Cancer stem cells (CSCs) were isolated in multiple tumor types, including human glioblastomas, and although the presence of surface markers selectively expressed on CSCs can be used to isolate them, no marker/pattern of markers are sufficiently robust to definitively identify stem cells in tumors. Several markers were evaluated for their prognostic value with promising early results, however none of them was proven to be clinically useful in large-scale studies, leading to outstanding efforts to identify new markers. Given the heterogeneity of human glioblastomas further investigations are necessary to identify both cancer stem cell-specific markers and the molecular mechanisms sustaining the tumorigenic potential of these cells to develop tailored treatments. Markers for glioblastoma stem cells such as CD133, CD15, integrin-α6, L1CAM might be informative to identify these cells but cannot be conclusively linked to a stem cell phenotype. Overlap of expression, functional state and morphology of different subpopulations lead to carefully consider the techniques employed so far to isolate these cells. Due to a dearth of methods and markers reliably identifying the candidate cancer stem cells, the isolation/enrichment of cancer stem cells to be therapeutically targeted remains a major challenge. 1. Introduction The cancer stem cell hypothesis postulates that a small subpopulation of cancer cells possessing self-renewal characteristics are responsible for initiating and maintaining cancer growth. According to the CSC model, the large populations found in a tumor might represent diverse stages of differentiation. The biological characteristics shared by normal stem cells (NSCs) and CSCs mainly involve self-renewal and differentiation potential, survival ability, niche-specific microenvironment requirements, and specific homing to injury sites and may have important implications in terms of new approaches to cancer. The identification of new therapeutic targets based on the CSC model represents a great challenge. Glioblastoma multiforme (WHO grade IV) is the most aggressive among the brain tumors of adults and displays striking morphologic variation among different patients. GBM contains a mixture cell populations with high propensity to infiltrate throughout the brain (making complete surgical resection impossible). It has been demonstrated that the bulk of malignant cells in GBM is generated by rare fractions of self-renewing, multipotent tumor-initiating cells (CSCs) also called tumor-initiating cells or tumor-propagating cells [1, 2] responsible for tumor
References
[1]
R. Galli, E. Binda, U. Orfanelli et al., “Isolation and characterization of tumorigenic, stem-like neural precursors from human glioblastoma,” Cancer Research, vol. 64, no. 19, pp. 7011–7021, 2004.
[2]
S. K. Singh, C. Hawkins, I. D. Clarke et al., “Identification of human brain tumour initiating cells,” Nature, vol. 432, no. 7015, pp. 396–401, 2004.
[3]
S. Bao, Q. Wu, R. E. McLendon et al., “Glioma stem cells promote radioresistance by preferential activation of the DNA damage response,” Nature, vol. 444, no. 7120, pp. 756–760, 2006.
[4]
M. Al-Hajj, M. S. Wicha, A. Benito-Hernandez, S. J. Morrison, and M. F. Clarke, “Prospective identification of tumorigenic breast cancer cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 100, no. 7, pp. 3983–3988, 2003.
[5]
K. Kelly and J. J. Yin, “Prostate cancer and metastasis initiating stem cells,” Cell Research, vol. 18, no. 5, pp. 528–537, 2008.
[6]
C. J. Lee, J. Dosch, and D. M. Simeone, “Pancreatic cancer stem cells,” Journal of Clinical Oncology, vol. 26, no. 17, pp. 2806–2812, 2008.
[7]
L. Ricci-Vitiani, D. G. Lombardi, E. Pilozzi et al., “Identification and expansion of human colon-cancer-initiating cells,” Nature, vol. 445, no. 7123, pp. 111–115, 2007.
[8]
E. Quintana, M. Shackleton, M. S. Sabel, D. R. Fullen, T. M. Johnson, and S. J. Morrison, “Efficient tumour formation by single human melanoma cells,” Nature, vol. 456, no. 7222, pp. 593–598, 2008.
[9]
C. M. Baum, I. L. Weissman, A. S. Tsukamoto, A. M. Buckle, and B. Peault, “Isolation of a candidate human hematopoietic stem-cell population,” Proceedings of the National Academy of Sciences of the United States of America, vol. 89, no. 7, pp. 2804–2808, 1992.
[10]
T. Reya, S. J. Morrison, M. F. Clarke, and I. L. Weissman, “Stem cells, cancer, and cancer stem cells,” Nature, vol. 414, no. 6859, pp. 105–111, 2001.
[11]
M. F. Clarke, J. E. Dick, P. B. Dirks et al., “Cancer stem cells—perspectives on current status and future directions: AACR workshop on cancer stem cells,” Cancer Research, vol. 66, no. 19, pp. 9339–9344, 2006.
[12]
J. E. Dick, “Stem cell concepts renew cancer research,” Blood, vol. 112, no. 13, pp. 4793–4807, 2008.
[13]
S. M. Pollard, L. Conti, Y. Sun, D. Goffredo, and A. Smith, “Adherent neural stem (NS) cells from fetal and adult forebrain,” Cerebral Cortex, vol. 16, supplement 1, pp. i112–120, 2006.
[14]
Y. Sun, S. Pollard, L. Conti et al., “Long-term tripotent differentiation capacity of human neural stem (NS) cells in adherent culture,” Molecular and Cellular Neuroscience, vol. 38, no. 2, pp. 245–258, 2008.
[15]
B. A. Reynolds, W. Tetzlaff, and S. Weiss, “A multipotent EGF-responsive striatal embryonic progenitor cell produces neurons and astrocytes,” Journal of Neuroscience, vol. 12, no. 11, pp. 4565–4574, 1992.
[16]
B. A. Reynolds and S. Weiss, “Generation of neurons and astrocytes from isolated cells of the adult mammalian central nervous system,” Science, vol. 255, no. 5052, pp. 1707–1710, 1992.
[17]
J. Lee, S. Kotliarova, Y. Kotliarov et al., “Tumor stem cells derived from glioblastomas cultured in bFGF and EGF more closely mirror the phenotype and genotype of primary tumors than do serum-cultured cell lines,” Cancer Cell, vol. 9, no. 5, pp. 391–403, 2006.
[18]
D. R. Laks, M. Masterman-Smith, K. Visnyei et al., “Neurosphere formation is an independent predictor of clinical outcome in malignant glioma,” Stem Cells, vol. 27, no. 4, pp. 980–987, 2009.
[19]
A. H. Yin, S. Miraglia, E. D. Zanjani et al., “AC133, a novel marker for human hematopoietic stem and progenitor cells,” Blood, vol. 90, no. 12, pp. 5002–5012, 1997.
[20]
S. Miraglia, W. Godfrey, A. H. Yin et al., “A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning,” Blood, vol. 90, no. 12, pp. 5013–5021, 1997.
[21]
M. Peichev, A. J. Naiyer, D. Pereira et al., “Expression of VEGFR-2 and AC133 by circulating human CD34+ cells identifies a population of functional endothelial precursors,” Blood, vol. 95, no. 3, pp. 952–958, 2000.
[22]
Y. Torrente, M. Belicchi, M. Sampaolesi et al., “Human circulating AC133+ stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle,” Journal of Clinical Investigation, vol. 114, no. 2, pp. 182–195, 2004.
[23]
G. D. Richardson, C. N. Robson, S. H. Lang, D. E. Neal, N. J. Maitland, and A. T. Collins, “CD133, a novel marker for human prostatic epithelial stem cells,” Journal of Cell Science, vol. 117, no. 16, pp. 3539–3545, 2004.
[24]
K. G. Leong, B. E. Wang, L. Johnson, and W. Q. Gao, “Generation of a prostate from a single adult stem cell,” Nature, vol. 456, no. 7223, pp. 804–808, 2008.
[25]
N. Uchida, D. W. Buck, D. He et al., “Direct isolation of human central nervous system stem cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 97, no. 26, pp. 14720–14725, 2000.
[26]
S. Tamaki, K. Eckert, D. He et al., “Engraftment of sorted/expanded human central nervous system stem cells from fetal brain,” Journal of Neuroscience Research, vol. 69, no. 6, pp. 976–986, 2002.
[27]
P. H. Schwartz, P. J. Bryant, T. J. Fuja, H. Su, D. K. O'Dowd, and H. Klassen, “Isolation and characterization of neural progenitor cells from post-mortem human cortex,” Journal of Neuroscience Research, vol. 74, no. 6, pp. 838–851, 2003.
[28]
M. Bhatia, “AC133 expression in human stem cells,” Leukemia, vol. 15, no. 11, pp. 1685–1688, 2001.
[29]
A. T. Collins, P. A. Berry, C. Hyde, M. J. Stower, and N. J. Maitland, “Prospective identification of tumorigenic prostate cancer stem cells,” Cancer Research, vol. 65, no. 23, pp. 10946–10951, 2005.
[30]
C. A. O'Brien, A. Pollett, S. Gallinger, and J. E. Dick, “A human colon cancer cell capable of initiating tumour growth in immunodeficient mice,” Nature, vol. 445, no. 7123, pp. 106–110, 2007.
[31]
A. Eramo, F. Lotti, G. Sette et al., “Identification and expansion of the tumorigenic lung cancer stem cell population,” Cell Death and Differentiation, vol. 15, no. 3, pp. 504–514, 2008.
[32]
A. Suetsugu, M. Nagaki, H. Aoki, T. Motohashi, T. Kunisada, and H. Moriwaki, “Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells,” Biochemical and Biophysical Research Communications, vol. 351, no. 4, pp. 820–824, 2006.
[33]
M. D. Taylor, H. Poppleton, C. Fuller et al., “Radial glia cells are candidate stem cells of ependymoma,” Cancer Cell, vol. 8, no. 4, pp. 323–335, 2005.
[34]
E. Monzani, F. Facchetti, E. Galmozzi et al., “Melanoma contains CD133 and ABCG2 positive cells with enhanced tumourigenic potential,” European Journal of Cancer, vol. 43, no. 5, pp. 935–946, 2007.
[35]
G. Ferrandina, G. Bonanno, L. Pierelli et al., “Expression of CD133-1 and CD133-2 in ovarian cancer,” International Journal of Gynecological Cancer, vol. 18, no. 3, pp. 506–514, 2008.
[36]
S. K. Singh, I. D. Clarke, M. Terasaki et al., “Identification of a cancer stem cell in human brain tumors,” Cancer Research, vol. 63, no. 18, pp. 5821–5828, 2003.
[37]
V. Clement, V. Dutoit, D. Marino, P. Y. Dietrich, and I. Radovanovic, “Limits of CD133 as a marker of glioma self-renewing cells,” International Journal of Cancer, vol. 125, no. 1, pp. 244–248, 2009.
[38]
K. M. Joo, S. Y. Kim, X. Jin et al., “Clinical and biological implications of CD133-positive and CD133-negative cells in glioblastomas,” Laboratory Investigation, vol. 88, no. 8, pp. 808–815, 2008.
[39]
Q. Shu, K. W. Kwong, J. M. Su et al., “Direct orthotopic transplantation of fresh surgical specimen preserves CD133+ tumor cells in clinically relevant mouse models of medulloblastoma and glioma,” Stem Cells, vol. 26, no. 6, pp. 1414–1424, 2008.
[40]
J. Wang, P. O. Sakariassen, O. Tsinkalovsky et al., “CD133 negative glioma cells form tumors in nude rats and give rise to CD133 positive cells,” International Journal of Cancer, vol. 122, no. 4, pp. 761–768, 2008.
[41]
M. J. Son, K. Woolard, D. H. Nam, J. Lee, and H. A. Fine, “SSEA-1 is an enrichment marker for tumor-initiating cells in human glioblastoma,” Cell Stem Cell, vol. 4, no. 5, pp. 440–452, 2009.
[42]
F. Zeppernick, R. Ahmadi, B. Campos et al., “Stem cell marker CD133 affects clinical outcome in glioma patients,” Clinical Cancer Research, vol. 14, no. 1, pp. 123–129, 2008.
[43]
D. Beier, J. Wischhusen, W. Dietmaier et al., “CD133 expression and cancer stem cells predict prognosis in high-grade oligodendroglial tumors,” Brain Pathology, vol. 18, no. 3, pp. 370–377, 2008.
[44]
K. Christensen, H. D. Schroder, and B. W. Kristensen, “CD133 identifies perivascular niches in grade II-IV astrocytomas,” Journal of Neuro-Oncology, vol. 90, no. 2, pp. 157–170, 2008.
[45]
H. Immervoll, D. Hoem, P. Sakariassen, O. J. Steffensen, and A. Molven, “Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas,” BMC Cancer, vol. 8, article 48, 2008.
[46]
R. Pallini, L. Ricci-Vitiani, G. L. Banna et al., “Cancer stem cell analysis and clinical outcome in patients with glioblastoma multiforme,” Clinical Cancer Research, vol. 14, no. 24, pp. 8205–8212, 2008.
[47]
J. Rebetz, D. Tian, A. Persson et al., “Glial progenitor-like phenotype in low-grade glioma and enhanced CD133-expression and neuronal lineage differentiation potential in high-grade glioma,” PLoS ONE, vol. 3, no. 4, Article ID e1936, 2008.
[48]
N. Thon, K. Damianoff, J. Hegermann et al., “Presence of pluripotent CD133+ cells correlates with malignancy of gliomas,” Molecular and Cellular Neuroscience, vol. 43, no. 1, pp. 51–59, 2010.
[49]
M. Zhang, T. Song, L. Yang et al., “Nestin and CD133: valuable stem cell-specific markers for determining clinical outcome of glioma patients,” Journal of Experimental and Clinical Cancer Research, vol. 27, no. 1, article 85, 2008.
[50]
P. Metellus, I. Nanni-Metellus, C. Delfino et al., “Prognostic impact of CD133 mRNA expression in 48 glioblastoma patients treated with concomitant radiochemotherapy: a prospective patient cohort at a single institution,” Annals of Surgical Oncology, vol. 18, no. 10, pp. 2937–2945, 2011.
[51]
A. Raso, S. Mascelli, R. Biassoni et al., “High levels of PROM1 (CD133) transcript are a potential predictor of poor prognosis in medulloblastoma,” Neuro-Oncology, vol. 13, no. 5, pp. 500–508, 2011.
[52]
J. W. Yu, P. Zhang, J. G. Wu et al., “Expressions and clinical significances of CD133 protein and CD133 mRNA in primary lesion of gastric adenocacinoma,” Journal of Experimental and Clinical Cancer Research, vol. 29, no. 1, article 141, 2010.
[53]
D. Corbeil, K. Roper, A. Hellwig et al., “The human AC133 hematopoietic stem cell antigen is also expressed in epithelial cells and targeted to plasma membrane protrusions,” The Journal of Biological Chemistry, vol. 275, no. 8, pp. 5512–5520, 2000.
[54]
M. Florek, M. Haase, A. M. Marzesco et al., “Prominin-1/CD133, a neural and hematopoietic stem cell marker, is expressed in adult human differentiated cells and certain types of kidney cancer,” Cell and Tissue Research, vol. 319, no. 1, pp. 15–26, 2005.
[55]
S. Bidlingmaier, X. Zhu, and B. Liu, “The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells,” Journal of Molecular Medicine, vol. 86, no. 9, pp. 1025–1032, 2008.
[56]
S. K. Hermansen, K. G. Christensen, S. S. Jensen, and B. W. Kristensen, “Inconsistent immunohistochemical expression patterns of four different CD133 antibody clones in glioblastoma,” The Journal of Histochemistry and Cytochemistry, vol. 59, no. 4, pp. 391–407, 2011.
[57]
K. Kemper, M. R. Sprick, M. de Bree et al., “The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation,” Cancer Research, vol. 70, no. 2, pp. 719–729, 2010.
[58]
S. V. Shmelkov, J. M. Butler, A. T. Hooper et al., “CD133 expression is not restricted to stem cells, and both CD133+ and CD133？ metastatic colon cancer cells initiate tumors,” Journal of Clinical Investigation, vol. 118, no. 6, pp. 2111–2120, 2008.
[59]
D. Beier, P. Hau, M. Proescholdt et al., “CD133+ and CD133？ glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles,” Cancer Research, vol. 67, no. 9, pp. 4010–4015, 2007.
[60]
C. Lottaz, D. Beier, K. Meyer et al., “Transcriptional profiles of CD133+ and CD133？ glioblastoma-derived cancer stem cell lines suggest different cells of origin,” Cancer Research, vol. 70, no. 5, pp. 2030–2040, 2010.
[61]
R. Chen, M. C. Nishimura, S. M. Bumbaca et al., “A hierarchy of self-renewing tumor-initiating cell types in glioblastoma,” Cancer Cell, vol. 17, no. 4, pp. 362–375, 2010.
[62]
E. Quintana, M. Shackleton, H. R. Foster et al., “Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized,” Cancer Cell, vol. 18, no. 5, pp. 510–523, 2010.
[63]
A. Roesch, M. Fukunaga-Kalabis, E. C. Schmidt et al., “A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth,” Cell, vol. 141, no. 4, pp. 583–594, 2010.
[64]
S. Bao, Q. Wu, Z. Li et al., “Targeting cancer stem cells through L1CAM suppresses glioma growth,” Cancer Research, vol. 68, no. 15, pp. 6043–6048, 2008.
[65]
P. F. Maness and M. Schachner, “Neural recognition molecules of the immunoglobulin superfamily: signaling transducers of axon guidance and neuronal migration,” Nature Neuroscience, vol. 10, no. 1, pp. 19–26, 2007.
[66]
S. Izumoto, T. Ohnishi, N. Arita, S. Hiraga, T. Taki, and T. Hayakawa, “Gene expression of neural cell adhesion molecule L1 in malignant gliomas and biological significance of L1 in glioma invasion,” Cancer Research, vol. 56, no. 6, pp. 1440–1444, 1996.
[67]
T. Suzuki, S. Izumoto, Y. Fujimoto, M. Maruno, Y. Ito, and T. Yoshimine, “Clinicopathological study of cellular proliferation and invasion in gliomatosis cerebri: important role of neural cell adhesion molecule L1 in tumour invasion,” Journal of Clinical Pathology, vol. 58, no. 2, pp. 166–171, 2005.
[68]
M. J. E. Arlt, I. Novak-Hofer, D. Gast et al., “Efficient inhibition of intra-peritoneal tumor growth and dissemination of human ovarian carcinoma cells in nude mice by anti-L1-cell adhesion molecule monoclonal antibody treatment,” Cancer Research, vol. 66, no. 2, pp. 936–943, 2006.
[69]
A. Thies, M. Schachner, I. Moll et al., “Overexpression of the cell adhesion molecule L1 is associated with metastasis in cutaneous malignant melanoma,” European Journal of Cancer, vol. 38, no. 13, pp. 1708–1716, 2002.
[70]
Y. Allory, Y. Matsuoka, C. Bazille, E. I. Christensen, P. Ronco, and H. Debiec, “The L1 cell adhesion molecule is induced in renal cancer cells and correlates with metastasis in clear cell carcinomas,” Clinical Cancer Research, vol. 11, no. 3, pp. 1190–1197, 2005.
[71]
Y. J. Boo, J. M. Park, J. Kim et al., “L1 expression as a marker for poor prognosis, tumor progression, and short survival in patients with colorectal cancer,” Annals of Surgical Oncology, vol. 14, no. 5, pp. 1703–1711, 2007.
[72]
L. Cheng, Q. Wu, Z. Huang et al., “L1CAM regulates DNA damage checkpoint response of glioblastoma stem cells through NBS1,” The EMBO Journal, vol. 30, no. 5, pp. 800–813, 2011.
[73]
F. Yu, H. Yao, P. Zhu et al., “let-7 regulates self renewal and tumorigenicity of breast cancer cells,” Cell, vol. 131, no. 6, pp. 1109–1123, 2007.
[74]
C. Li, D. G. Heidt, P. Dalerba et al., “Identification of pancreatic cancer stem cells,” Cancer Research, vol. 67, no. 3, pp. 1030–1037, 2007.
[75]
L. Patrawala, T. Calhoun, R. Schneider-Broussard et al., “Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells,” Oncogene, vol. 25, no. 12, pp. 1696–1708, 2006.
[76]
J. Anido, A. Saez-Borderias, A. Gonzalez-Junca, et al., “TGF-β receptor inhibitors target the CD44(high)/Id1(high) glioma-initiating cell population in human glioblastoma,” Cancer Cell, vol. 18, no. 6, pp. 655–668, 2010.
[77]
L. E. Barrett, Z. Granot, C. Coker, et al., “Self-renewal does not predict tumor growth potential in mouse models of high-grade glioma,” Cancer Cell, vol. 21, no. 1, pp. 11–24, 2012.
[78]
H. S. Nam and R. Benezra, “High levels of Id1 expression define B1 type adult neural stem cells,” Cell Stem Cell, vol. 5, no. 5, pp. 515–526, 2009.
[79]
A. Capela and S. Temple, “LeX/ssea-1 is expressed by adult mouse CNS stem cells, identifying them as nonependymal,” Neuron, vol. 35, no. 5, pp. 865–875, 2002.
[80]
A. Capela and S. Temple, “LeX is expressed by principle progenitor cells in the embryonic nervous system, is secreted into their environment and binds Wnt-1,” Developmental Biology, vol. 291, no. 2, pp. 300–313, 2006.
[81]
T. A. Read, M. P. Fogarty, S. L. Markant et al., “Identification of CD15 as a marker for tumor-propagating cells in a mouse model of medulloblastoma,” Cancer Cell, vol. 15, no. 2, pp. 135–147, 2009.
[82]
P. E. Hall, J. D. Lathia, M. A. Caldwell, and C. Ffrench-Constant, “Laminin enhances the growth of human neural stem cells in defined culture media,” BMC Neuroscience, vol. 9, article 71, 2008.
[83]
T. M. Fael Al-Mayhani, S. L. R. Ball, J. W. Zhao et al., “An efficient method for derivation and propagation of glioblastoma cell lines that conserves the molecular profile of their original tumours,” Journal of Neuroscience Methods, vol. 176, no. 2, pp. 192–199, 2009.
[84]
Q. Shen, Y. Wang, E. Kokovay et al., “Adult SVZ stem cells lie in a vascular niche: a quantitative analysis of niche cell-cell interactions,” Cell Stem Cell, vol. 3, no. 3, pp. 289–300, 2008.
[85]
J. D. Lathia, J. Gallagher, J. M. Heddleston et al., “Integrin Alpha 6 regulates glioblastoma stem cells,” Cell Stem Cell, vol. 6, no. 5, pp. 421–432, 2010.
[86]
S. P. Leon, R. D. Folkerth, and P. M. Black, “Microvessel density is a prognostic indicator for patients with astroglial brain tumors,” Cancer, vol. 77, no. 2, pp. 362–372, 1996.
[87]
C. Calabrese, H. Poppleton, M. Kocak et al., “A perivascular niche for brain tumor stem cells,” Cancer Cell, vol. 11, no. 1, pp. 69–82, 2007.
[88]
Z. Li, S. Bao, Q. Wu et al., “Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells,” Cancer Cell, vol. 15, no. 6, pp. 501–513, 2009.
[89]
J. M. Heddleston, Z. Li, R. E. McLendon, A. B. Hjelmeland, and J. N. Rich, “The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype,” Cell Cycle, vol. 8, no. 20, pp. 3274–3284, 2009.
[90]
R. Wang, K. Chadalavada, J. Wilshire et al., “Glioblastoma stem-like cells give rise to tumour endothelium,” Nature, vol. 468, no. 7325, pp. 829–833, 2010.
[91]
M. A. Goodell, K. Brose, G. Paradis, A. S. Conner, and R. C. Mulligan, “Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo,” Journal of Experimental Medicine, vol. 183, no. 4, pp. 1797–1806, 1996.
[92]
M. Kim and C. M. Morshead, “Distinct populations of forebrain neural stem and progenitor cells can be isolated using side-population analysis,” Journal of Neuroscience, vol. 23, no. 33, pp. 10703–10709, 2003.
[93]
C. Wu and B. A. Alman, “Side population cells in human cancers,” Cancer Letters, vol. 268, no. 1, pp. 1–9, 2008.
[94]
G. A. Challen and M. H. Little, “A side order of stem cells: the SP phenotype,” Stem Cells, vol. 24, no. 1, pp. 3–12, 2006.
[95]
T. Kondo, T. Setoguchi, and T. Taga, “Persistence of a small subpopulation of cancer stem-like cells in the C6 glioma cell line,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 3, pp. 781–786, 2004.
[96]
M. A. Harris, H. Yang, B. E. Low et al., “Cancer stem cells are enriched in the side population cells in a mouse model of glioma,” Cancer Research, vol. 68, no. 24, pp. 10051–10059, 2008.
[97]
C. Hirschmann-Jax, A. E. Foster, G. G. Wulf et al., “A distinct “side population” of cells with high drug efflux capacity in human tumor cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 39, pp. 14228–14233, 2004.
[98]
L. Patrawala, T. Calhoun, R. Schneider-Broussard, J. Zhou, K. Claypool, and D. G. Tang, “Side population is enriched in tumorigenic, stem-like cancer cells, whereas ABCG2+ and ABCG2？ cancer cells are similarly tumorigenic,” Cancer Research, vol. 65, no. 14, pp. 6207–6219, 2005.
[99]
J. Burkert, W. R. Otto, and N. A. Wright, “Side populations of gastrointestinal cancers are not enriched in stem cells,” Journal of Pathology, vol. 214, no. 5, pp. 564–573, 2008.
[100]
A. M. Bleau, D. Hambardzumyan, T. Ozawa et al., “PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells,” Cell Stem Cell, vol. 4, no. 3, pp. 226–235, 2009.
[101]
N. Charles, T. Ozawa, M. Squatrito et al., “Perivascular nitric oxide activates notch signaling and promotes stem-like character in PDGF-induced glioma cells,” Cell Stem Cell, vol. 6, no. 2, pp. 141–152, 2010.
[102]
E. H. Huang, M. J. Hynes, T. Zhang et al., “Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis,” Cancer Research, vol. 69, no. 8, pp. 3382–3389, 2009.
[103]
C. Ginestier, M. H. Hur, E. Charafe-Jauffret et al., “ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome,” Cell Stem Cell, vol. 1, no. 5, pp. 555–567, 2007.
[104]
J. Douville, R. Beaulieu, and D. Balicki, “ALDH1 as a functional marker of cancer stem and progenitor cells,” Stem Cells and Development, vol. 18, no. 1, pp. 17–26, 2009.
[105]
R. W. Storms, A. P. Trujillo, J. B. Springer et al., “Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 96, no. 16, pp. 9118–9123, 1999.
[106]
T. Gentry, S. Foster, L. Winstead, E. Deibert, M. Fiordalisi, and A. Balber, “Simultaneous isolation of human BM hematopoietic, endothelial and mesenchymal progenitor cells by flow sorting based on aldehyde dehydrogenase activity: implications for cell therapy,” Cytotherapy, vol. 9, no. 3, pp. 259–274, 2007.
[107]
T. J. Povsic, K. L. Zavodni, F. L. Kelly et al., “Circulating progenitor cells can be reliably identified on the basis of aldehyde dehydrogenase activity,” Journal of the American College of Cardiology, vol. 50, no. 23, pp. 2243–2248, 2007.
[108]
W. Matsui, C. A. Huff, Q. Wang et al., “Characterization of clonogenic multiple myeloma cells,” Blood, vol. 103, no. 6, pp. 2332–2336, 2004.
[109]
D. J. Pearce, D. Taussig, C. Simpson et al., “Characterization of cells with a high aldehyde dehydrogenase activity from cord blood and acute myeloid leukemia samples,” Stem Cells, vol. 23, no. 6, pp. 752–760, 2005.
[110]
D. Ucar, C. R. Cogle, J. R. Zucali et al., “Aldehyde dehydrogenase activity as a functional marker for lung cancer,” Chemico-Biological Interactions, vol. 178, no. 1-3, pp. 48–55, 2009.
[111]
S. Corti, F. Locatelli, D. Papadimitriou et al., “Identification of a primitive brain-derived neural stem cell population based on aldehyde dehydrogenase activity,” Stem Cells, vol. 24, no. 4, pp. 975–985, 2006.
[112]
C. van den Hoogen, G. van der Horst, H. Cheung et al., “High aldehyde dehydrogenase activity identifies tumor-initiating and metastasis-initiating cells in human prostate cancer,” Cancer Research, vol. 70, no. 12, pp. 5163–5173, 2010.
[113]
M. Rasper, A. Schafer, G. Piontek, et al., “Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity,” Neuro-Oncology, vol. 12, no. 10, pp. 1024–1033, 2010.
[114]
S. C. Yu and X. W. Bian, “Enrichment of cancer stem cells based on heterogeneity of invasiveness,” Stem Cell Reviews and Reports, vol. 5, no. 1, pp. 66–71, 2009.
[115]
A. Tamase, T. Muraguchi, K. Naka et al., “Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 40, pp. 17163–17168, 2009.
[116]
V. Clement, D. Marino, C. Cudalbu et al., “Marker-independent identification of glioma-initiating cells,” Nature Methods, vol. 7, no. 3, pp. 224–228, 2010.
[117]
S. Pece, D. Tosoni, S. Confalonieri et al., “Biological and molecular heterogeneity of breast cancers correlates with their cancer stem cell content,” Cell, vol. 140, no. 1, pp. 62–73, 2010.
[118]
J. L. Dembinski and S. Krauss, “Characterization and functional analysis of a slow cycling stem cell-like subpopulation in pancreas adenocarcinoma,” Clinical and Experimental Metastasis, vol. 26, no. 7, pp. 611–623, 2009.
[119]
L. P. Deleyrolle, A. Harding, K. Cato et al., “Evidence for label-retaining tumour-initiating cells in human glioblastoma,” Brain, vol. 134, no. 5, pp. 1331–1343, 2011.
