Skip to main content

Advertisement

SpringerLink
Log in

Innovative Therapeutic Strategies Targeting Colorectal Cancer Stem Cells

  • Basic Science Foundations in Colorectal Cancer (J Roper, Section Editor)
  • Published:
Current Colorectal Cancer Reports

Abstract

Colorectal cancer is the fourth most common cause of cancer-related death. Although many advances in the treatment of this disease have been made, a large number of patients develop metastasis and resistance to current therapies. The current evidence indicates that cancer stem cells (CSCs) and epithelial-to-mesenchymal transition (EMT) have crucial roles in colorectal carcinogenesis and metastasis. It is also very important to understand the mechanisms that allow the survival of CSCs, such as metabolic reprogramming, which permits them to obtain specific properties or the activation of alternative signaling pathways in response to first-line therapies. In this review, we discuss the failure of conventional therapies for colorectal cancer and provide a brief analysis of new therapeutic strategies for targeting non-responsive CSC. We highlight the use of combination therapies, such as horizontal or vertical targeting, as the most efficient strategy for eradicating these subpopulations of cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently have been highlighted as: • Of importance •• Of major importance

  1. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

    Article  CAS  PubMed  Google Scholar 

  2. Vogelstein B, Fearon ER, Hamilton SR, Kern SE, Preisinger AC, Leppert M, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988;319(9):525–32.

    Article  CAS  PubMed  Google Scholar 

  3. Nowell PC. The clonal evolution of tumor cell populations. Science. 1976;194(4260):23–8.

    Article  CAS  PubMed  Google Scholar 

  4. Pardal R, Clarke MF, Morrison SJ. Applying the principles of stem-cell biology to cancer. Nat Rev Cancer. 2003;3(12):895–902.

    Article  CAS  PubMed  Google Scholar 

  5. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414(6859):105–11.

    Article  CAS  PubMed  Google Scholar 

  6. Visvader JE. Cells of origin in cancer. Nature. 2011;469(7330):314–22.

    Article  CAS  PubMed  Google Scholar 

  7. Dalerba P, Cho RW, Clarke MF. Cancer stem cells: models and concepts. Annu Rev Med. 2007;58:267–84.

    Article  CAS  PubMed  Google Scholar 

  8. 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(11):767–75.

    Article  CAS  PubMed  Google Scholar 

  9. Vermeulen L, Sprick MR, Kemper K, Stassi G, Medema JP. Cancer stem cells—old concepts, new insights. Cell Death Differ. 2008;15(6):947–58.

    Article  CAS  PubMed  Google Scholar 

  10. Boman BM, Wicha MS. Cancer stem cells: a step toward the cure. J Clin Oncol Off J Am Soc Clin Oncol. 2008;26(17):2795–9.

    Article  Google Scholar 

  11. Floor SL, Dumont JE, Maenhaut C, Raspe E. Hallmarks of cancer: of all cancer cells, all the time? Trends Mol Med. 2012;18(9):509–15.

    Article  CAS  PubMed  Google Scholar 

  12. Visvader JE, Lindeman GJ. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer. 2008;8(10):755–68.

    Article  CAS  PubMed  Google Scholar 

  13. Wicha MS, Liu S, Dontu G. Cancer stem cells: an old idea—a paradigm shift. Cancer Res. 2006;66(4):1883–90. discussion 95–6.

    Article  CAS  PubMed  Google Scholar 

  14. 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(6119):543–8.

    Article  CAS  PubMed  Google Scholar 

  15. •• Medema JP. Cancer stem cells: the challenges ahead. Nat Cell Biol. 2013;15(4):338–44. Critical analysis about the main features and markers used for their isolation and characterization.

    Article  CAS  PubMed  Google Scholar 

  16. Sipos F, Constantinovits M, Muzes G. Intratumoral functional heterogeneity and chemotherapy. World J Gastroenterol. 2014;20(10):2429–32.

    Article  PubMed  PubMed Central  Google Scholar 

  17. 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(7123):106–10.

    Article  PubMed  CAS  Google Scholar 

  18. 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(7123):111–5.

    Article  CAS  PubMed  Google Scholar 

  19. 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 U S A. 2007;104(24):10158–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Du L, Wang H, He L, Zhang J, Ni B, Wang X, et al. CD44 is of functional importance for colorectal cancer stem cells. Clin Cancer Res. 2008;14(21):6751–60.

    Article  CAS  PubMed  Google Scholar 

  21. Todaro M, Perez Alea M, Scopelliti A, Medema JP, Stassi G. IL-4-mediated drug resistance in colon cancer stem cells. Cell Cycle. 2008;7(3):309–13.

    Article  CAS  PubMed  Google Scholar 

  22. Vermeulen L, Todaro M, de Sousa MF, Sprick MR, Kemper K, Perez Alea M, et al. Single-cell cloning of colon cancer stem cells reveals a multi-lineage differentiation capacity. Proc Natl Acad Sci U S A. 2008;105(36):13427–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M, et al. Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science. 2012;337(6095):730–5.

    Article  CAS  PubMed  Google Scholar 

  24. Huang EH, Hynes MJ, Zhang T, Ginestier C, Dontu G, Appelman H, et al. Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis. Cancer Res. 2009;69(8):3382–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. •• Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M, et al. CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell. 2014;14(3):342–56. The study highlights the role of cd44v6 expression in colon cancer as a prognostic predictive biomarker for the identification of metastatic subpopulation of colon cancer stem cell.

    Article  CAS  PubMed  Google Scholar 

  26. Lv L, Liu HG, Dong SY, Yang F, Wang QX, Guo GL, et al. Upregulation of CD44v6 contributes to acquired chemoresistance via the modulation of autophagy in colon cancer SW480 cells. Tumour Biol J Int Soc Oncodev Biol Med. 2016;37(7):8811–24.

    Article  CAS  Google Scholar 

  27. Garza-Trevino EN, Said-Fernandez SL, Martinez-Rodriguez HG. Understanding the colon cancer stem cells and perspectives on treatment. Cancer Cell Int. 2015;15(1):2. This review discusses the role of colon cancer stem cells as main responsible for chemo resistance, minimal residual disease, and tumor recurrence. In particular, the study analyzes several therapeutic strategies against colorectal cancer stem cells.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. • Hammond WA, Swaika A, Mody K. Pharmacologic resistance in colorectal cancer: a review. Ther Ad Med Oncol. 2016;8(1):57–84. A comprehensive literature research about the mechanism involving in pharmacological resistance of colorectal cancer.

    CAS  Google Scholar 

  29. Moitra K, Lou H, Dean M. Multidrug efflux pumps and cancer stem cells: insights into multidrug resistance and therapeutic development. Clin Pharmacol Ther. 2011;89(4):491–502.

    Article  CAS  PubMed  Google Scholar 

  30. Siegel R, Desantis C, Jemal A. Colorectal cancer statistics, 2014. CA Cancer J Clin. 2014;64(2):104–17.

    Article  PubMed  Google Scholar 

  31. Longley DB, Johnston PG. Molecular mechanisms of drug resistance. J Pathol. 2005;205(2):275–92.

    Article  CAS  PubMed  Google Scholar 

  32. Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, et al. Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer. 2012;48(10):1466–75.

    Article  CAS  PubMed  Google Scholar 

  33. An Y, Ongkeko WM. ABCG2: the key to chemoresistance in cancer stem cells? Expert Opin Drug Metab Toxicol. 2009;5(12):1529–42.

    Article  CAS  PubMed  Google Scholar 

  34. DeGorter MK, Xia CQ, Yang JJ, Kim RB. Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol. 2012;52:249–73.

    Article  CAS  PubMed  Google Scholar 

  35. Mo W, Zhang JT. Human ABCG2: structure, function, and its role in multidrug resistance. Int J Biochem Mole Biol. 2012;3(1):1–27.

    CAS  Google Scholar 

  36. Huang WC, Hsieh YL, Hung CM, Chien PH, Chien YF, Chen LC, et al. BCRP/ABCG2 inhibition sensitizes hepatocellular carcinoma cells to sorafenib. PLoS One. 2013;8(12), e83627.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Leonard GD, Fojo T, Bates SE. The role of ABC transporters in clinical practice. Oncologist. 2003;8(5):411–24.

    Article  CAS  PubMed  Google Scholar 

  38. Cojoc M, Mabert K, Muders MH, Dubrovska A. A role for cancer stem cells in therapy resistance: cellular and molecular mechanisms. Semin Cancer Biol. 2015;31:16–27.

    Article  CAS  PubMed  Google Scholar 

  39. 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(5):555–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ma I, Allan AL. The role of human aldehyde dehydrogenase in normal and cancer stem cells. Stem Cell Rev. 2011;7(2):292–306.

    Article  CAS  PubMed  Google Scholar 

  41. Marcato P, Dean CA, Giacomantonio CA, Lee PW. Aldehyde dehydrogenase: its role as a cancer stem cell marker comes down to the specific isoform. Cell Cycle. 2011;10(9):1378–84.

    Article  CAS  PubMed  Google Scholar 

  42. Singh S, Brocker C, Koppaka V, Chen Y, Jackson BC, Matsumoto A, et al. Aldehyde dehydrogenases in cellular responses to oxidative/electrophilic stress. Free Radic Biol Med. 2013;56:89–101.

    Article  CAS  PubMed  Google Scholar 

  43. Ajani JA, Wang X, Song S, Suzuki A, Taketa T, Sudo K, et al. ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients. Mol Oncol. 2014;8(1):142–9.

    Article  CAS  PubMed  Google Scholar 

  44. Magni M, Shammah S, Schiro R, Mellado W, Dalla-Favera R, Gianni AM. Induction of cyclophosphamide-resistance by aldehyde-dehydrogenase gene transfer. Blood. 1996;87(3):1097–103.

    CAS  PubMed  Google Scholar 

  45. Parajuli B, Georgiadis TM, Fishel ML, Hurley TD. Development of selective inhibitors for human aldehyde dehydrogenase 3A1 (ALDH3A1) for the enhancement of cyclophosphamide cytotoxicity. Chem Biochem Eur J Chem Biol. 2014;15(5):701–12.

    Article  CAS  Google Scholar 

  46. Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139(5):871–90.

    Article  CAS  PubMed  Google Scholar 

  47. •• Grigore AD, Jolly MK, Jia D, Farach-Carson MC, Levine H. Tumor budding: the name is EMT. Partial EMT. Journal of clinical medicine. 2016; 5 (5). Tumor budding can be considered as a partial epithelial-mesenchymal transition. This review discusses the heterogeneity of this phenomenon, its clinical significance in many cancer types, and its possible application in clinical practice.

  48. Kalluri R, Weinberg RA. The basics of epithelial-mesenchymal transition. J Clin Invest. 2009;119(6):1420–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ocana OH, Corcoles R, Fabra A, Moreno-Bueno G, Acloque H, Vega S, et al. Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1. Cancer Cell. 2012;22(6):709–24.

    Article  CAS  PubMed  Google Scholar 

  50. 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(3):316–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Estrella V, Chen T, Lloyd M, Wojtkowiak J, Cornnell HH, Ibrahim-Hashim A, et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res. 2013;73(5):1524–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gjorevski N, Boghaert E, Nelson CM. Regulation of epithelial-mesenchymal transition by transmission of mechanical stress through epithelial tissues. Cancer Microenviron Off J Int Cancer Micro Environ Soc. 2012;5(1):29–38.

    Article  Google Scholar 

  53. Lopez-Novoa JM, Nieto MA. Inflammation and EMT: an alliance towards organ fibrosis and cancer progression. EMBO Mol Med. 2009;1(6–7):303–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sahlgren C, Gustafsson MV, Jin S, Poellinger L, Lendahl U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci U S A. 2008;105(17):6392–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9(4):265–73.

    Article  CAS  PubMed  Google Scholar 

  56. Qi L, Sun B, Liu Z, Cheng R, Li Y, Zhao X. Wnt3a expression is associated with epithelial-mesenchymal transition and promotes colon cancer progression. J Exp Clin Cancer Res. 2014;33:107.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. •• De Craene B, Berx G. Regulatory networks defining EMT during cancer initiation and progression. Nat Rev Cancer. 2013;13(2):97–110. This review highlights the interconnection between the epithelial to mesenchymal transition (EMT) induction factors and these regulatory networks. EMT is a process regulated at different levels, including transcriptional, translational, and post-translational control; regulation by non-coding RNAs; and differential splicing events.

    Article  PubMed  CAS  Google Scholar 

  58. Vandewalle C, Comijn J, De Craene B, Vermassen P, Bruyneel E, Andersen H, et al. SIP1/ZEB2 induces EMT by repressing genes of different epithelial cell-cell junctions. Nucleic Acids Res. 2005;33(20):6566–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Gomez I, Pena C, Herrera M, Munoz C, Larriba MJ, Garcia V, et al. TWIST1 is expressed in colorectal carcinomas and predicts patient survival. PLoS One. 2011;6(3), e18023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Peinado H, Ballestar E, Esteller M, Cano A. Snail mediates E-cadherin repression by the recruitment of the Sin3A/histone deacetylase 1 (HDAC1)/HDAC2 complex. Mol Cell Biol. 2004;24(1):306–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Abshire CF, Carroll JL, Dragoi AM. FLASH protects ZEB1 from degradation and supports cancer cells’ epithelial-to-mesenchymal transition. Oncogenesis. 2016;5(8), e254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Xu Q, Deng F, Qin Y, Zhao Z, Wu Z, Xing Z, et al. Long non-coding RNA regulation of epithelial-mesenchymal transition in cancer metastasis. Cell Death Dis. 2016;7(6), e2254.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Li Q, Liang X, Wang Y, Meng X, Xu Y, Cai S, et al. miR-139-5p inhibits the epithelial-mesenchymal transition and enhances the chemotherapeutic sensitivity of colorectal cancer cells by downregulating BCL2. Scientific reports. 2016;6:27157.

  64. Pan X, Wang ZX, Wang R. MicroRNA-21: a novel therapeutic target in human cancer. Cancer Biol Ther. 2010;10(12):1224–32.

    Article  CAS  PubMed  Google Scholar 

  65. Tsai JH, Donaher JL, Murphy DA, Chau S, Yang J. Spatiotemporal regulation of epithelial-mesenchymal transition is essential for squamous cell carcinoma metastasis. Cancer Cell. 2012;22(6):725–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Cho SH, Park YS, Kim HJ, Kim CH, Lim SW, Huh JW, et al. CD44 enhances the epithelial-mesenchymal transition in association with colon cancer invasion. Int J Oncol. 2012;41(1):211–8.

    CAS  PubMed  Google Scholar 

  67. Scheel C, Weinberg RA. Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links. Semin Cancer Biol. 2012;22(5–6):396–403.

    Article  CAS  PubMed  Google Scholar 

  68. 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(4):704–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fischer KR, Durrans A, Lee S, Sheng J, Li F, Wong ST, et al. Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance. Nature. 2015;527(7579):472–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Davis FM, Stewart TA, Thompson EW, Monteith GR. Targeting EMT in cancer: opportunities for pharmacological intervention. Trends Pharmacol Sci. 2014;35(9):479–88.

    Article  CAS  PubMed  Google Scholar 

  71. •• Marcucci F, Stassi G, De Maria R. Epithelial-mesenchymal transition: a new target in anticancer drug discovery. Nat Rev Drug Discov. 2016;15(5):311–25. A perspective analysis about EMT as a new target for anti-tumor therapy. This review summarizes different compounds and their mechanisms to target this process at different levels: EMT induction inhibitors, MET-promoting compounds, and mesenchymal tumor cell targeted drugs.

    Article  CAS  PubMed  Google Scholar 

  72. Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29(2):117–29.

    Article  CAS  PubMed  Google Scholar 

  73. Neuzillet C, Tijeras-Raballand A, Cohen R, Cros J, Faivre S, Raymond E, et al. Targeting the TGFbeta pathway for cancer therapy. Pharmacol Ther. 2015;147:22–31.

    Article  CAS  PubMed  Google Scholar 

  74. Smith AL, Robin TP, Ford HL. Molecular pathways: targeting the TGF-beta pathway for cancer therapy. Clin Cancer Res. 2012;18(17):4514–21.

    Article  CAS  PubMed  Google Scholar 

  75. Balanis N, Wendt MK, Schiemann BJ, Wang Z, Schiemann WP, Carlin CR. Epithelial to mesenchymal transition promotes breast cancer progression via a fibronectin-dependent STAT3 signaling pathway. J Biol Chem. 2013;288(25):17954–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xiong H, Hong J, Du W, Lin YW, Ren LL, Wang YC, et al. Roles of STAT3 and ZEB1 proteins in E-cadherin down-regulation and human colorectal cancer epithelial-mesenchymal transition. J Biol Chem. 2012;287(8):5819–32.

    Article  CAS  PubMed  Google Scholar 

  77. Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124(4):1853–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11(8):753–62.

    Article  PubMed  CAS  Google Scholar 

  79. Hollande F, Pannequin J, Joubert D. The long road to colorectal cancer therapy: searching for the right signals. Drug Res Rev Comm Antimicrobial Antican Chem. 2010;13(1–2):44–56.

    CAS  Google Scholar 

  80. •• Van Emburgh BO, Sartore-Bianchi A, Di Nicolantonio F, Siena S, Bardelli A. Acquired resistance to EGFR-targeted therapies in colorectal cancer. Mol Oncol. 2014;8(6):1084–94. The review describes different acquired resistance mechanisms to EGFR target therapies in colorectal cancer. In particular, the study focuses on the EGFR-MAPK pathway alteration and amplification, in preclinical and clinical studies.

    Article  PubMed  CAS  Google Scholar 

  81. Webster RM. Combination therapies in oncology. Nat Rev Drug Discov. 2016;15(2):81–2.

    Article  CAS  PubMed  Google Scholar 

  82. Cohen DJ, Hochster HS. Rationale for combining biotherapy in the treatment of advanced colon cancer. Gastrointestinal Cancer Res GCR. 2008;2(3):145–51.

    Google Scholar 

  83. Yap TA, Omlin A, de Bono JS. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol Off J Am Soc Clin Oncol. 2013;31(12):1592–605.

    Article  CAS  Google Scholar 

  84. De Roock W, De Vriendt V, Normanno N, Ciardiello F, Tejpar SKRAS, BRAF. PIK3CA, and PTEN mutations: implications for targeted therapies in metastatic colorectal cancer. Lancet Oncol. 2011;12(6):594–603.

    Article  PubMed  CAS  Google Scholar 

  85. • Dienstmann R, Salazar R, Tabernero J. Overcoming resistance to anti-EGFR therapy in colorectal cancer. American Society of Clinical Oncology educational book / ASCO American Society of Clinical Oncology Meeting. 2015:e149-56. The work represents a complete overview on principles of genetic and non-genetic molecular alteration associated with EGFR therapy resistances in colorectal cancer. It provides several evidences on the role of molecular heterogeneity of colon rectal cancer in the acquired resistance phenomenon.

  86. Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res Off J Am Assoc Cancer Res. 2015;21(4):730–8.

    Article  CAS  Google Scholar 

  87. Stahel R, Bogaerts J, Ciardiello F, de Ruysscher D, Dubsky P, Ducreux M, et al. Optimising translational oncology in clinical practice: strategies to accelerate progress in drug development. Cancer Treat Rev. 2015;41(2):129–35.

    Article  CAS  PubMed  Google Scholar 

  88. Tabernero J, Van Cutsem E, Lakomy R, Prausova J, Ruff P, van Hazel GA, et al. Aflibercept versus placebo in combination with fluorouracil, leucovorin and irinotecan in the treatment of previously treated metastatic colorectal cancer: prespecified subgroup analyses from the VELOUR trial. Eur J Cancer. 2014;50(2):320–31.

    Article  CAS  PubMed  Google Scholar 

  89. Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med. 2004;350(23):2335–42.

    Article  CAS  PubMed  Google Scholar 

  90. Liska D, Chen CT, Bachleitner-Hofmann T, Christensen JG, Weiser MR. HGF rescues colorectal cancer cells from EGFR inhibition via MET activation. Clin Cancer Res Off J Am Assoc Cancer Res. 2011;17(3):472–82.

    Article  CAS  Google Scholar 

  91. Bardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, et al. Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer. Cancer Dis. 2013;3(6):658–73.

    Article  CAS  Google Scholar 

  92. • Oddo D, Sennott EM, Barault L, Valtorta E, Arena S, Cassingena A, et al. Molecular landscape of acquired resistance to targeted therapy combinations in BRAF-mutant colorectal cancer. Cancer Res. 2016;76(15):4504–15. The study analyzes the resistance mechanism of B-Raf mutant colorectal cancer, and it suggests a possible therapeutic approach using a vertical combination therapy of inhibitors against ERK, B-RAF, and EGFR.

    Article  CAS  PubMed  Google Scholar 

  93. Pietrantonio F, Oddo D, Gloghini A, Valtorta E, Berenato R, Barault L, et al. MET-driven resistance to dual EGFR and BRAF blockade may be overcome by switching from EGFR to MET inhibition in BRAF-mutated colorectal cancer. Cancer Discovery. 2016;6(9):963–71.

    Article  CAS  PubMed  Google Scholar 

  94. •• Sartore-Bianchi A, Trusolino L, Martino C, Bencardino K, Lonardi S, Bergamo F, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES): a proof-of-concept, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(6):738–46. A phase two trial, multicenter performed in four Italian academic cancer centers. K-RAS wild-type colorectal cancer patients, with HER2-positive tumors, were treated with a novel combination of trastuzumab and lapatinib. This combination was well tolerated and active in treatment refractory patients.

    Article  CAS  PubMed  Google Scholar 

  95. Schirripa M, Lenz HJ. Colorectal cancer: overcoming resistance to anti-EGFR therapy—where do we stand? Nat Rev Gastroenterol Hepatol. 2016;13(5):258–9.

    Article  CAS  PubMed  Google Scholar 

  96. Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309–14.

    Article  CAS  PubMed  Google Scholar 

  97. Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11(2):85–95.

    Article  CAS  PubMed  Google Scholar 

  98. Peiris-Pages M, Martinez-Outschoorn UE, Pestell RG, Sotgia F, Lisanti MP. Cancer stem cell metabolism. Breast Cancer Res BCR. 2016;18(1):55.

    Article  PubMed  Google Scholar 

  99. •• Sancho P, Barneda D, Heeschen C. Hallmarks of cancer stem cell metabolism. Br J Cancer. 2016;114(12):1305–12. Detailed overview of metabolic changes in cancer stem cell metabolism.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Margineantu DH, Hockenbery DM. Mitochondrial functions in stem cells. Current Opinion Gen Dev. 2016;38:110–7.

    Article  CAS  Google Scholar 

  101. Ren F, Wang K, Zhang T, Jiang J, Nice EC, Huang C. New insights into redox regulation of stem cell self-renewal and differentiation. Biochim Biophys Acta. 2015;1850(8):1518–26.

    Article  CAS  PubMed  Google Scholar 

  102. Porporato PE, Payen VL, Perez-Escuredo J, De Saedeleer CJ, Danhier P, Copetti T, et al. A mitochondrial switch promotes tumor metastasis. Cell Rep. 2014;8(3):754–66.

    Article  CAS  PubMed  Google Scholar 

  103. • Eales KL, Hollinshead KE, Tennant DA. Hypoxia and metabolic adaptation of cancer cells. Oncogenesis. 2016;5:e190. This study analyzes the role of hypoxia-induced metabolic changes in cancer cells during tumor progression.

  104. Morrison SJ, Kimble J. Asymmetric and symmetric stem-cell divisions in development and cancer. Nature. 2006;441(7097):1068–74.

    Article  CAS  PubMed  Google Scholar 

  105. Katajisto P, Dohla J, Chaffer CL, Pentinmikko N, Marjanovic N, Iqbal S, et al. Stem cells. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness. Science. 2015;348(6232):340–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Cao X, Fang L, Gibbs S, Huang Y, Dai Z, Wen P, et al. Glucose uptake inhibitor sensitizes cancer cells to daunorubicin and overcomes drug resistance in hypoxia. Cancer Chemother Pharmacol. 2007;59(4):495–505.

    Article  CAS  PubMed  Google Scholar 

  107. Zhou Y, Tozzi F, Chen J, Fan F, Xia L, Wang J, et al. Intracellular ATP levels are a pivotal determinant of chemoresistance in colon cancer cells. Cancer Res. 2012;72(1):304–14.

    Article  CAS  PubMed  Google Scholar 

  108. Lu CW, Lin SC, Chien CW, Lin SC, Lee CT, Lin BW, et al. Overexpression of pyruvate dehydrogenase kinase 3 increases drug resistance and early recurrence in colon cancer. Am J Pathol. 2011;179(3):1405–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhang C, Tian Y, Song F, Fu C, Han B, Wang Y. Salinomycin inhibits the growth of colorectal carcinoma by targeting tumor stem cells. Oncol Rep. 2015;34(5):2469–76.

    CAS  PubMed  Google Scholar 

  110. Nangia-Makker P, Yu Y, Vasudevan A, Farhana L, Rajendra SG, Levi E, et al. Metformin: a potential therapeutic agent for recurrent colon cancer. PLoS One. 2014;9(1), e84369.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Tamada M, Nagano O, Tateyama S, Ohmura M, Yae T, Ishimoto T, et al. Modulation of glucose metabolism by CD44 contributes to antioxidant status and drug resistance in cancer cells. Cancer Res. 2012;72(6):1438–48.

    Article  CAS  PubMed  Google Scholar 

  112. Nagano O, Okazaki S, Saya H. Redox regulation in stem-like cancer cells by CD44 variant isoforms. Oncogene. 2013;32(44):5191–8.

    Article  CAS  PubMed  Google Scholar 

  113. Ma MZ, Chen G, Wang P, Lu WH, Zhu CF, Song M, et al. Xc- inhibitor sulfasalazine sensitizes colorectal cancer to cisplatin by a GSH-dependent mechanism. Cancer Lett. 2015;368(1):88–96.

    Article  CAS  PubMed  Google Scholar 

  114. •• Potze L, Di Franco S, Grandela C, Pras-Raves ML, Picavet DI, van Veen HA, et al. Betulinic acid induces a novel cell death pathway that depends on cardiolipin modification. Oncogene. 2016;35(4):427–37. Study about the use of the natural compound betulininc acid to target colorectal cancer stem cell’s metabolism, showing for the first time how interfering with lipid metabolism (in particular through SCD-1 inhibition) could be considered a promising strategy to kill cancer stem cells.

    Article  CAS  PubMed  Google Scholar 

  115. Potze L, di Franco S, Kessler JH, Stassi G, Medema JP. Betulinic acid kills colon cancer stem cells. Curr Stem Cell Res Ther. 2016;11(5):427–33.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank Tatiana Terranova for manuscript editing and proofreading.

Author information

Author notes

    Authors and Affiliations

    1. Department of Surgical and Oncological Sciences, Cellular and Molecular Pathophysiology Laboratory, University of Palermo, Via del Vespro 131, 90127, Palermo, Italy

      Alessandro Giammona, Laura Rosa Mangiapane, Simone Di Franco, Antonina Benfante & Giorgio Stassi

    2. Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), University of Palermo, Via del Vespro 131, 90127, Palermo, Italy

      Matilde Todaro

    3. DiBiMIS, University of Palermo, Piazza delle Cliniche 2, 90127, Palermo, Italy

      Matilde Todaro

    Authors
    1. Alessandro Giammona
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Laura Rosa Mangiapane
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Simone Di Franco
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Antonina Benfante
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Matilde Todaro
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Giorgio Stassi
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Giorgio Stassi.

    Ethics declarations

    Conflict of Interest

    The authors declare that they have no conflict of interest.

    Human and Animal Rights and Informed Consent

    This article does not contain any studies with human or animal subjects performed by any of the authors.

    Financial Support

    This work was supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) to G.S. (AIRC IG 16746 and MoH RF-2011- 02349126) and M.T. (AIRC IG 14415). S.D.F. is an AIRC fellowship recipient for 2016 and a Fondazione Veronesi Post-Doctoral fellowship recipient for 2017.

    Additional information

    This article is part of the Topical Collection on Basic Science Foundations in Colorectal Cancer

    Alessandro Giammona, Laura Rosa Mangiapane and Simone Di Franco contributed equally to this work.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Giammona, A., Mangiapane, L.R., Di Franco, S. et al. Innovative Therapeutic Strategies Targeting Colorectal Cancer Stem Cells. Curr Colorectal Cancer Rep 13, 91–100 (2017). https://doi.org/10.1007/s11888-017-0353-x

    Download citation

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s11888-017-0353-x

    Keywords

    Search

    Navigation