang, S.N., Huang, F.T., Huang, Y.J., Zhong, W. and Yu, Z. (2010) Characterization of a Cancer Stem Cell-Like Side Population Derived from Human Pancreatic Adenocarcinoma Cells. Tumori, 96, 985-992.
Wang, Z.W., Li, Y.W., Kong, D.J., Banerjee, S., Ahmad, A., Azmi, A.S., et al. (2009) Acquisition of Epithelial-Mesenchymal Transition Phenotype of Gemcitabine-Resistant Pancreatic Cancer Cells Is Linked with Activation of the Notch Signaling Pathway. Cancer Research, 69, 2400-2407. http://dx.doi.org/10.1158/0008-5472.CAN-08-4312
Banerjee, S., Nomura, A., Sangwan, V., Chugh, R., Dudeja, V., Vickers, S.M. and Saluja, A. (2014) CD133+ Tumor Initiating Cells in a Syngenic Murine Model of Pancreatic Cancer Respond to Minnelide. Clinical Cancer Research, 20, 2388-2399. http://dx.doi.org/10.1158/1078-0432.CCR-13-2947
Li, S.H., Fu, J., Watkins, D.N., Srivastava, R.K. and Shankar, S. (2013) Sulforaphane Regulates Self-Renewal of Pancreatic Cancer Stem Cells through the Modulation of Sonic Hedgehog-GLI Pathway. Molecular and Cellular Biochemistry, 373, 217-227. http://dx.doi.org/10.1007/s11010-012-1493-6
Herrera, V.L., Decano, J.L., Tan, G.A., Moran, A.M., Pasion, K.A., Matsubara, Y. and Ruiz-Opazo, N. (2014) DEspR Roles in Tumor Vasculo-Angiogenesis, Invasiveness, CSC-Survival and Anoikis Resistance: A “Common Receptor Coordinator” Paradigm. PLoS ONE, 9, e85821. http://dx.doi.org/10.1371/journal.pone.0085821
Kim, S.K., Kim, H., Lee, D.H., Kim, T.H., Kim, T., Chung, C., Koh, G.Y., Kim, H. and Lim, D.S. (2013) Reversing the Intractable Nature of Pancreatic Cancer by Selectively Targeting ALDH-High, Therapy-Resistant Cancer Cells. PLoS ONE, 8, e78130. http://dx.doi.org/10.1371/journal.pone.0078130
Wang, X., Liu, Q., Hou, B., Zhang, W., Yan, M., Jia, H.M., et al. (2013) Concomitant Targeting of Multiple Key Transcription Factors Effectively Disrupts Cancer Stem Cells Enriched in Side Population of Human Pancreatic Cancer Cells. PLoS ONE, 8, e73942. http://dx.doi.org/10.1371/journal.pone.0073942
Lonardo, E., Hermann, P.C., Mueller, M.T., Huber, S., Balic, A., Miranda-Lorenzo, I., et al. (2011) Nodal/Activin Signaling Drives Self-Renewal and Tumorigenicity of Pancreatic Cancer Stem Cells and Provides a Target for Combined Drug Therapy. Cell Stem Cell, 9, 433-446. http://dx.doi.org/10.1016/j.stem.2011.10.001
Huang, J., Li, C., Wang, Y., Lv, H.Y., Guo, Y.L., Dai, H.R., et al. (2013) Cytokine-Induced Killer (CIK) Cells Bound with Anti-CD3/Anti-CD133 Bispecific Antibodies Target CD133 (High) Cancer Stem Cells in Vitro and in Vivo. Clinical Immunology, 149, 156-168. http://dx.doi.org/10.1016/j.clim.2013.07.006
Himoudi, N., Morgenstern, D.A., Yan, M., Vernay, B., Saraiva, L., Wu, Y., et al. (2012) ?Human γδ T Lymphocytes Are Licensed for Professional Antigen Presentation by Interaction with Opsonized Target Cells. Journal of Immunology, 188, 1708-1716. http://dx.doi.org/10.4049/jimmunol.1102654
Braza, M.S. and Klein, B. (2013) Anti-Tumour Immunotherapy with Vγ9Vδ2 T Lymphocytes: From the Bench to the Bedside. British Journal of Haematology, 160, 123-132. http://dx.doi.org/10.1111/bjh.12090
Oberg, H.H., Peipp, M., Kellner, C., Sebens, S., Krause, S., Petrick, D., et al. (2014) Novel Bispecific Antibodies Increase γδ T-Cell Cytotoxicity against Pancreatic Cancer Cells. Cancer Research, 74, 1349-1360. http://dx.doi.org/10.1158/0008-5472.CAN-13-0675
Visus, C., Wang, Y., Lozano-Leon, A., Ferris, R.L., Silver, S., Szczepanski, M.J., et al. (2011) Targeting ALDHbright Human Carcinoma-Initiating Cells with ALDH1A1-Specific CD8+ T Cells. Clinical Cancer Research, 17, 6174-6184. http://dx.doi.org/10.1158/1078-0432.CCR-11-1111