Acquired resistance has curtailed cancer survival since the dawn of the chemotherapy age more than half a century ago. Although the application of stem cell (SC) concepts to cancer captured the imagination of scientists for many years, only the last decade has yielded substantial evidence that cancer SCs (CSCs) contribute to chemotherapy resistance. Recent studies suggest that the functional and molecular properties of CSCs constitute therapeutic opportunities to improve the efficacy of chemotherapy. Here we review how these properties have stimulated combination strategies that suppress acquired resistance across a spectrum of malignancies. The clinical implementation of these strategies promises to rejuvenate the effort against an enduring challenge.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Cell Death Discovery Open Access 31 October 2022
Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma
Journal of Biomedical Science Open Access 08 March 2021
MiR-153 reduces stem cell-like phenotype and tumor growth of lung adenocarcinoma by targeting Jagged1
Stem Cell Research & Therapy Open Access 06 May 2020
Subscribe to Journal
Get full journal access for 1 year
only $2.38 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Chabner BA, Roberts TG Jr. . Timeline: chemotherapy and the war on cancer. Nat Rev Cancer 2005; 5: 65–72.
Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674.
Gorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science 2001; 293: 876–880.
Dick JE . Stem cell concepts renew cancer research. Blood 2008; 112: 4793–4807.
Nguyen LV, Vanner R, Dirks P, Eaves CJ . Cancer stem cells: an evolving concept. Nat Rev Cancer 2012; 12: 133–143.
Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV et al. Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer 2012; 12: 767–775.
Magee JA, Piskounova E, Morrison SJ . Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 2012; 21: 283–296.
Visvader JE, Lindeman GJ . Cancer stem cells: current status and evolving complexities. Cell Stem Cell 2012; 10: 717–728.
Estey E, Dohner H . Acute myeloid leukaemia. Lancet 2006; 368: 1894–1907.
Bonnet D, Dick JE . Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med 1997; 3: 730–737.
Eppert K, Takenaka K, Lechman ER, Waldron L, Nilsson B, van Galen P et al. Stem cell gene expression programs influence clinical outcome in human leukemia. Nat Med 2011; 17: 1086–1093.
van Rhenen A, Feller N, Kelder A, Westra AH, Rombouts E, Zweegman S et al. High stem cell frequency in acute myeloid leukemia at diagnosis predicts high minimal residual disease and poor survival. Clin Cancer Res 2005; 11: 6520–6527.
Gerber JM, Smith BD, Ngwang B, Zhang H, Vala MS, Morsberger L et al. A clinically relevant population of leukemic CD34(+)CD38(−) cells in acute myeloid leukemia. Blood 2012; 119: 3571–3577.
Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol 2007; 25: 1315–1321.
Cortes J, Hochhaus A, Hughes T, Kantarjian H . Front-line and salvage therapies with tyrosine kinase inhibitors and other treatments in chronic myeloid leukemia. J Clin Oncol 2011; 29: 524–531.
Huntly BJ, Gilliland DG . Leukaemia stem cells and the evolution of cancer-stem-cell research. Nat Rev Cancer 2005; 5: 311–321.
Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002; 99: 319–325.
Bhatia R, Holtz M, Niu N, Gray R, Snyder DS, Sawyers CL et al. Persistence of malignant hematopoietic progenitors in chronic myelogenous leukemia patients in complete cytogenetic remission following imatinib mesylate treatment. Blood 2003; 101: 4701–4707.
Chu S, McDonald T, Lin A, Chakraborty S, Huang Q, Snyder DS et al. Persistence of leukemia stem cells in chronic myelogenous leukemia patients in prolonged remission with imatinib treatment. Blood 2011; 118: 5565–5572.
Minami Y, Abe A, Minami M, Kitamura K, Hiraga J, Mizuno S et al. Retention of CD34+ CML stem/progenitor cells during imatinib treatment and rapid decline after treatment with second-generation BCR-ABL inhibitors. Leukemia 2012; 26: 2142–2143.
Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD et al. Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 2010; 17: 427–442.
Li L, Wang L, Li L, Wang Z, Ho Y, McDonald T et al. Activation of p53 by SIRT1 inhibition enhances elimination of CML leukemia stem cells in combination with imatinib. Cancer Cell 2012; 21: 266–281.
Goff DJ, Recart AC, Sadarangani A, Chun HJ, Barrett CL, Krajewska M et al. A Pan-BCL2 inhibitor renders bone-marrow-resident human leukemia stem cells sensitive to tyrosine kinase inhibition. Cell stem cell 2013; 12: 316–328.
Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF . Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA 2003; 100: 3983–3988.
Yu F, Yao H, Zhu P, Zhang X, Pan Q, Gong C et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 2007; 131: 1109–1123.
Li X, Lewis MT, Huang J, Gutierrez C, Osborne CK, Wu MF et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J Natl Cancer Inst 2008; 100: 672–679.
Ginestier C, Hur MH, Charafe-Jauffret E, Monville F, Dutcher J, Brown M et al. ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell 2007; 1: 555–567.
Sakakibara M, Fujimori T, Miyoshi T, Nagashima T, Fujimoto H, Suzuki HT et al. Aldehyde dehydrogenase 1-positive cells in axillary lymph node metastases after chemotherapy as a prognostic factor in patients with lymph node-positive breast cancer. Cancer 2012; 118: 3899–3910.
Creighton CJ, Li X, Landis M, Dixon JM, Neumeister VM, Sjolund A et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc Natl Acad Sci USA 2009; 106: 13820–13825.
Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 2009; 5: 168–177.
Harris CA, Ward RL, Dobbins TA, Drew AK, Pearson S . The efficacy of HER2-targeted agents in metastatic breast cancer: a meta-analysis. Ann Oncol 2011; 22: 1308–1317.
Korkaya H, Paulson A, Iovino F, Wicha MS . HER2 regulates the mammary stem/progenitor cell population driving tumorigenesis and invasion. Oncogene 2008; 27: 6120–6130.
Korkaya H, Wicha MS . HER2and breast cancer stem cells: more than meets the eye. Cancer Res 2013; 73: 3489–3493.
Magnifico A, Albano L, Campaner S, Delia D, Castiglioni F, Gasparini P et al. Tumor-initiating cells of HER2-positive carcinoma cell lines express the highest oncoprotein levels and are sensitive to trastuzumab. Clin Cancer Res 2009; 15: 2010–2021.
Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell 2012; 47: 570–584.
O'Brien CA, Pollett A, Gallinger S, Dick JE . A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 2007; 445: 106–110.
Ricci-Vitiani L, Lombardi DG, Pilozzi E, Biffoni M, Todaro M, Peschle C et al. Identification and expansion of human colon-cancer-initiating cells. Nature 2007; 445: 111–115.
Dalerba P, Dylla SJ, Park IK, Liu R, Wang X, Cho RW et al. Phenotypic characterization of human colorectal cancer stem cells. Proc Natl Acad Sci USA 2007; 104: 10158–10163.
Todaro M, Alea MP, Di Stefano AB, Cammareri P, Vermeulen L, Iovino F et al. Colon cancer stem cells dictate tumor growth and resist cell death by production of interleukin-4. Cell Stem cell 2007; 1: 389–402.
Pang R, Law WL, Chu AC, Poon JT, Lam CS, Chow AK et al. A subpopulation of CD26+ cancer stem cells with metastatic capacity in human colorectal cancer. Cell Stem cell 2010; 6: 603–615.
Hermann PC, Huber SL, Herrler T, Aicher A, Ellwart JW, Guba M et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem cell 2007; 1: 313–323.
Li C, Wu JJ, Hynes M, Dosch J, Sarkar B, Welling TH et al. c-Met is a marker of pancreatic cancer stem cells and therapeutic target. Gastroenterology 2011; 141: 2218–27 e5.
Tajima H, Ohta T, Kitagawa H, Okamoto K, Sakai S, Kinoshita J et al. Neoadjuvant chemotherapy with gemcitabine for pancreatic cancer increases in situ expression of the apoptosis marker M30 and stem cell marker CD44. Oncology Lett 2012; 3: 1186–1190.
Bertolini G, Roz L, Perego P, Tortoreto M, Fontanella E, Gatti L 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: 16281–16286.
Lee TK, Castilho A, Cheung VC, Tang KH, Ma S, Ng IO . CD24(+) liver tumor-initiating cells drive self-renewal and tumor initiation through STAT3-mediated NANOG regulation. Cell Stem Cell 2011; 9: 50–63.
Qin J, Liu X, Laffin B, Chen X, Choy G, Jeter CR et al. The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 2012; 10: 556–569.
Domingo-Domenech J, Vidal SJ, Rodriguez-Bravo V, Castillo-Martin M, Quinn SA, Rodriguez-Barrueco R et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012; 22: 373–388.
Collins AT, Berry PA, Hyde C, Stower MJ, Maitland NJ . Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res 2005; 65: 10946–10951.
Patrawala L, Calhoun-Davis T, Schneider-Broussard R, Tang DG . Hierarchical organization of prostate cancer cells in xenograft tumors: the CD44+alpha2beta1+ cell population is enriched in tumor-initiating cells. Cancer Res 2007; 67: 6796–6805.
Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T et al. Identification of human brain tumour initiating cells. Nature 2004; 432: 396–401.
Liu G, Yuan X, Zeng Z, Tunici P, Ng H, Abdulkadir IR et al. Analysis of gene expression and chemoresistance of CD133+ cancer stem cells in glioblastoma. Mol Cancer 2006; 5: 67.
Pistollato F, Abbadi S, Rampazzo E, Persano L, Della Puppa A, Frasson C et al. Intratumoral hypoxic gradient drives stem cells distribution and MGMT expression in glioblastoma. Stem Cells 2010; 28: 851–862.
Persano L, Pistollato F, Rampazzo E, Della Puppa A, Abbadi S, Frasson C et al. BMP2 sensitizes glioblastoma stem-like cells to Temozolomide by affecting HIF-1alpha stability and MGMT expression. Cell Death Dis 2012; 3: e412.
Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012; 488: 522–526.
Evangelista M, Tian H, de Sauvage FJ . The hedgehog signaling pathway in cancer. Clin Cancer Res 2006; 12 (20 Pt 1): 5924–5928.
Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P et al. Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 2008; 14: 238–249.
Zhao C, Chen A, Jamieson CH, Fereshteh M, Abrahamsson A, Blum J et al. Hedgehog signalling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 2009; 458: 776–779.
Clevers H, Nusse R . Wnt/beta-catenin signaling and disease. Cell 2012; 149: 1192–1205.
Hu Y, Chen Y, Douglas L, Li S . beta-Catenin is essential for survival of leukemic stem cells insensitive to kinase inhibition in mice with BCR-ABL-induced chronic myeloid leukemia. Leukemia 2009; 23: 109–116.
Heidel FH, Bullinger L, Feng Z, Wang Z, Neff TA, Stein L et al. Genetic and pharmacologic inhibition of beta-catenin targets imatinib-resistant leukemia stem cells in CML. Cell Stem cell 2012; 10: 412–424.
Massague J . TGFbeta in Cancer. Cell 2008; 134: 215–230.
Lonardo E, Hermann PC, Mueller MT, Huber S, Balic A, Miranda-Lorenzo I et al. Nodal/Activin signaling drives self-renewal and tumorigenicity of pancreatic cancer stem cells and provides a target for combined drug therapy. Cell Stem cell 2011; 9: 433–446.
Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M et al. TGF-beta inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest 2013; 123: 1348–1358.
Reedijk M . Notch signaling and breast cancer. Adv Exp Med Biol 2012; 727: 241–257.
Qiu M, Peng Q, Jiang I, Carroll C, Han G, Rymer I et al. Specific inhibition of Notch1 signaling enhances the antitumor efficacy of chemotherapy in triple negative breast cancer through reduction of cancer stem cells. Cancer Lett 2013; 328: 261–270.
Schott AF, Landis M, Dontu G, Griffith KA, Layman RM, Krop I et al. Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res 2013; 19: 1512–1524.
Huang ME, Ye YC, Chen SR, Chai JR, Lu JX, Zhoa L et al. Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988; 72: 567–572.
Piccirillo SG, Reynolds BA, Zanetti N, Lamorte G, Binda E, Broggi G et al. Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 2006; 444: 761–765.
Chirasani SR, Sternjak A, Wend P, Momma S, Campos B, Herrmann IM et al. Bone morphogenetic protein-7 release from endogenous neural precursor cells suppresses the tumourigenicity of stem-like glioblastoma cells. Brain 2010; 133 (Pt 7): 1961–1972.
Tate CM, Pallini R, Ricci-Vitiani L, Dowless M, Shiyanova T, D'Alessandris GQ et al. A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells. Cell Death Differ 2012; 19: 1644–1654.
Lombardo Y, Scopelliti A, Cammareri P, Todaro M, Iovino F, Ricci-Vitiani L et al. Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 2011; 140: 297–309.
Fuchs E . The tortoise and the hair: slow-cycling cells in the stem cell race. Cell 2009; 137: 811–819.
Goss PE, Chambers AF . Does tumour dormancy offer a therapeutic target? Nat Rev Cancer 2010; 10: 871–877.
Aguirre-Ghiso JA . Models, mechanisms and clinical evidence for cancer dormancy. Nat Rev Cancer 2007; 7: 834–846.
Li L, Bhatia R . Stem cell quiescence. Clin Cancer Res 2011; 17: 4936–4941.
Copland M, Hamilton A, Elrick LJ, Baird JW, Allan EK, Jordanides N et al. Dasatinib (BMS-354825) targets an earlier progenitor population than imatinib in primary CML but does not eliminate the quiescent fraction. Blood 2006; 107: 4532–4539.
Jorgensen HG, Allan EK, Jordanides NE, Mountford JC, Holyoake TL . Nilotinib exerts equipotent antiproliferative effects to imatinib and does not induce apoptosis in CD34+ CML cells. Blood 2007; 109: 4016–4019.
Jorgensen HG, Copland M, Allan EK, Jiang X, Eaves A, Eaves C et al. Intermittent exposure of primitive quiescent chronic myeloid leukemia cells to granulocyte-colony stimulating factor in vitro promotes their elimination by imatinib mesylate. Clin Cancer Res 2006; 12: 626–633.
Essers MA, Offner S, Blanco-Bose WE, Waibler Z, Kalinke U, Duchosal MA et al. IFNalpha activates dormant haematopoietic stem cells in vivo. Nature 2009; 458: 904–908.
Schurch C, Riether C, Amrein MA, Ochsenbein AF . Cytotoxic T cells induce proliferation of chronic myeloid leukemia stem cells by secreting interferon-gamma. J Exp Med 2013; 210: 605–621.
Takeishi S, Matsumoto A, Onoyama I, Naka K, Hirao A, Nakayama KI . Ablation of fbxw7 eliminates leukemia-initiating cells by preventing quiescence. Cancer Cell 2013; 23: 347–361.
Saito Y, Uchida N, Tanaka S, Suzuki N, Tomizawa-Murasawa M, Sone A et al. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat Biotechnol 2010; 28: 275–280.
Lowenberg B, Boogaerts MA, Daenen SM, Verhoef GE, Hagenbeek A, Vellenga E et al. Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. J Clin Oncol 1997; 15: 3496–3506.
Zittoun R, Suciu S, Mandelli F, de Witte T, Thaler J, Stryckmans P et al. Granulocyte-macrophage colony-stimulating factor associated with induction treatment of acute myelogenous leukemia: a randomized trial by the European Organization for Research and Treatment of Cancer Leukemia Cooperative Group. J Clin Oncol 1996; 14: 2150–2159.
Lowenberg B, van Putten W, Theobald M, Gmur J, Verdonck L, Sonneveld P et al. Effect of priming with granulocyte colony-stimulating factor on the outcome of chemotherapy for acute myeloid leukemia. N Engl J Med 2003; 349: 743–752.
Pabst T, Vellenga E, van Putten W, Schouten HC, Graux C, Vekemans MC et al. Favorable effect of priming with granulocyte colony-stimulating factor in remission induction of acute myeloid leukemia restricted to dose escalation of cytarabine. Blood 2012; 119: 5367–5373.
Dawson MA, Kouzarides T . Cancer epigenetics: from mechanism to therapy. Cell 2012; 150: 12–27.
van Vlerken LE, Hurt EM, Hollingsworth RE . The role of epigenetic regulation in stem cell and cancer biology. J Mol Med 2012; 90: 791–801.
Shimono Y, Zabala M, Cho RW, Lobo N, Dalerba P, Qian D et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 2009; 138: 592–603.
Iliopoulos D, Lindahl-Allen M, Polytarchou C, Hirsch HA, Tsichlis PN, Struhl K . Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Molecular Cell 2010; 39: 761–772.
Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med 2011; 17: 211–215.
Liu C, Tang DG . MicroRNA regulation of cancer stem cells. Cancer Res 2011; 71: 5950–5954.
Tsai HC, Li H, Van Neste L, Cai Y, Robert C, Rassool FV et al. Transient low doses of DNA-demethylating agents exert durable antitumor effects on hematological and epithelial tumor cells. Cancer Cell 2012; 21: 430–446.
Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA et al. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature 2011; 478: 524–528.
Bolden JE, Peart MJ, Johnstone RW . Anticancer activities of histone deacetylase inhibitors. Nat Rev Drug Discov 2006; 5: 769–784.
Brown JM, Attardi LD . The role of apoptosis in cancer development and treatment response. Nat Rev Cancer 2005; 5: 231–237.
Pommier Y, Sordet O, Antony S, Hayward RL, Kohn KW . Apoptosis defects and chemotherapy resistance: molecular interaction maps and networks. Oncogene 2004; 23: 2934–2949.
Martinou JC, Youle RJ . Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. Developmental Cell 2011; 21: 92–101.
Domen J, Gandy KL, Weissman IL . Systemic overexpression of BCL-2 in the hematopoietic system protects transgenic mice from the consequences of lethal irradiation. Blood 1998; 91: 2272–2282.
Domen J, Cheshier SH, Weissman IL . The role of apoptosis in the regulation of hematopoietic stem cells: overexpression of Bcl-2 increases both their number and repopulation potential. J Exp Med 2000; 191: 253–264.
Lang JY, Hsu JL, Meric-Bernstam F, Chang CJ, Wang Q, Bao Y et al. BikDD eliminates breast cancer initiating cells and synergizes with lapatinib for breast cancer treatment. Cancer Cell 2011; 20: 341–356.
Culig Z . Cytokine disbalance in common human cancers. Biochim Biophys Acta 2011; 1813: 308–314.
Charafe-Jauffret E, Ginestier C, Iovino F, Wicinski J, Cervera N, Finetti P et al. Breast cancer cell lines contain functional cancer stem cells with metastatic capacity and a distinct molecular signature. Cancer Res 2009; 69: 1302–1313.
Ginestier C, Liu S, Diebel ME, Korkaya H, Luo M, Brown M et al. CXCR1 blockade selectively targets human breast cancer stem cells in vitro and in xenografts. J Clin Investigation 2010; 120: 485–497.
Rajeshkumar NV, Rasheed ZA, Garcia-Garcia E, Lopez-Rios F, Fujiwara K, Matsui WH et al. A combination of DR5 agonistic monoclonal antibody with gemcitabine targets pancreatic cancer stem cells and results in long-term disease control in human pancreatic cancer model. Mol Cancer Ther 2010; 9: 2582–2592.
Naka K, Hoshii T, Muraguchi T, Tadokoro Y, Ooshio T, Kondo Y et al. TGF-beta-FOXO signalling maintains leukaemia-initiating cells in chronic myeloid leukaemia. Nature 2010; 463: 676–680.
Ward PS, Thompson CB . Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012; 21: 297–308.
Koppenol WH, Bounds PL, Dang CV . Otto Warburg's contributions to current concepts of cancer metabolism. Nat Rev Cancer 2011; 11: 325–337.
Carracedo A, Cantley LC, Pandolfi PP . Cancer metabolism: fatty acid oxidation in the limelight. Nat Revi Cancer 2013; 13: 227–232.
Locasale JW . Serine, glycine and one-carbon units: cancer metabolism in full circle. Nat Rev Cancer 2013; 13: 572–583.
Cairns RA, Harris IS, Mak TW . Regulation of cancer cell metabolism. Nat Rev Cancer 2011; 11: 85–95.
Hirsch HA, Iliopoulos D, Joshi A, Zhang Y, Jaeger SA, Bulyk M et al. A transcriptional signature and common gene networks link cancer with lipid metabolism and diverse human diseases. Cancer Cell 2010; 17: 348–361.
Menendez JA, Joven J, Cufi S, Corominas-Faja B, Oliveras-Ferraros C, Cuyas E et al. The Warburg effect version 2.0: metabolic reprogramming of cancer stem cells. Cell Cycle 2013; 12: 1166–1179.
Zhang G, Yang P, Guo P, Miele L, Sarkar FH, Wang Z et al. Unraveling the mystery of cancer metabolism in the genesis of tumor-initiating cells and development of cancer. Biochim Biophys Acta 2013; 1836: 49–59.
Dong C, Yuan T, Wu Y, Wang Y, Fan TW, Miriyala S et al. Loss of FBP1 by Snail-mediated repression provides metabolic advantages in basal-like breast cancer. Cancer Cell 2013; 23: 316–331.
Ginestier C, Monville F, Wicinski J, Cabaud O, Cervera N, Josselin E et al. Mevalonate metabolism regulates Basal breast cancer stem cells and is a potential therapeutic target. Stem Cells 2012; 30: 1327–1337.
Zhang WC, Shyh-Chang N, Yang H, Rai A, Umashankar S, Ma S et al. Glycine decarboxylase activity drives non-small cell lung cancer tumor-initiating cells and tumorigenesis. Cell 2012; 148: 259–272.
Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K . Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res 2009; 69: 7507–7511.
Iliopoulos D, Hirsch HA, Struhl K . Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res 2011; 71: 3196–3201.
Iliopoulos D, Hirsch HA, Struhl K . An epigenetic switch involving NF-kappaB, Lin28, Let-7 MicroRNA, and IL6 links inflammation to cell transformation. Cell 2009; 139: 693–706.
Hirsch HA, Iliopoulos D, Struhl K . Metformin inhibits the inflammatory response associated with cellular transformation and cancer stem cell growth. Proc Natl Acad Sci USA 2013; 110: 972–977.
Iliopoulos D, Hirsch HA, Wang G, Struhl K . Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc Natl Acad Sci USA 2011; 108: 1397–1402.
Wurth R, Pattarozzi A, Gatti M, Bajetto A, Corsaro A, Parodi A et al. Metformin selectively affects human glioblastoma tumor-initiating cell viability: A role for metformin-induced inhibition of Akt. Cell Cycle 2013; 12: 145–156.
Vazquez-Martin A, Oliveras-Ferraros C, Del Barco S, Martin-Castillo B, Menendez JA . The anti-diabetic drug metformin suppresses self-renewal and proliferation of trastuzumab-resistant tumor-initiating breast cancer stem cells. Breast Cancer Res Treat 2011; 126: 355–364.
Voog J, Jones DL . Stem cells and the niche: a dynamic duo. Cell Stem Cell 2010; 6: 103–115.
Borovski T, De Sousa EMF, Vermeulen L, Medema JP . Cancer stem cell niche: the place to be. Cancer Res 2011; 71: 634–639.
Hanahan D, Coussens LM . Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012; 21: 309–322.
Sugiyama T, Kohara H, Noda M, Nagasawa T . Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 2006; 25: 977–988.
Jin L, Tabe Y, Konoplev S, Xu Y, Leysath CE, Lu H et al. CXCR4 up-regulation by imatinib induces chronic myelogenous leukemia (CML) cell migration to bone marrow stroma and promotes survival of quiescent CML cells. Molecular Cancer Ther 2008; 7: 48–58.
Weisberg E, Azab AK, Manley PW, Kung AL, Christie AL, Bronson R et al. Inhibition of CXCR4 in CML cells disrupts their interaction with the bone marrow microenvironment and sensitizes them to nilotinib. Leukemia 2012; 26: 985–990.
Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al. A perivascular niche for brain tumor stem cells. Cancer Cell 2007; 11: 69–82.
Borovski T, Beke P, van Tellingen O, Rodermond HM, Verhoeff JJ, Lascano V et al. Therapy-resistant tumor microvascular endothelial cells contribute to treatment failure in glioblastoma multiforme. Oncogene 2012; 32: 1539–1548.
Zhang B, Li M, McDonald T, Holyoake TL, Moon RT, Campana D et al. Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-Cadherin and Wnt-beta-catenin signaling. Blood 2013; 121: 1824–1838.
Lonardo E, Frias-Aldeguer J, Hermann PC, Heeschen C . Pancreatic stellate cells form a niche for cancer stem cells and promote their self-renewal and invasiveness. Cell Cycle 2012; 11: 1282–1290.
Lu J, Ye X, Fan F, Xia L, Bhattacharya R, Bellister S et al. Endothelial cells promote the colorectal cancer stem cell phenotype through a soluble form of Jagged-1. Cancer Cell 2013; 23: 171–185.
Ghajar CM, Peinado H, Mori H, Matei IR, Evason KJ, Brazier H et al. The perivascular niche regulates breast tumour dormancy. Nat Cell Biol 2013; 15: 807–817.
Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 2009; 138: 645–659.
Oak PS, Kopp F, Thakur C, Ellwart JW, Rapp UR, Ullrich A et al. Combinatorial treatment of mammospheres with trastuzumab and salinomycin efficiently targets HER2-positive cancer cells and cancer stem cells. Int J Cancer 2012; 131: 2808–2819.
Vermeulen L, De Sousa EMF, van der Heijden M, Cameron K, de Jong JH, Borovski T et al. Wnt activity defines colon cancer stem cells and is regulated by the microenvironment. Nat Cell Biol 2010; 12: 468–476.
Higgins CF . The ABC of channel regulation. Cell 1995; 82: 693–696.
Dean M, Fojo T, Bates S . Tumour stem cells and drug resistance. Nat Rev Cancer 2005; 5: 275–284.
Tamaki A, Ierano C, Szakacs G, Robey RW, Bates SE . The controversial role of ABC transporters in clinical oncology. Essays Biochem 2011; 50: 209–232.
Quintana E, Shackleton M, Sabel MS, Fullen DR, Johnson TM, Morrison SJ . Efficient tumour formation by single human melanoma cells. Nature 2008; 456: 593–598.
Schatton T, Murphy GF, Frank NY, Yamaura K, Waaga-Gasser AM, Gasser M et al. Identification of cells initiating human melanomas. Nature 2008; 451: 345–349.
Quintana E, Shackleton M, Foster HR, Fullen DR, Sabel MS, Johnson TM et al. Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized. Cancer Cell 2010; 18: 510–523.
Luo Y, Dallaglio K, Chen Y, Robinson WA, Robinson SE, McCarter MD et al. ALDH1A isozymes are markers of human melanoma stem cells and potential therapeutic targets. Stem Cells 2012; 30: 2100–2113.
Ishizawa K, Rasheed ZA, Karisch R, Wang Q, Kowalski J, Susky E et al. Tumor-initiating cells are rare in many human tumors. Cell Stem Cell 2010; 7: 279–282.
Kreso A, O'Brien CA, van Galen P, Gan OI, Notta F, Brown AM et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science 2013; 339: 543–548.
Mani SA, Guo W, Liao MJ, Eaton EN, Ayyanan A, Zhou AY et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 2008; 133: 704–715.
Chaffer CL, Marjanovic ND, Lee T, Bell G, Kleer CG, Reinhardt F et al. Poised chromatin at the ZEB1 promoter enables breast cancer cell plasticity and enhances tumorigenicity. Cell 2013; 154: 61–74.
Singh A, J Settleman . EMT cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 2010; 29: 4741–4751.
Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ et al. Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 2011; 145: 926–940.
Roesch A, Fukunaga-Kalabis M, Schmidt EC, Zabierowski SE, Brafford PA, Vultur A et al. A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 2010; 141: 583–594.
Roesch A, Vultur A, Bogeski I, Wang H, Zimmermann KM, Speicher D et al. Overcoming intrinsic multidrug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1B(high) cells. Cancer Cell 2013; 23: 811–825.
Sharma SV, Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 2010; 141: 69–80.
Beier D, Rohrl S, Pillai DR, Schwarz S, Kunz-Schughart LA, Leukel P et al. Temozolomide preferentially depletes cancer stem cells in glioblastoma. Cancer Res 2008; 68: 5706–5715.
Early Breast Cancer Trialists' Collaborative G, Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 2005; 365: 1687–1717.
Rousseau B, Chibaudel B, Bachet JB, Larsen AK, Tournigand C, Louvet C et al. Stage II and stage III colon cancer: treatment advances and future directions. Cancer J 2010; 16: 202–209.
Liu R, Wang X, Chen GY, Dalerba P, Gurney A, Hoey T et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N Eng J Med 2007; 356: 217–226.
Dalerba P, Kalisky T, Sahoo D, Rajendran PS, Rothenberg ME, Leyrat AA et al. Single-cell dissection of transcriptional heterogeneity in human colon tumors. Nat Biotechnol 2011; 29: 1120–1127.
Aktas B, Tewes M, Fehm T, Hauch S, Kimmig R, Kasimir-Bauer S . Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res 2009; 11: R46.
Liu S, Li N, Yu X, Xiao X, Cheng K, Hu J et al. Expression of intercellular adhesion molecule 1 by hepatocellular carcinoma stem cells and circulating tumor cells. Gastroenterology 2013; 144: 1031–41 e10.
Nadal R, Ortega FG, Salido M, Lorente JA, Rodriguez-Rivera M, Delgado-Rodriguez M et al. CD133 expression in circulating tumor cells from breast cancer patients: Potential role in resistance to chemotherapy. Int J Cancer 2013; 133: 2398–2407.
Raimondi C, Gradilone A, Naso G, Vincenzi B, Petracca A, Nicolazzo C et al. Epithelial-mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Res Treat 2011; 130: 449–455.
This work was supported by the Hariri Family Foundation and the TJ Martell Foundation.
The authors declare no conflict of interest.
About this article
Cite this article
Vidal, S., Rodriguez-Bravo, V., Galsky, M. et al. Targeting cancer stem cells to suppress acquired chemotherapy resistance. Oncogene 33, 4451–4463 (2014). https://doi.org/10.1038/onc.2013.411
- cancer stem cells
- apoptosis and survival
This article is cited by
Cell Death Discovery (2022)
Journal of Cancer Research and Clinical Oncology (2022)
Dissecting the mechanism of temozolomide resistance and its association with the regulatory roles of intracellular reactive oxygen species in glioblastoma
Journal of Biomedical Science (2021)
Targeting Hedgehog signalling in CD133-positive hepatocellular carcinoma: improving Lenvatinib therapeutic efficiency
Medical Oncology (2021)
Hedgehog signaling promotes sorafenib resistance in hepatocellular carcinoma patient-derived organoids
Journal of Experimental & Clinical Cancer Research (2020)