FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W2000502676> ?p ?o ?g. }

• W2000502676 endingPage "1890" @default.
• W2000502676 startingPage "1880" @default.
• W2000502676 abstract "The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review. The cancer stem-cell (CSC) hypothesis suggests that there is a small subset of cancer cells that are responsible for tumor initiation and growth, possessing properties such as indefinite self-renewal, slow replication, intrinsic resistance to chemotherapy and radiotherapy, and an ability to give rise to differentiated progeny. Through the use of xenotransplantation assays, putative CSCs have been identified in many cancers, often identified by markers usually expressed in normal stem cells. This is also the case in lung cancer, and the accumulated data on side population cells, CD133, CD166, CD44 and ALDH1 are beginning to clarify the true phenotype of the lung cancer stem cell. Furthermore, it is now clear that many of the pathways of normal stem cells, which guide cellular proliferation, differentiation, and apoptosis are also prominent in CSCs; the Hedgehog (Hh), Notch, and Wnt signaling pathways being notable examples. The CSC hypothesis suggests that there is a small reservoir of cells within the tumor, which are resistant to many standard therapies, and can give rise to new tumors in the form of metastases or relapses after apparent tumor regression. Therapeutic interventions that target CSC pathways are still in their infancy and clinical data of their efficacy remain limited. However Smoothened inhibitors, gamma-secretase inhibitors, anti-DLL4 antagonists, Wnt antagonists, and CBP/β-catenin inhibitors have all shown promising anticancer effects in early studies. The evidence to support the emerging picture of a lung cancer CSC phenotype and the development of novel therapeutic strategies to target CSCs are described in this review. The cancer stem-cell (CSC) hypothesis is a concept that has received a great deal of recent attention in recent years. Normal stem cells are characterized by a number of peculiar properties; multipotency, that is, the ability to differentiate into different cell types; self-renewal; and the ability to proliferate. These properties clearly have important parallels in oncogenesis and malignancy. Indeed, the concept that tumors may be derived from a rare population of embryo-like cells was discussed by Virchow1Virchow R An address on the value of pathological experiments.Br Med J. 1881; 2: 198-203Crossref PubMed Scopus (33) Google Scholar as early as the mid-nineteenth century. Other physicians of the time postulated that cancers may arise from dormant embryonic remnants in the body, which become activated to form tumors.2Durante F Nesso fisio-pathologico tra la struttura dei nei materni e la genesi di alcuni tumori maligni.Arch Memor Observ Chir Pract. 1874; 11: 217-226Google Scholar,3Cohnheim J Congenitales, quergestreiftes Muskelsarkon der Nireren.Virchows Arch. 1875; 65: 64Crossref Scopus (0) Google Scholar However, it is only in recent years that putative CSCs have been identified. CSCs can be defined as a rare population of stem-like cancer cells that define the clinical phenotype of tumors, with important roles in initiation, progression, and maintenance of tumors. An important concept in this model is that tumors are heterogenous, composed of neoplastic cells, vasculature, immune cells, and stromal elements. According to this model, tumors may be regarded as abnormal organs that contain a hierarchy of cells including self-renewing stem cells and highly proliferative progenitor cells that in turn give rise to the differentiated cells comprising the bulk of the tumor. It is important to note that although the CSCs may share many characteristics with normal stem cells, it is not certain that all CSCs in all cancer subtypes are derived from normal stem cells. It is also possible that cancer stem cells may arise from committed progenitor cells, which acquire stem-like characteristics. There is now evidence in many cancer subtypes that CSCs may arise from both normal stem cells4Kim CF Jackson EL Woolfenden AE et al.Identification of bronchioalveolar stem cells in normal lung and lung cancer.Cell. 2005; 121: 823-835Abstract Full Text Full Text PDF PubMed Scopus (1475) Google Scholar, 5Barker N Ridgway RA van Es JH et al.Crypt stem cells as the cells-of-origin of intestinal cancer.Nature. 2009; 457: 608-611Crossref PubMed Scopus (1152) Google Scholar, 6Barker N Huch M Kujala P et al.Lgr5(+ve) stem cells drive self-renewal in the stomach and build long-lived gastric units in vitro.Cell Stem Cell. 2010; 6: 25-36Abstract Full Text Full Text PDF PubMed Scopus (640) Google Scholar, 7Fialkow PJ Denman AM Jacobson RJ Lowenthal MN Chronic myelocytic leukemia. Origin of some lymphocytes from leukemic stem cells.J Clin Invest. 1978; 62: 815-823Crossref PubMed Google Scholar, 8Wang X Kruithof-de Julio M Economides KD et al.A luminal epithelial stem cell that is a cell of origin for prostate cancer.Nature. 2009; 461: 495-500Crossref PubMed Scopus (410) Google Scholar, 9Ooi AT Mah V Nickerson DW et al.Presence of a putative tumor-initiating progenitor cell population predicts poor prognosis in smokers with non-small cell lung cancer.Cancer Res. 2010; 70: 6639-6648Crossref PubMed Scopus (0) Google Scholar and differentiated progenitor cells.10Jamieson CH Ailles LE Dylla SJ et al.Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML.N Engl J Med. 2004; 351: 657-667Crossref PubMed Scopus (1114) Google Scholar, 11Goldstein AS Huang J Guo C Garraway IP Witte ON Identification of a cell of origin for human prostate cancer.Science. 2010; 329: 568-571Crossref PubMed Scopus (330) Google Scholar, 12Lim E Vaillant F Wu D kConFab et al.Aberrant luminal progenitors as the candidate target population for basal tumor development in BRCA1 mutation carriers.Nat Med. 2009; 15: 907-913Crossref PubMed Scopus (764) Google Scholar, 13Molyneux G Geyer FC Magnay FA et al.BRCA1 basal-like breast cancers originate from luminal epithelial progenitors and not from basal stem cells.Cell Stem Cell. 2010; 7: 403-417Abstract Full Text Full Text PDF PubMed Scopus (358) Google Scholar Importantly, one study in breast cancer has shown that undifferentiated estrogen receptor (ER) negative and poorly differentiated ER positive tumors arise from mammary stem cells whereas less-aggressive ER positive tumors arise from ER positive intermediate progenitor cells.14Dontu G El-Ashry D Wicha MS Breast cancer, stem/progenitor cells and the estrogen receptor.Trends Endocrinol Metab. 2004; 15: 193-197Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar Therefore, it is possible that the origin of CSCs may vary considerably among different cancers, among subtypes of individual cancers, and even among different stages of the same malignancy. This issue of the likely origin of CSCs has been reviewed in detail elsewhere.15Visvader JE Cells of origin in cancer.Nature. 2011; 469: 314-322Crossref PubMed Scopus (685) Google Scholar The experimental demonstration of the capacity for self-renewal, and the production of differentiated progeny, demonstrated by xenotransplantation models of metastasis, has succeeded in identifying putative CSCs in many cancer subtypes such as cancers of the brain, breast, lung, and of the hematopoietic system.16Singh SK Clarke ID Terasaki M et al.Identification of a cancer stem cell in human brain tumors.Cancer Res. 2003; 63: 5821-5828PubMed Google Scholar, 17Al-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: 3983-3988Crossref PubMed Scopus (6506) Google Scholar, 18Bonnet D Dick JE Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.Nat Med. 1997; 3: 730-737Crossref PubMed Scopus (4292) Google Scholar, 19Ho MM Ng AV Lam S Hung JY Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells.Cancer Res. 2007; 67: 4827-4833Crossref PubMed Scopus (710) Google Scholar, 20Eramo A Lotti F Sette G et al.Identification and expansion of the tumorigenic lung cancer stem cell population.Cell Death Differ. 2008; 15: 504-514Crossref PubMed Scopus (1080) Google Scholar, 21Jiang F Qiu Q Khanna A et al.Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer.Mol Cancer Res. 2009; 7: 330-338Crossref PubMed Scopus (479) Google Scholar Many of these putative stem cells also exhibit resistance to standard forms of treatment such as chemotherapy and radiotherapy.22Bao S Wu Q McLendon RE et al.Glioma stem cells promote radioresistance by preferential activation of the DNA damage response.Nature. 2006; 444: 756-760Crossref PubMed Scopus (3454) Google Scholar, 23Liu G Yuan X Zeng Z et al.Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma.Mol Cancer. 2006; 5: 67Crossref PubMed Scopus (1173) Google Scholar, 24Wulf GG Wang RY Kuehnle I et al.A leukemic stem cell with intrinsic drug efflux capacity in acute myeloid leukemia.Blood. 2001; 98: 1166-1173Crossref PubMed Scopus (273) Google Scholar, 25Hirschmann-Jax C Foster AE Wulf GG et al.A distinct “side population” of cells with high drug efflux capacity in human tumor cells.Proc Natl Acad Sci USA. 2004; 101: 14228-14233Crossref PubMed Scopus (981) Google Scholar This property is also shared by normal stem cells, often mediated by the overexpression of adenosine triphosphate–binding cassette (ABC) transporters that efflux drugs out of the cell, and conservation in CSCs is one of the likely causes of chemoresistance.26Chaudhary PM Roninson IB Expression and activity of P-glycoprotein, a multidrug efflux pump, in human hematopoietic stem cells.Cell. 1991; 66: 85-94Abstract Full Text PDF PubMed Google Scholar Therefore, CSCs can be the source of all the malignant cells in a primary tumor, can compose the small subset of drug- resistant cells that are responsible for relapse after a chemotherapy-induced remission, and can give rise to distant metastases (Fig. 1). Given that metastatic and relapsed tumors are responsible for the majority of cancer deaths, it may be reasonable to suppose that therapies that specifically target CSCs may help to improve outcomes. In recent years, there has been an increasing amount of evidence to support a CSC phenotype in human lung cancer.19Ho MM Ng AV Lam S Hung JY Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells.Cancer Res. 2007; 67: 4827-4833Crossref PubMed Scopus (710) Google Scholar, 20Eramo A Lotti F Sette G et al.Identification and expansion of the tumorigenic lung cancer stem cell population.Cell Death Differ. 2008; 15: 504-514Crossref PubMed Scopus (1080) Google Scholar, 21Jiang F Qiu Q Khanna A et al.Aldehyde dehydrogenase 1 is a tumor stem cell-associated marker in lung cancer.Mol Cancer Res. 2009; 7: 330-338Crossref PubMed Scopus (479) Google Scholar Many of these markers have also been found in other tumors and indeed in normal stem cells. One such phenotype is the so-called side population (SP) cells, which are capable of excluding Hoechst 33342 dye by ABC transporters. In addition, cells expressing the cell surface markers CD133 and CD166, cells with elevated nuclear β-catenin and elevated aldehyde dehydrogenase activity have also been shown to be indicative of a stem-cell–like population (Table 1).TABLE 1Putative Cancer Stem Cell Markers in NSCLC and SCLCType of CancerCSC MarkerReferencesNSCLCSPHo et al.19CD 133Eramo et al.20Bertolini et al.37ALDHJiang et al.21Ucar et al.53CD166Zhang et al.65CD 44Leung et al.69Nuclear ß-cateninGiangreco et al.75Levina et al.76SCLCSPSalcido et al.31CD 133Eramo et al.20NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer; SP, side population; ALDH, aldehyde dehydrogenase. Open table in a new tab NSCLC, non-small-cell lung cancer; SCLC, small-cell lung cancer; SP, side population; ALDH, aldehyde dehydrogenase. SP cells are now widely regarded to be stem cells in a number of malignancies, such as lung, breast, and glioblastomas as well as in normal hematopoietic cells.25Hirschmann-Jax C Foster AE Wulf GG et al.A distinct “side population” of cells with high drug efflux capacity in human tumor cells.Proc Natl Acad Sci USA. 2004; 101: 14228-14233Crossref PubMed Scopus (981) Google Scholar,27Wu C Alman BA Side population cells in human cancers.Cancer Lett. 2008; 268: 1-9Abstract Full Text Full Text PDF PubMed Scopus (248) Google Scholar, 28Zhou S Schuetz JD Bunting KD et al.The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.Nat Med. 2001; 7: 1028-1034Crossref PubMed Scopus (1753) Google Scholar, 29Hadnagy A Gaboury L Beaulieu R Balicki D SP analysis may be used to identify cancer stem cell populations.Exp Cell Res. 2006; 312: 3701-3710Crossref PubMed Scopus (247) Google Scholar, 30Goodell MA Brose K Paradis G Conner AS Mulligan RC Isolation and functional properties of murine hematopoietic stem cells that are replicating in vivo.J Exp Med. 1996; 183: 1797-1806Crossref PubMed Scopus (2228) Google Scholar They are characterized by the ability to efflux Hoechst 33342 dye from within the cell, and this particular subpopulation of cells can be isolated using fluorescence-activating cell sorting (FACS). SP cells have been shown to exhibit many of the required characteristics of stem cells such as self-renewal, production of differentiated progenitor cells, and the capacity to form tumors in non-obese diabetic/severe combined immunodeficiency mice. SP cells have been shown to express ABC transporters such as ABCG2, MDR1, ABCA2 etc., which have important roles in chemoresistance by active efflux of the drug from within the cell.28Zhou S Schuetz JD Bunting KD et al.The ABC transporter Bcrp1/ABCG2 is expressed in a wide variety of stem cells and is a molecular determinant of the side-population phenotype.Nat Med. 2001; 7: 1028-1034Crossref PubMed Scopus (1753) Google Scholar SP cells have been successfully identified in both non–small-cell and small-cell lung cancer cell lines.19Ho MM Ng AV Lam S Hung JY Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells.Cancer Res. 2007; 67: 4827-4833Crossref PubMed Scopus (710) Google Scholar,31Salcido CD Larochelle A Taylor BJ Dunbar CE Varticovski L Molecular characterisation of side population cells with cancer stem cell-like characteristics in small-cell lung cancer.Br J Cancer. 2010; 102: 1636-1644Crossref PubMed Scopus (93) Google Scholar Ho et al.19Ho MM Ng AV Lam S Hung JY Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells.Cancer Res. 2007; 67: 4827-4833Crossref PubMed Scopus (710) Google Scholar examined the SP fraction in six non–small-cell lung cancer (NSCLC) cell lines and a small number of clinical samples. They found that the SP fraction was the tumorigenic population in a xenotransplantation model requiring far fewer cells to initiate a tumor than the non-SP fraction. Subsequent analysis of the SP-derived tumors also showed their differentiation into both SP and non-SP cells. This repopulation ability was also confirmed in vitro. ABC transporters such as ABCG2, ABCA2, and MDR1 were significantly up-regulated in the SP fraction, and the SP fraction demonstrated increased resistance to a panel of seven different chemotherapy drugs. In addition, human telomerase reverse transcriptase expression was higher in the SP, suggesting that this fraction may represent a reservoir with unlimited proliferative potential for generating cancer cells. Salcido et al.31Salcido CD Larochelle A Taylor BJ Dunbar CE Varticovski L Molecular characterisation of side population cells with cancer stem cell-like characteristics in small-cell lung cancer.Br J Cancer. 2010; 102: 1636-1644Crossref PubMed Scopus (93) Google Scholar similarly examined the SP fraction in a number of small-cell lung cancer (SCLC) cell lines. The cell lines examined contained SP cells at a rate of less than 1% of the total population. Again SP cells were much more tumorigenic than non-SP cells with as few as 50 to 100 SP cells successfully forming tumors in immunodeficient mice, and again the xenograft tumors subsequently regenerated both SP and non-SP cells. In addition, the neuroendocrine markers CD56 and CD90, characteristic of SCLC, were expressed significantly less in SP fraction cells than in the non-SP fraction, consistent with the primitive nature of SP cells. SP fraction cells had up-regulated genes that are involved in pathways modulating stemness, including MYC, FGF1, OCT4, KLF4, NOTCH2, WNT, and ABCG2. These data strongly suggest that the SP population is composed of highly undifferentiated cells with stem cell-like characteristics and resistance to standard chemotherapy. The CD133 antigen, also sometimes referred to as Prominin 1 (PROM1), is a 120 kDa five transmembrane glycoprotein. Its function is currently not known but its expression on the cell surface has been demonstrated to be a specific marker for CSCs in a number of malignancies including central nervous system tumors, colon, breast, prostate, and ovarian cancers.16Singh SK Clarke ID Terasaki M et al.Identification of a cancer stem cell in human brain tumors.Cancer Res. 2003; 63: 5821-5828PubMed Google Scholar,17Al-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: 3983-3988Crossref PubMed Scopus (6506) Google Scholar,32Ricci-Vitiani L Lombardi DG Pilozzi E et al.Identification and expansion of human colon-cancer-initiating cells.Nature. 2007; 445: 111-115Crossref PubMed Scopus (2719) Google Scholar, 33O’Brien CA Pollett A Gallinger S Dick JE A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.Nature. 2007; 445: 106-110Crossref PubMed Scopus (2832) Google Scholar, 34Collins AT Berry PA Hyde C Stower MJ Maitland NJ Prospective identification of tumorigenic prostate cancer stem cells.Cancer Res. 2005; 65: 10946-10951Crossref PubMed Scopus (1963) Google Scholar, 35Bapat SA Mali AM Koppikar CB Kurrey NK Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer.Cancer Res. 2005; 65: 3025-3029Crossref PubMed Google Scholar There is now also considerable evidence to suggest that CD133 expression on a subpopulation of lung cancer cells also identifies CSCs.20Eramo A Lotti F Sette G et al.Identification and expansion of the tumorigenic lung cancer stem cell population.Cell Death Differ. 2008; 15: 504-514Crossref PubMed Scopus (1080) Google Scholar,36Tirino V Desiderio V d’Aquino R et al.Detection and characterization of CD133+ cancer stem cells in human solid tumours.PLoS ONE. 2008; 3: e3469Crossref PubMed Scopus (0) Google Scholar, 37Bertolini G Roz L Perego P et al.Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment.Proc Natl Acad Sci USA. 2009; 106: 16281-16286Crossref PubMed Scopus (505) Google Scholar, 38Jiang T Collins BJ Jin N et al.Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer.Cancer Res. 2009; 69: 845-854Crossref PubMed Scopus (98) Google Scholar Eramo et al.20Eramo A Lotti F Sette G et al.Identification and expansion of the tumorigenic lung cancer stem cell population.Cell Death Differ. 2008; 15: 504-514Crossref PubMed Scopus (1080) Google Scholar demonstrated that there is a rare population of CD133 positive cells in SCLC and in all subtypes of NSCLC. Lung cancer cells dissociated from primary tumors and grown in serum-free media containing epidermal growth factor and fibroblast growth factor formed spheroid bodies, which became enriched for CD133 positive cells and could be maintained indefinitely. In contrast, CD133 negative cells did not acquire CD133 positivity and died within 2 to 3 weeks of culture. Upon the exposure of CD133 positive cells to serum-containing media, the lung cancer spheres adhered to the plastic and acquired the typical morphological appearance of differentiated cells. In the process of differentiation CD133 expression was lost, confirming its specificity for undifferentiated cells. CD133 positive cells were also found to express BCRP1/ABCG2 ABC transporter and were found to be relatively chemoresistant to cisplatin, etoposide, paclitaxel, and gemcitabine. Xenograft experiments also established that the CD133 positive population was highly tumorigenic, with as few as 104 CD133+ cells consistently generating tumors in NOD/SCID mice, whereas 10 times that amount of CD133- cells were not tumorigenic. Subsequent histological examination of xenograft tumors confirmed the generation of a differentiated cell population with a similar number of CD133+ cells as the parent tumor. These results were largely replicated in the work of Bertolini et al.37Bertolini G Roz L Perego P et al.Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment.Proc Natl Acad Sci USA. 2009; 106: 16281-16286Crossref PubMed Scopus (505) Google Scholar They also found a rare subpopulation of lung cancer cells expressing CD133 with a much lower level of positivity in normal lung tissue. Similarly, they also confirmed the increased tumor-initiating capacity of CD133+cells in xenograft models. CD133+ cells isolated from established xenografts, primary tumor specimens, and cell lines by FACS were found to be considerably more tumorigenic upon injection into NOD/SCID mice. Gene-expression analysis showed that genes associated with maintenance of stemness such as OCT4 and NANOG, and adhesion and motility genes such as α-6 integrin and CXCR4, were up-regulated in CD133+ cells. In addition, the expression of ABC transporter genes associated with the multidrug-resistance phenotype such as ABCC1 and ABCG2 were also found to increase in the CD133+ fraction. Chemoresistance to cisplatin of the CD133+ fraction was demonstrated in both in vitro and in vivo models. In vitro, exposure of lung cancer cell line A549 to cisplatin resulted in an eightfold increase in the number of CD133+ cells. In vivo, mice with six different lung cancer xenografts were treated with weekly cisplatin. Mice were killed at 7 days after the last treatment and at the time of tumor regrowth. FACS analysis of the resected tumors revealed marked enrichment of CD133+ cells shortly after chemotherapy but this reverted to original levels at time of tumor regrowth. These findings suggest that CD133+ cells persist in exposure to chemotherapy and are subsequently able to re-establish a tumor that had previously responded to treatment. Levels of CD133 expression in primary tumors as determined by immunohistochemistry were compared with clinical outcomes in a small cohort of advanced-stage patients undergoing platinum-based chemotherapy. There was a trend toward decreased progression-free survival in those patients found to express CD133 in their primary tumors, which is consistent with the above data regarding the relative chemoresistance of CD133+ cells. Interestingly, Zhu et al.39Zhu L Gibson P Currle DS et al.Prominin 1 marks intestinal stem cells that are susceptible to neoplastic transformation.Nature. 2009; 457: 603-607Crossref PubMed Scopus (453) Google Scholar have reported that in a murine intestinal model, PROM1/CD133 marks an adult solid tissue stem cell that is susceptible to neoplastic transformation, supporting a model of a Prom1/CD133+ cancer stem cell. Using tamoxifen-induced Cre to activate fluorescence in CD133+ cells the investigators showed that PROM1/CD133 positivity successfully identifies normal stem cells in the intestine, giving rise to all differentiated cell types of the intestinal epithelium. In addition, activation of endogenous Wnt signaling in mice containing a Cre-dependent mutant allele of β-Catenin resulted in neoplastic transformation of PROM1/CD133+ cells in the intestine. These data suggest that CD133+ normal stem cells may be the cell of origin in certain cancers. Furthermore, in SCLC, it has been suggested that the neuroendocrine-regulating transcription factor, achaete-scute complex homologue 1 (ASCL1) may be an important regulator of stem-cell markers such as CD133 and aldehyde dehydrogenase (ALDH). Jiang et al.38Jiang T Collins BJ Jin N et al.Achaete-scute complex homologue 1 regulates tumor-initiating capacity in human small cell lung cancer.Cancer Res. 2009; 69: 845-854Crossref PubMed Scopus (98) Google Scholar showed that ASCL1 caused induction of both CD133 and ALDH1A1, and that using siRNA transfection to repress ASCL1 caused reduced growth and inhibited soft agar clonogenicity in cultured SCLC. It was also shown that SCLC direct xenograft tumors that were enriched for CD133 positivity had greatly increased tumorigenicity. In addition, the knockdown of ASCL1 in these xenografts using ASCL1 shRNA caused a marked decrease in their tumor-initiating potential when compared with controls. However, there have been some conflicting data on the role of CD133 and CSCs. Meng et al.40Meng X Li M Wang X Wang Y Ma D Both CD133+ and CD133- subpopulations of A549 and H446 cells contain cancer-initiating cells.Cancer Sci. 2009; 100: 1040-1046Crossref PubMed Scopus (0) Google Scholar found that CD133 status in A549 and H446 cell lines was not significantly related to proliferative capacity, invasiveness, drug resistance, or tumorigenic ability in xenograft models. Salnikov et al.41Salnikov AV Gladkich J Moldenhauer G Volm M Mattern J Herr I CD133 is indicative for a resistance phenotype but does not represent a prognostic marker for survival of non-small cell lung cancer patients.Int J Cancer. 2010; 126: 950-958PubMed Google Scholar also demonstrated that CD133 expression in NSCLC was not prognostic. Therefore, although there are some conflicting data in this area, the weight of the available data strongly suggests an important role for CD133 in correctly identifying lung CSCs. ALDH enzyme activity has also emerged as a promising marker of CSCs and indeed of normal stem cells. It has been known for some time that ALDH is highly expressed in normal hematopoietic stem cells,42Kastan MB Schlaffer E Russo JE Colvin OM Civin CI Hilton J Direct demonstration of elevated aldehyde dehydrogenase in human hematopoietic progenitor cells.Blood. 1990; 75: 1947-1950Crossref PubMed Google Scholar,43Storms RW Trujillo AP Springer JB et al.Isolation of primitive human hematopoietic progenitors on the basis of aldehyde dehydrogenase activity.Proc Natl Acad Sci USA. 1999; 96: 9118-9123Crossref PubMed Scopus (348) Google Scholar and in addition to being a putative stem-cell marker, ALDH activity also has a known role in drug resistance.44Manthey CL Landkamer GJ Sladek NE Identification of the mouse aldehyde dehydrogenases important in aldophosphamide detoxification.Cancer Res. 1990; 50: 4991-5002PubMed Google Scholar, 45Hilton J Role of aldehyde dehydrogenase in cyclophosphamide-resistant L1210 leukemia.Cancer Res. 1984; 44: 5156-5160PubMed Google Scholar, 46Sladek NE Landkamer GJ Restoration of sensitivity to oxazaphosphorines by inhibitors of aldehyde dehydrogenase activity in cultured oxazaphosphorine-resistant L1210 and cross-linking agent-resistant P388 cell lines.Cancer Res. 1985; 45: 1549-1555PubMed Google Scholar, 47von Eitzen U Meier-Tackmann D Agarwal DP Goedde HW Detoxification of cyclophosphamide by human aldehyde dehydrogenase isozymes.Cancer Lett. 1994; 76: 45-49Abstract Full Text PDF PubMed Scopus (0) Google Scholar ALDH activity has been used as a basis for an FACS method to sort viable hematopoietic stem cells from mixed cell populations for further study (Aldeflour assay, Stem Cell Technologies, Vancouver, BC, V5Z 1B3, Canada). This method has been subsequently applied in many malignancies and ALDH activity has identified potential CSCs in leukemia, breast cancer, brain cancer, head and neck squamous cell cancers, colon cancer, and also now lung cancers.48Cheung AM Wan TS Leung JC et al.Aldehyde dehydrogenase activity in leukemic blasts defines a subgroup of acute myeloid leukemia with adverse progno" @default.
• W2000502676 created "2016-06-24" @default.
• W2000502676 creator A5014439190 @default.
• W2000502676 creator A5033082307 @default.
• W2000502676 creator A5033519199 @default.
• W2000502676 creator A5043621658 @default.
• W2000502676 creator A5060504556 @default.
• W2000502676 creator A5061866475 @default.
• W2000502676 creator A5084298463 @default.
• W2000502676 date "2012-12-01" @default.
• W2000502676 modified "2023-10-18" @default.
• W2000502676 title "The Cancer Stem-Cell Hypothesis: Its Emerging Role in Lung Cancer Biology and Its Relevance for Future Therapy" @default.
• W2000502676 cites W1483167997 @default.
• W2000502676 cites W1495710350 @default.
• W2000502676 cites W1500827124 @default.
• W2000502676 cites W1607596367 @default.
• W2000502676 cites W1611210979 @default.
• W2000502676 cites W1964470628 @default.
• W2000502676 cites W1965431780 @default.
• W2000502676 cites W1967656020 @default.
• W2000502676 cites W1969202196 @default.
• W2000502676 cites W1970170800 @default.
• W2000502676 cites W1974089576 @default.
• W2000502676 cites W1975306683 @default.
• W2000502676 cites W1975635025 @default.
• W2000502676 cites W1978747495 @default.
• W2000502676 cites W1979547093 @default.
• W2000502676 cites W1983357205 @default.
• W2000502676 cites W1985447080 @default.
• W2000502676 cites W1988459185 @default.
• W2000502676 cites W1990099538 @default.
• W2000502676 cites W1992676863 @default.
• W2000502676 cites W1993423043 @default.
• W2000502676 cites W1994599132 @default.
• W2000502676 cites W2001144553 @default.
• W2000502676 cites W2002249795 @default.
• W2000502676 cites W2007775064 @default.
• W2000502676 cites W2008549209 @default.
• W2000502676 cites W2009886857 @default.
• W2000502676 cites W2011994267 @default.
• W2000502676 cites W2012962381 @default.
• W2000502676 cites W2014406829 @default.
• W2000502676 cites W2022881840 @default.
• W2000502676 cites W2023316892 @default.
• W2000502676 cites W2023427658 @default.
• W2000502676 cites W2024166942 @default.
• W2000502676 cites W2025109766 @default.
• W2000502676 cites W2029231546 @default.
• W2000502676 cites W2030199762 @default.
• W2000502676 cites W2035316009 @default.
• W2000502676 cites W2035469701 @default.
• W2000502676 cites W2036041106 @default.
• W2000502676 cites W2037416803 @default.
• W2000502676 cites W2044409007 @default.
• W2000502676 cites W2045729702 @default.
• W2000502676 cites W2047267718 @default.
• W2000502676 cites W2049700579 @default.
• W2000502676 cites W2051055358 @default.
• W2000502676 cites W2053354626 @default.
• W2000502676 cites W2055296003 @default.
• W2000502676 cites W2059022111 @default.
• W2000502676 cites W2060551076 @default.
• W2000502676 cites W2062069005 @default.
• W2000502676 cites W2063478423 @default.
• W2000502676 cites W2064980964 @default.
• W2000502676 cites W2071133953 @default.
• W2000502676 cites W2073302269 @default.
• W2000502676 cites W2073759231 @default.
• W2000502676 cites W2076949588 @default.
• W2000502676 cites W2078597021 @default.
• W2000502676 cites W2081447858 @default.
• W2000502676 cites W2082210456 @default.
• W2000502676 cites W2082436048 @default.
• W2000502676 cites W2084488214 @default.
• W2000502676 cites W2084745919 @default.
• W2000502676 cites W2086943348 @default.
• W2000502676 cites W2090562908 @default.
• W2000502676 cites W2092123619 @default.
• W2000502676 cites W2094238788 @default.
• W2000502676 cites W2097387056 @default.
• W2000502676 cites W2098345971 @default.
• W2000502676 cites W2099293048 @default.
• W2000502676 cites W2099762777 @default.
• W2000502676 cites W2101029920 @default.
• W2000502676 cites W2103519363 @default.
• W2000502676 cites W2104098330 @default.
• W2000502676 cites W2105902643 @default.
• W2000502676 cites W2105953048 @default.
• W2000502676 cites W2107337105 @default.
• W2000502676 cites W2108035852 @default.
• W2000502676 cites W2108707301 @default.
• W2000502676 cites W2110838173 @default.
• W2000502676 cites W2111724542 @default.
• W2000502676 cites W2113342764 @default.
• W2000502676 cites W2113702155 @default.
• W2000502676 cites W2114921350 @default.
• W2000502676 cites W2115001053 @default.
• W2000502676 cites W2118758371 @default.

• next