The role of CD133 in cancer: a concise review

Health, United States (2016) Centers for disease control and prevention 2016. http://www.cdc.gov/nchs/hus/contents2016.htm#019 Economic Impact of Cancer American Cancer Society (2018) https://www.cancer.org/cancer/cancer-basics/economic-impact-of-cancer.html Rahman M, Deleyrolle L, Vedam-Mai V, Azari H, Abd-El-Barr M, Reynolds BA (2011) The cancer stem cell hypothesis: failures and pitfalls. Neurosurgery 68(2):531–545 (discussion 45) Talukdar S, Emdad L, Das SK, Sarkar D, Fisher PB (2016) Evolving strategies for therapeutically targeting cancer stem cells. Adv Cancer Res 131:159–191 Shackleton M, Quintana E, Fearon ER, Morrison SJ (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5):822–829 McGranahan N, Swanton C (2017) Clonal heterogeneity and tumor evolution: past, present, and the future. Cell 168(4):613–628 Nowell PC (1976) The clonal evolution of tumor cell populations. Science 194(4260):23–28 Zhao B, Hemann MT, Lauffenburger DA (2016) Modeling tumor clonal evolution for drug combinations design. Trends Cancer 2(3):144–158 Greaves M, Maley CC (2012) Clonal evolution in cancer. Nature 481(7381):306–313 Sidransky D, Mikkelsen T, Schwechheimer K, Rosenblum ML, Cavanee W, Vogelstein B (1992) Clonal expansion of p53 mutant cells is associated with brain tumour progression. Nature 355(6363):846–847 Shah SP, Morin RD, Khattra J, Prentice L, Pugh T, Burleigh A et al (2009) Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature 461(7265):809–813 Campbell PJ, Yachida S, Mudie LJ, Stephens PJ, Pleasance ED, Stebbings LA et al (2010) The patterns and dynamics of genomic instability in metastatic pancreatic cancer. Nature 467(7319):1109–1113 Yachida S, Jones S, Bozic I, Antal T, Leary R, Fu B et al (2010) Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 467(7319):1114–1117 Ding L, Ley TJ, Larson DE, Miller CA, Koboldt DC, Welch JS et al (2012) Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing. Nature 481(7382):506–510 Schuh A, Becq J, Humphray S, Alexa A, Burns A, Clifford R et al (2012) Monitoring chronic lymphocytic leukemia progression by whole genome sequencing reveals heterogeneous clonal evolution patterns. Blood 120(20):4191–4196 Walter MJ, Shen D, Ding L, Shao J, Koboldt DC, Chen K et al (2012) Clonal architecture of secondary acute myeloid leukemia. N Engl J Med 366(12):1090–1098 Fisher R, Pusztai L, Swanton C (2013) Cancer heterogeneity: implications for targeted therapeutics. Br J Cancer 108(3):479–485 Ebben JD, Treisman DM, Zorniak M, Kutty RG, Clark PA, Kuo JS (2010) The cancer stem cell paradigm: a new understanding of tumor development and treatment. Expert Opin Ther Targets 14(6):621–632 Borovski T, Vermeulen L, Sprick MR, Medema JP (2009) One renegade cancer stem cell? Cell Cycle 8(6):803–808 Vermeulen L, Sprick MR, Kemper K, Stassi G, Medema JP (2008) Cancer stem cells—old concepts, new insights. Cell Death Differ 15(6):947–958 Garg M (2017) Epithelial plasticity and cancer stem cells: major mechanisms of cancer pathogenesis and therapy resistance. World J Stem Cells 9(8):118–126 Krause M, Dubrovska A, Linge A, Baumann M (2017) Cancer stem cells: radioresistance, prediction of radiotherapy outcome and specific targets for combined treatments. Adv Drug Deliv Rev 109:63–73 Kim WT, Ryu CJ (2017) Cancer stem cell surface markers on normal stem cells. BMB Rep 50(6):285–298 Corbeil D, Karbanova J, Fargeas CA, Jaszai J (2013) Prominin-1 (CD133): molecular and cellular features across species. Adv Exp Med Biol 777:3–24 Liu Y, Ren S, Xie L, Cui C, Xing Y, Liu C et al (2015) Mutation of N-linked glycosylation at Asn548 in CD133 decreases its ability to promote hepatoma cell growth. Oncotarget 6(24):20650–20660 Elsaba TM, Martinez-Pomares L, Robins AR, Crook S, Seth R, Jackson D et al (2010) The stem cell marker CD133 associates with enhanced colony formation and cell motility in colorectal cancer. PLoS ONE 5(5):e10714 Kemper K, Sprick MR, de Bree M, Scopelliti A, Vermeulen L, Hoek M et al (2010) The AC133 epitope, but not the CD133 protein, is lost upon cancer stem cell differentiation. Cancer Res 70(2):719–729 Thamm K, Graupner S, Werner C, Huttner WB, Corbeil D (2016) Monoclonal Antibodies 13A4 and AC133 do not recognize the canine ortholog of mouse and human stem cell antigen prominin-1 (CD133). PLoS ONE 11(10):e0164079 Bidlingmaier S, Zhu X, Liu B (2008) The utility and limitations of glycosylated human CD133 epitopes in defining cancer stem cells. J Mol Med (Berl) 86(9):1025–1032 Shmelkov SV, Jun L, St Clair R, McGarrigle D, Derderian CA, Usenko JK et al (2004) Alternative promoters regulate transcription of the gene that encodes stem cell surface protein AC133. Blood 103(6):2055–2061 Grosse-Gehling P, Fargeas CA, Dittfeld C, Garbe Y, Alison MR, Corbeil D et al (2013) CD133 as a biomarker for putative cancer stem cells in solid tumours: limitations, problems and challenges. J Pathol 229(3):355–378 Fargeas CA, Joester A, Missol-Kolka E, Hellwig A, Huttner WB, Corbeil D (2004) Identification of novel Prominin-1/CD133 splice variants with alternative C-termini and their expression in epididymis and testis. J Cell Sci 117(Pt 18):4301–4311 Corbeil D, Roper K, Fargeas CA, Joester A, Huttner WB (2001) Prominin: a story of cholesterol, plasma membrane protrusions and human pathology. Traffic 2(2):82–91 Su YJ, Lin WH, Chang YW, Wei KC, Liang CL, Chen SC et al (2015) Polarized cell migration induces cancer type-specific CD133/integrin/Src/Akt/GSK3beta/beta-catenin signaling required for maintenance of cancer stem cell properties. Oncotarget 6(35):38029–38045 Roper K, Corbeil D, Huttner WB (2000) Retention of prominin in microvilli reveals distinct cholesterol-based lipid micro-domains in the apical plasma membrane. Nat Cell Biol 2(9):582–592 Zacchigna S, Oh H, Wilsch-Brauninger M, Missol-Kolka E, Jaszai J, Jansen S et al (2009) Loss of the cholesterol-binding protein prominin-1/CD133 causes disk dysmorphogenesis and photoreceptor degeneration. J Neurosci 29(7):2297–2308 Kosodo Y, Roper K, Haubensak W, Marzesco AM, Corbeil D, Huttner WB (2004) Asymmetric distribution of the apical plasma membrane during neurogenic divisions of mammalian neuroepithelial cells. EMBO J 23(11):2314–2324 Bauer N, Wilsch-Brauninger M, Karbanova J, Fonseca AV, Strauss D, Freund D et al (2011) Haematopoietic stem cell differentiation promotes the release of prominin-1/CD133-containing membrane vesicles—a role of the endocytic-exocytic pathway. EMBO Mol Med 3(7):398–409 Marzesco AM, Janich P, Wilsch-Brauninger M, Dubreuil V, Langenfeld K, Corbeil D et al (2005) Release of extracellular membrane particles carrying the stem cell marker prominin-1 (CD133) from neural progenitors and other epithelial cells. J Cell Sci 118(Pt 13):2849–2858 Bauer N, Fonseca AV, Florek M, Freund D, Jaszai J, Bornhauser M et al (2008) New insights into the cell biology of hematopoietic progenitors by studying prominin-1 (CD133). Cells Tissues Organs 188(1–2):127–138 Jaksch M, Munera J, Bajpai R, Terskikh A, Oshima RG (2008) Cell cycle-dependent variation of a CD133 epitope in human embryonic stem cell, colon cancer, and melanoma cell lines. Cancer Res 68(19):7882–7886 Bussolati B, Moggio A, Collino F, Aghemo G, D’Armento G, Grange C et al (2012) Hypoxia modulates the undifferentiated phenotype of human renal inner medullary CD133+ progenitors through Oct4/miR-145 balance. Am J Physiol Renal Physiol 302(1):F116–F128 Maeda K, Ding Q, Yoshimitsu M, Kuwahata T, Miyazaki Y, Tsukasa K et al (2016) CD133 modulate HIF-1alpha expression under hypoxia in emt phenotype pancreatic cancer stem-like cells. Int J Mol Sci 17(7):1025 Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD et al (2009) Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. Oncogene 28(45):3949–3959 Iida H, Suzuki M, Goitsuka R, Ueno H (2012) Hypoxia induces CD133 expression in human lung cancer cells by up-regulation of OCT3/4 and SOX2. Int J Oncol 40(1):71–79 Griguer CE, Oliva CR, Gobin E, Marcorelles P, Benos DJ, Lancaster JR Jr et al (2008) CD133 is a marker of bioenergetic stress in human glioma. PLoS ONE 3(11):e3655 Yang C, Yang Y, Gupta N, Liu X, He A, Liu L et al (2007) Pentaspan membrane glycoprotein, prominin-1, is involved in glucose metabolism and cytoskeleton alteration. Biochemistry (Mosc) 72(8):854–862 Bourseau-Guilmain E, Griveau A, Benoit JP, Garcion E (2011) The importance of the stem cell marker prominin-1/CD133 in the uptake of transferrin and in iron metabolism in human colon cancer Caco-2 cells. PLoS ONE 6(9):e25515 Bisson I, Prowse DM (2009) WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res 19(6):683–697 Rappa G, Mercapide J, Anzanello F, Le TT, Johlfs MG, Fiscus RR et al (2013) Wnt interaction and extracellular release of prominin-1/CD133 in human malignant melanoma cells. Exp Cell Res 319(6):810–819 Mak AB, Nixon AM, Kittanakom S, Stewart JM, Chen GI, Curak J et al (2012) Regulation of CD133 by HDAC6 promotes beta-catenin signaling to suppress cancer cell differentiation. Cell Rep 2(4):951–963 Brossa A, Papadimitriou E, Collino F, Incarnato D, Oliviero S, Camussi G et al (2018) Role of CD133 molecule in Wnt response and renal repair. Stem Cells Transl Med 7(3):283–294 Dubrovska A, Kim S, Salamone RJ, Walker JR, Maira SM, Garcia-Echeverria C et al (2009) The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc Natl Acad Sci USA 106(1):268–273 Sahlberg SH, Spiegelberg D, Glimelius B, Stenerlow B, Nestor M (2014) Evaluation of cancer stem cell markers CD133, CD44, CD24: association with AKT isoforms and radiation resistance in colon cancer cells. PLoS ONE 9(4):e94621 Wei Y, Jiang Y, Zou F, Liu Y, Wang S, Xu N et al (2013) Activation of PI3K/Akt pathway by CD133-p85 interaction promotes tumorigenic capacity of glioma stem cells. Proc Natl Acad Sci USA 110(17):6829–6834 Shmelkov SV, Butler JM, Hooper AT, Hormigo A, Kushner J, Milde T et al (2008) CD133 expression is not restricted to stem cells, and both CD133+ and CD133− metastatic colon cancer cells initiate tumors. J Clin Invest 118(6):2111–2120 Yin AH, Miraglia S, Zanjani ED, Almeida-Porada G, Ogawa M, Leary AG et al (1997) AC133, a novel marker for human hematopoietic stem and progenitor cells. Blood 90(12):5002–5012 Miraglia S, Godfrey W, Yin AH, Atkins K, Warnke R, Holden JT et al (1997) A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning. Blood 90(12):5013–5021 Kuci S, Wessels JT, Buhring HJ, Schilbach K, Schumm M, Seitz G et al (2003) Identification of a novel class of human adherent CD34− stem cells that give rise to SCID-repopulating cells. Blood 101(3):869–876 Arndt K, Grinenko T, Mende N, Reichert D, Portz M, Ripich T et al (2013) CD133 is a modifier of hematopoietic progenitor frequencies but is dispensable for the maintenance of mouse hematopoietic stem cells. Proc Natl Acad Sci USA 110(14):5582–5587 Tamaki S, Eckert K, He D, Sutton R, Doshe M, Jain G et al (2002) Engraftment of sorted/expanded human central nervous system stem cells from fetal brain. J Neurosci Res 69(6):976–986 Uchida N, Buck DW, He D, Reitsma MJ, Masek M, Phan TV et al (2000) Direct isolation of human central nervous system stem cells. Proc Natl Acad Sci USA 97(26):14720–14725 Lee A, Kessler JD, Read TA, Kaiser C, Corbeil D, Huttner WB et al (2005) Isolation of neural stem cells from the postnatal cerebellum. Nat Neurosci 8(6):723–729 Sun Y, Kong W, Falk A, Hu J, Zhou L, Pollard S et al (2009) CD133 (Prominin) negative human neural stem cells are clonogenic and tripotent. PLoS ONE 4(5):e5498 Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT (2004) CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117(Pt 16):3539–3545 Leong KG, Wang BE, Johnson L, Gao WQ (2008) Generation of a prostate from a single adult stem cell. Nature 456(7223):804–808 Collins AT, Habib FK, Maitland NJ, Neal DE (2001) Identification and isolation of human prostate epithelial stem cells based on alpha(2)beta(1)-integrin expression. J Cell Sci 114(Pt 21):3865–3872 Schmelz M, Moll R, Hesse U, Prasad AR, Gandolfi JA, Hasan SR et al (2005) Identification of a stem cell candidate in the normal human prostate gland. Eur J Cell Biol 84(2–3):341–354 Missol-Kolka E, Karbanova J, Janich P, Haase M, Fargeas CA, Huttner WB et al (2011) Prominin-1 (CD133) is not restricted to stem cells located in the basal compartment of murine and human prostate. Prostate 71(3):254–267 Wei X, Orjalo AV, Xin L (2016) CD133 does not enrich for the stem cell activity in vivo in adult mouse prostates. Stem Cell Res 16(3):597–606 Immervoll H, Hoem D, Sakariassen PO, Steffensen OJ, Molven A (2008) Expression of the “stem cell marker” CD133 in pancreas and pancreatic ductal adenocarcinomas. BMC Cancer 8:48 Lardon J, Corbeil D, Huttner WB, Ling Z, Bouwens L (2008) Stem cell marker prominin-1/AC133 is expressed in duct cells of the adult human pancreas. Pancreas 36(1):e1–e6 Rountree CB, Ding W, Dang H, Vankirk C, Crooks GM (2011) Isolation of CD133+ liver stem cells for clonal expansion. J Vis Exp 56:3183 Schmelzer E, Zhang L, Bruce A, Wauthier E, Ludlow J, Yao HL et al (2007) Human hepatic stem cells from fetal and postnatal donors. J Exp Med 204(8):1973–1987 Feng HL, Liu YQ, Yang LJ, Bian XC, Yang ZL, Gu B et al (2010) Expression of CD133 correlates with differentiation of human colon cancer cells. Cancer Biol Ther 9(3):216–223 Fukamachi H, Shimada S, Ito K, Ito Y, Yuasa Y (2011) CD133 is a marker of gland-forming cells in gastric tumors and Sox17 is involved in its regulation. Cancer Sci 102(7):1313–1321 Karbanova J, Missol-Kolka E, Fonseca AV, Lorra C, Janich P, Hollerova H et al (2008) The stem cell marker CD133 (Prominin-1) is expressed in various human glandular epithelia. J Histochem Cytochem 56(11):977–993 Jaszai J, Janich P, Farkas LM, Fargeas CA, Huttner WB, Corbeil D (2007) Differential expression of Prominin-1 (CD133) and Prominin-2 in major cephalic exocrine glands of adult mice. Histochem Cell Biol 128(5):409–419 Sagrinati C, Netti GS, Mazzinghi B, Lazzeri E, Liotta F, Frosali F et al (2006) Isolation and characterization of multipotent progenitor cells from the Bowman’s capsule of adult human kidneys. J Am Soc Nephrol 17(9):2443–2456 Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al (2004) Identification of human brain tumour initiating cells. Nature 432(7015):396–401 Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ (2005) Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 65(23):10946–10951 O’Brien CA, Pollett A, Gallinger S, Dick JE (2007) A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445(7123):106–110 Eramo A, Lotti F, Sette G, Pilozzi E, Biffoni M, Di Virgilio A et al (2008) Identification and expansion of the tumorigenic lung cancer stem cell population. Cell Death Differ 15(3):504–514 Suetsugu A, Nagaki M, Aoki H, Motohashi T, Kunisada T, Moriwaki H (2006) Characterization of CD133+ hepatocellular carcinoma cells as cancer stem/progenitor cells. Biochem Biophys Res Commun 351(4):820–824 Kryczek I, Liu S, Roh M, Vatan L, Szeliga W, Wei S et al (2012) Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells. Int J Cancer 130(1):29–39 Cioffi M, D’Alterio C, Camerlingo R, Tirino V, Consales C, Riccio A et al (2015) Identification of a distinct population of CD133(+)CXCR4(+) cancer stem cells in ovarian cancer. Sci Rep 5:10357 Singh SK, Clarke ID, Terasaki M, Bonn VE, Hawkins C, Squire J et al (2003) Identification of a cancer stem cell in human brain tumors. Cancer Res 63(18):5821–5828 Beier D, Hau P, Proescholdt M, Lohmeier A, Wischhusen J, Oefner PJ et al (2007) CD133(+) and CD133(−) glioblastoma-derived cancer stem cells show differential growth characteristics and molecular profiles. Cancer Res 67(9):4010–4015 Li B, McCrudden CM, Yuen HF, Xi X, Lyu P, Chan KW et al (2017) CD133 in brain tumor: the prognostic factor. Oncotarget 8(7):11144–11159 Wu B, Sun C, Feng F, Ge M, Xia L (2015) Do relevant markers of cancer stem cells CD133 and Nestin indicate a poor prognosis in glioma patients? A systematic review and meta-analysis. J Exp Clin Cancer Res 34:44 Zeppernick F, Ahmadi R, Campos B, Dictus C, Helmke BM, Becker N et al (2008) Stem cell marker CD133 affects clinical outcome in glioma patients. Clin Cancer Res 14(1):123–129 Han M, Guo L, Zhang Y, Huang B, Chen A, Chen W et al (2016) Clinicopathological and prognostic significance of CD133 in glioma patients: a meta-analysis. Mol Neurobiol 53(1):720–727 Vander Griend DJ, Karthaus WL, Dalrymple S, Meeker A, DeMarzo AM, Isaacs JT (2008) The role of CD133 in normal human prostate stem cells and malignant cancer-initiating cells. Cancer Res 68(23):9703–9711 Zhou J, Wang H, Cannon V, Wolcott KM, Song H, Yates C (2011) Side population rather than CD133(+) cells distinguishes enriched tumorigenicity in hTERT-immortalized primary prostate cancer cells. Mol Cancer 10:112 Wang L, Huang X, Zheng X, Wang X, Li S, Zhang L et al (2013) Enrichment of prostate cancer stem-like cells from human prostate cancer cell lines by culture in serum-free medium and chemoradiotherapy. Int J Biol Sci 9(5):472–479 Reyes EE, Gillard M, Duggan R, Wroblewski K, Kregel S, Isikbay M et al (2015) Molecular analysis of CD133-positive circulating tumor cells from patients with metastatic castration-resistant prostate cancer. J Transl Sci 1(1):4 Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al (2007) Identification and expansion of human colon-cancer-initiating cells. Nature 445(7123):111–115 Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW et al (2007) Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 104(24):10158–10163 Ozawa M, Ichikawa Y, Zheng YW, Oshima T, Miyata H, Nakazawa K et al (2014) Prognostic significance of CD44 variant 2 upregulation in colorectal cancer. Br J Cancer 111(2):365–374 Chen S, Song X, Chen Z, Li X, Li M, Liu H et al (2013) CD133 expression and the prognosis of colorectal cancer: a systematic review and meta-analysis. PLoS ONE 8(2):e56380 Fang C, Fan C, Wang C, Huang Q, Meng W, Yu Y et al (2017) Prognostic value of CD133(+) CD54(+) CD44(+) circulating tumor cells in colorectal cancer with liver metastasis. Cancer Med 6(12):2850–2857 Horst D, Kriegl L, Engel J, Kirchner T, Jung A (2009) Prognostic significance of the cancer stem cell markers CD133, CD44, and CD166 in colorectal cancer. Cancer Invest 27(8):844–850 Wang BB, Li ZJ, Zhang FF, Hou HT, Yu JK, Li F (2016) Clinical significance of stem cell marker CD133 expression in colorectal cancer. Histol Histopathol 31(3):299–306 Wu Y, Wu PY (2009) CD133 as a marker for cancer stem cells: progresses and concerns. Stem Cells Dev 18(8):1127–1134 Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S et al (2012) Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 148(1–2):259–272 Li J, Chen JN, Zeng TT, He F, Chen SP, Ma S et al (2016) CD133+ liver cancer stem cells resist interferon-gamma-induced autophagy. BMC Cancer 16:15 Ma S, Lee TK, Zheng BJ, Chan KW, Guan XY (2008) CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene 27(12):1749–1758 Rountree CB, Ding W, He L, Stiles B (2009) Expansion of CD133-expressing liver cancer stem cells in liver-specific phosphatase and tensin homolog deleted on chromosome 10-deleted mice. Stem Cells 27(2):290–299 Ding W, Mouzaki M, You H, Laird JC, Mato J, Lu SC et al (2009) CD133+ liver cancer stem cells from methionine adenosyl transferase 1A-deficient mice demonstrate resistance to transforming growth factor (TGF)-beta-induced apoptosis. Hepatology 49(4):1277–1286 Chen YL, Lin PY, Ming YZ, Huang WC, Chen RF, Chen PM et al (2017) The effects of the location of cancer stem cell marker CD133 on the prognosis of hepatocellular carcinoma patients. BMC Cancer 17(1):474 Choi YJ, Ingram PN, Yang K, Coffman L, Iyengar M, Bai S et al (2015) Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2. Proc Natl Acad Sci USA 112(50):E6882–E6888 Roy L, Bobbs A, Sattler R, Kurkewich JL, Dausinas PB, Nallathamby P et al (2018) CD133 promotes adhesion to the ovarian cancer metastatic niche. Cancer Growth Metastasis 11:1179064418767882 Meyer MJ, Fleming JM, Lin AF, Hussnain SA, Ginsburg E, Vonderhaar BK (2010) CD44posCD49fhiCD133/2hi defines xenograft-initiating cells in estrogen receptor-negative breast cancer. Cancer Res 70(11):4624–4633 Croker AK, Goodale D, Chu J, Postenka C, Hedley BD, Hess DA et al (2009) High aldehyde dehydrogenase and expression of cancer stem cell markers selects for breast cancer cells with enhanced malignant and metastatic ability. J Cell Mol Med 13(8B):2236–2252 Costa WH, Rocha RM, Cunha IW, Fonseca FP, Guimaraes GC, Zequi Sde C (2012) CD133 immunohistochemical expression predicts progression and cancer-related death in renal cell carcinoma. World J Urol 30(4):553–558 Kim K, Ihm H, Ro JY, Cho YM (2011) High-level expression of stem cell marker CD133 in clear cell renal cell carcinoma with favorable prognosis. Oncol Lett 2(6):1095–1100 Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M et al (2007) Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1(3):313–323 Kim MP, Fleming JB, Wang H, Abbruzzese JL, Choi W, Kopetz S et al (2011) ALDH activity selectively defines an enhanced tumor-initiating cell population relative to CD133 expression in human pancreatic adenocarcinoma. PLoS ONE 6(6):e20636 Rocco A, Liguori E, Pirozzi G, Tirino V, Compare D, Franco R et al (2012) CD133 and CD44 cell surface markers do not identify cancer stem cells in primary human gastric tumors. J Cell Physiol 227(6):2686–2693 Takaishi S, Okumura T, Tu S, Wang SS, Shibata W, Vigneshwaran R et al (2009) Identification of gastric cancer stem cells using the cell surface marker CD44. Stem Cells 27(5):1006–1020 Suva ML, Riggi N, Stehle JC, Baumer K, Tercier S, Joseph JM et al (2009) Identification of cancer stem cells in Ewing’s sarcoma. Cancer Res 69(5):1776–1781 Tirino V, Desiderio V, d’Aquino R, De Francesco F, Pirozzi G, Graziano A et al (2008) Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS ONE 3(10):e3469 Tirino V, Desiderio V, Paino F, De Rosa A, Papaccio F, Fazioli F et al (2011) Human primary bone sarcomas contain CD133+ cancer stem cells displaying high tumorigenicity in vivo. FASEB J 25(6):2022–2030 Murat A, Migliavacca E, Gorlia T, Lambiv WL, Shay T, Hamou MF et al (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26(18):3015–3024 Colman H, Zhang L, Sulman EP, McDonald JM, Shooshtari NL, Rivera A et al (2010) A multigene predictor of outcome in glioblastoma. Neuro Oncol 12(1):49–57 Chen KH, Hsu CC, Song WS, Huang CS, Tsai CC, Kuo CD et al (2010) Celecoxib enhances radiosensitivity in medulloblastoma-derived CD133-positive cells. Childs Nerv Syst 26(11):1605–1612 Chen YC, Hsu HS, Chen YW, Tsai TH, How CK, Wang CY et al (2008) Oct-4 expression maintained cancer stem-like properties in lung cancer-derived CD133-positive cells. PLoS ONE 3(7):e2637 Blazek ER, Foutch JL, Maki G (2007) Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133− cells, and the CD133+ sector is enlarged by hypoxia. Int J Radiat Oncol Biol Phys 67(1):1–5 Lin J, Zhang XM, Yang JC, Ye YB, Luo SQ (2010) gamma-secretase inhibitor-I enhances radiosensitivity of glioblastoma cell lines by depleting CD133+ tumor cells. Arch Med Res 41(7):519–529 Barrantes-Freer A, Renovanz M, Eich M, Braukmann A, Sprang B, Spirin P et al (2015) CD133 expression is not synonymous to immunoreactivity for AC133 and fluctuates throughout the cell cycle in glioma stem-like cells. PLoS ONE 10(6):e0130519 Hermansen SK, Christensen KG, Jensen SS, Kristensen BW (2011) Inconsistent immunohistochemical expression patterns of four different CD133 antibody clones in glioblastoma. J Histochem Cytochem 59(4):391–407 Damek-Poprawa M, Volgina A, Korostoff J, Sollecito TP, Brose MS, O’Malley BW Jr et al (2011) Targeted inhibition of CD133+ cells in oral cancer cell lines. J Dent Res 90(5):638–645 Swaminathan SK, Olin MR, Forster CL, Cruz KS, Panyam J, Ohlfest JR (2010) Identification of a novel monoclonal antibody recognizing CD133. J Immunol Methods 361(1–2):110–115 Waldron NN, Kaufman DS, Oh S, Inde Z, Hexum MK, Ohlfest JR et al (2011) Targeting tumor-initiating cancer cells with dCD133KDEL shows impressive tumor reductions in a xenotransplant model of human head and neck cancer. Mol Cancer Ther 10(10):1829–1838 Waldron NN, Barsky SH, Dougherty PR, Vallera DA (2014) A bispecific EpCAM/CD133-targeted toxin is effective against carcinoma. Target Oncol 9(3):239–249 Zhao L, Yang Y, Zhou P, Ma H, Zhao X, He X et al (2015) Targeting CD133high colorectal cancer cells in vitro and in vivo with an asymmetric bispecific antibody. J Immunother 38(6):217–228 Wang Y, Chen M, Wu Z, Tong C, Dai H, Guo Y et al (2018) CD133-directed CAR T cells for advanced metastasis malignancies: a phase I trial. OncoImmunology 7:e1440169 Schmohl JU, Gleason MK, Dougherty PR, Miller JS, Vallera DA (2016) Heterodimeric bispecific single chain variable fragments (scFv) killer engagers (BiKEs) enhance NK-cell activity against CD133+ colorectal cancer cells. Target Oncol 11(3):353–361 Schmohl JU, Felices M, Oh F, Lenvik AJ, Lebeau AM, Panyam J et al (2017) Engineering of anti-CD133 trispecific molecule capable of inducing NK expansion and driving antibody-dependent cell-mediated cytotoxicity. Cancer Res Treat 49(4):1140–1152 Schmohl JU, Felices M, Todhunter D, Taras E, Miller JS, Vallera DA (2016) Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker. Oncotarget 7(45):73830–73844 Swaminathan SK, Roger E, Toti U, Niu L, Ohlfest JR, Panyam J (2013) CD133-targeted paclitaxel delivery inhibits local tumor recurrence in a mouse model of breast cancer. J Control Release 171(3):280–287 Jin C, Yang Z, Yang J, Li H, He Y, An J et al (2013) Paclitaxel-loaded nanoparticles decorated with anti-CD133 antibody: a targeted therapy for liver cancer stem cells. J Nanoparticle Res 16(1):2157 Lakhin AV, Tarantul VZ, Gening LV (2013) Aptamers: problems, solutions and prospects. Acta Naturae 5(4):34–43 Alibolandi M, Abnous K, Anvari S, Mohammadi M, Ramezani M, Taghdisi SM (2018) CD133-targeted delivery of self-assembled PEGylated carboxymethylcellulose-SN38 nanoparticles to colorectal cancer. Artif Cells Nanomed Biotechnol 8:1–11 Shigdar S, Qiao L, Zhou SF, Xiang D, Wang T, Li Y et al (2013) RNA aptamers targeting cancer stem cell marker CD133. Cancer Lett 330(1):84–95 ICT-121 [press release]. Dallas TX Immuno-Oncology News2017 Rudnick JD, Fink KL, Landolfi JC, Markert J, Piccioni DE, Glantz MJ et al (2017) Immunological targeting of CD133 in recurrent glioblastoma: a multi-center phase I translational and clinical study of autologous CD133 dendritic cell immunotherapy. J Clin Oncol 35(15_suppl):2059 Weng D, Jin X, Qin S, Lan X, Chen C, Sun X et al (2017) Radioimmunotherapy for CD133(+) colonic cancer stem cells inhibits tumor development in nude mice. Oncotarget 8(27):44004–44014 Jing H, Weidensteiner C, Reichardt W, Gaedicke S, Zhu X, Grosu AL et al (2016) Imaging and selective elimination of glioblastoma stem cells with theranostic near-infrared-labeled CD133-specific antibodies. Theranostics 6(6):862–874 Signoretti S, Waltregny D, Dilks J, Isaac B, Lin D, Garraway L et al (2000) p63 is a prostate basal cell marker and is required for prostate development. Am J Pathol 157(6):1769–1775 Brawer MK, Peehl DM, Stamey TA, Bostwick DG (1985) Keratin immunoreactivity in the benign and neoplastic human prostate. Cancer Res 45(8):3663–3667 De Marzo AM, Meeker AK, Epstein JI, Coffey DS (1998) Prostate stem cell compartments: expression of the cell cycle inhibitor p27Kip1 in normal, hyperplastic, and neoplastic cells. Am J Pathol 153(3):911–919 Alam TN, O’Hare MJ, Laczko I, Freeman A, Al-Beidh F, Masters JR et al (2004) Differential expression of CD44 during human prostate epithelial cell differentiation. J Histochem Cytochem 52(8):1083–1090 Bello-DeOcampo D, Kleinman HK, Deocampo ND, Webber MM (2001) Laminin-1 and alpha6beta1 integrin regulate acinar morphogenesis of normal and malignant human prostate epithelial cells. Prostate 46(2):142–153 Knox JD, Cress AE, Clark V, Manriquez L, Affinito KS, Dalkin BL et al (1994) Differential expression of extracellular matrix molecules and the alpha 6-integrins in the normal and neoplastic prostate. Am J Pathol 145(1):167–174 Lawson DA, Xin L, Lukacs RU, Cheng D, Witte ON (2007) Isolation and functional characterization of murine prostate stem cells. Proc Natl Acad Sci USA 104(1):181–186 Goldstein AS, Lawson DA, Cheng D, Sun W, Garraway IP, Witte ON (2008) Trop2 identifies a subpopulation of murine and human prostate basal cells with stem cell characteristics. Proc Natl Acad Sci USA 105(52):20882–20887 Petkova N, Hennenlotter J, Sobiesiak M, Todenhofer T, Scharpf M, Stenzl A et al (2013) Surface CD24 distinguishes between low differentiated and transit-amplifying cells in the basal layer of human prostate. Prostate 73(14):1576–1590 Wang Y, Hayward S, Cao M, Thayer K, Cunha G (2001) Cell differentiation lineage in the prostate. Differentiation 68(4–5):270–279 Wang X, Kruithof-de Julio M, Economides KD, Walker D, Yu H, Halili MV et al (2009) A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461(7263):495–500 Wang W, Epstein JI (2008) Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. Am J Surg Pathol 32(1):65–71 Beltran H, Rickman DS, Park K, Chae SS, Sboner A, MacDonald TY et al (2011) Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discov 1(6):487–495 Jaworska D, Krol W, Szliszka E (2015) Prostate cancer stem cells: research advances. Int J Mol Sci 16(11):27433–27449 Taylor RA, Toivanen R, Risbridger GP (2010) Stem cells in prostate cancer: treating the root of the problem. Endocr Relat Cancer 17(4):R273–R285 Toivanen R, Shen MM (2017) Prostate organogenesis: tissue induction, hormonal regulation and cell type specification. Development 144(8):1382–1398