Skip to main content
SpringerLink
Log in
Book cover

Cancer Stem Cells: Emerging Concepts and Future Perspectives in Translational Oncology pp 445–476Cite as

Targeting Cancer Stem Cells and the Tumor Microenvironment

  • Chapter

  • 1114 Accesses

Abstract

Compelling evidence indicates that the survival and behavior of cancer stem cells (CSCs) are positively regulated by specific stimuli received from the tumor microenvironment, which dictates the maintenance of stemness, invasiveness, and protection against drug-induced apoptotic signals. CSCs are per se endowed with multiple treatment resistance capabilities, thus the eradication of CSC pools offers a precious strategy in achieving a long-term cancer remission. Numerous therapies, aimed at eradicating CSCs, have been elaborated such as: (i) selective targeting of CSCs, (ii) modulating their stemness and (iii) influencing the microenvironment. In this context, markers commonly exploited to isolate and identify CSCs are optimal targets for monoclonal antibody-based drugs. Furthermore, the molecules that inhibit detoxifying enzymes and drug-efflux pumps, are able to selectively suppress CSCs. Auspicious outcomes have also been reported either by targeting pathways selectively operating in CSCs (e.g. Hedgehog, Wnt, Notch and FAK) or by using specific CSC cytotoxic agents. Other compounds are able to attenuate the unique stemness properties of CSCs by forcing cell differentiation, and this being the case in ATRA, HDACi, BMPs and Cyclopamine, among others. Targeting the interplay between paracrine signals arising in the tumor stroma and the nearby cancerous cells via the inhibition of VEGF, HIF, CD44v and CXCR4, is increasingly recognized as a significant factor in cancer treatment response and holds alluring prospects for a successful elimination of CSCs. In the present chapter, we discuss the latest findings in the optimization and tailoring of novel strategies that target both CSCs and tumor bulk for the eradication of malignancies.

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

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

References

  • Andersson ER, Lendahl U (2014) Therapeutic modulation of notch signalling–are we there yet? Nat Rev Drug Discov 13(5):357–378

    CAS  PubMed  Google Scholar 

  • Bao S, Wu Q, Sathornsumetee S, Hao Y, Li Z, Hjelmeland AB et al (2006) Stem cell-like glioma cells promote tumor angiogenesis through vascular endothelial growth factor. Cancer Res 66(16):7843–7848

    CAS  PubMed  Google Scholar 

  • Bao B, Wang Z, Ali S, Ahmad A, Azmi AS, Sarkar SH et al (2012) Metformin inhibits cell proliferation, migration and invasion by attenuating CSC function mediated by deregulating miRNAs in pancreatic cancer cells. Cancer Prev Res 5(3):355–364

    CAS  Google Scholar 

  • Bardsley MR, Horvath VJ, Asuzu DT, Lorincz A, Redelman D, Hayashi Y et al (2010) Kitlow stem cells cause resistance to Kit/platelet-derived growth factor alpha inhibitors in murine gastrointestinal stromal tumors. Gastroenterology 139(3):942–952

    PubMed Central  CAS  PubMed  Google Scholar 

  • Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A et al (2011) A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours. Nature 478(7369):399–403

    CAS  PubMed  Google Scholar 

  • Bergers G, Hanahan D (2008) Modes of resistance to anti-angiogenic therapy. Nat Rev Cancer 8(8):592–603

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bhat-Nakshatri P, Goswami CP, Badve S, Sledge GW Jr, Nakshatri H (2013) Identification of FDA-approved drugs targeting breast cancer stem cells along with biomarkers of sensitivity. Sci Rep 3:2530

    PubMed Central  PubMed  Google Scholar 

  • Boehmerle W, Endres M (2011) Salinomycin induces calpain and cytochrome c-mediated neuronal cell death. Cell Death Dis 2, e168

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bourguignon LY, Peyrollier K, Xia W, Gilad E (2008) Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells. J Biol Chem 283(25):17635–17651

    PubMed Central  CAS  PubMed  Google Scholar 

  • Burger JA, Peled A (2009) CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia 23(1):43–52

    CAS  PubMed  Google Scholar 

  • Busfield SJ, Biondo M, Wong M, Ramshaw HS, Lee EM, Ghosh S et al (2014) Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC. Leukemia 28(11):2213–2221

    CAS  PubMed  Google Scholar 

  • Butler LM, Agus DB, Scher HI, Higgins B, Rose A, Cordon-Cardo C et al (2000) Suberoylanilide hydroxamic acid, an inhibitor of histone deacetylase, suppresses the growth of prostate cancer cells in vitro and in vivo. Cancer Res 60(18):5165–5170

    CAS  PubMed  Google Scholar 

  • Calabrese C, Poppleton H, Kocak M, Hogg TL, Fuller C, Hamner B et al (2007) A perivascular niche for brain tumor stem cells. Cancer Cell 11(1):69–82

    CAS  PubMed  Google Scholar 

  • Campos B, Wan F, Farhadi M, Ernst A, Zeppernick F, Tagscherer KE et al (2010) Differentiation therapy exerts antitumor effects on stem-like glioma cells. Clin Cancer Res 16(10):2715–2728

    CAS  PubMed  Google Scholar 

  • Cao Y, Wang E, Pal K, Dutta SK, Bar-Sagi D et al (2012) VEGF exerts an angiogenesis-independent function in cancer cells to promote their malignant progression. Cancer Res 72(16):3912–3918

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cao Y, Eble JM, Moon E, Yuan H, Weitzel DH, Landon CD et al (2013) Tumor cells upregulate normoxic HIF-1alpha in response to doxorubicin. Cancer Res 73(20):6230–6242

    PubMed Central  CAS  PubMed  Google Scholar 

  • Catalano V, Turdo A, Di Franco S, Dieli F, Todaro M, Stassi G (2013) Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol 23(6 Pt B):522–532

    CAS  PubMed  Google Scholar 

  • Chaffer CL, Brueckmann I, Scheel C, Kaestli AJ, Wiggins PA, Rodrigues LO et al (2011) Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc Natl Acad Sci USA 108(19):7950–7955

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chakrabarti R, Wei Y, Hwang J, Hang X, Andres Blanco M, Choudhury A et al (2014) DeltaNp63 promotes stem cell activity in mammary gland development and basal-like breast cancer by enhancing Fzd7 expression and Wnt signalling. Nat Cell Biol 16(10):1004–1015

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen JK, Taipale J, Cooper MK, Beachy PA (2002) Inhibition of hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev 16(21):2743–2748

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen B, Dodge ME, Tang W, Lu J, Ma Z, Fan CW et al (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5(2):100–107

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG et al (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488(7412):522–526

    PubMed Central  CAS  PubMed  Google Scholar 

  • Chen X, Iliopoulos D, Zhang Q, Tang Q, Greenblatt MB, Hatziapostolou M et al (2014) XBP1 promotes triple-negative breast cancer by controlling the HIF1alpha pathway. Nature 508(7494):103–107

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cheng L, Huang Z, Zhou W, Wu Q, Donnola S, Liu JK et al (2013) Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth. Cell 153(1):139–152

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cioffi M, Dorado J, Baeuerle PA, Heeschen C (2012) EpCAM/CD3-Bispecific T-cell engaging antibody MT110 eliminates primary human pancreatic cancer stem cells. Clin Cancer Res 18(2):465–474

    CAS  PubMed  Google Scholar 

  • Clement V, Sanchez P, de Tribolet N, Radovanovic I, Ruiz i Altaba A (2007) HEDGEHOG-GLI1 signaling regulates human glioma growth, cancer stem cell self-renewal, and tumorigenicity. Curr Biol 17(2):165–172

    PubMed Central  CAS  PubMed  Google Scholar 

  • Conley SJ, Gheordunescu E, Kakarala P, Newman B, Korkaya H, Heath AN et al (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci USA 109(8):2784–2789

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cordenonsi M, Zanconato F, Azzolin L, Forcato M, Rosato A, Frasson C et al (2011) The Hippo transducer TAZ confers cancer stem cell-related traits on breast cancer cells. Cell 147(4):759–772

    CAS  PubMed  Google Scholar 

  • Covello KL, Kehler J, Yu H, Gordan JD, Arsham AM, Hu CJ et al (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20(5):557–570

    PubMed Central  CAS  PubMed  Google Scholar 

  • Curtin NJ, Szabo C (2013) Therapeutic applications of PARP inhibitors: anticancer therapy and beyond. Mol Aspects Med 34(6):1217–1256

    CAS  PubMed  Google Scholar 

  • Dean M, Fojo T, Bates S (2005) Tumour stem cells and drug resistance. Nat Rev Cancer 5(4):275–284

    CAS  PubMed  Google Scholar 

  • Del Bufalo D, Ciuffreda L, Trisciuoglio D, Desideri M, Cognetti F, Zupi G et al (2006) Antiangiogenic potential of the mammalian target of rapamycin inhibitor temsirolimus. Cancer Res 66(11):5549–5554

    PubMed  Google Scholar 

  • Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458(7239):780–783

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dierks C, Beigi R, Guo GR, Zirlik K, Stegert MR, Manley P et al (2008) Expansion of Bcr-Abl-positive leukemic stem cells is dependent on Hedgehog pathway activation. Cancer Cell 14(3):238–249

    CAS  PubMed  Google Scholar 

  • DiPersio JF, Micallef IN, Stiff PJ, Bolwell BJ, Maziarz RT, Jacobsen E et al (2009a) Phase III prospective randomized double-blind placebo-controlled trial of plerixafor plus granulocyte colony-stimulating factor compared with placebo plus granulocyte colony-stimulating factor for autologous stem-cell mobilization and transplantation for patients with non-Hodgkin’s lymphoma. J Clin Oncol 27(28):4767–4773

    CAS  PubMed  Google Scholar 

  • DiPersio JF, Stadtmauer EA, Nademanee A, Micallef IN, Stiff PJ, Kaufman JL et al (2009b) Plerixafor and G-CSF versus placebo and G-CSF to mobilize hematopoietic stem cells for autologous stem cell transplantation in patients with multiple myeloma. Blood 113(23):5720–5726

    CAS  PubMed  Google Scholar 

  • Elisei R, Schlumberger MJ, Muller SP, Schoffski P, Brose MS, Shah MH et al (2013) Cabozantinib in progressive medullary thyroid cancer. J Clin Oncol 31(29):3639–3646

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ellis LM, Hicklin DJ (2008) VEGF-targeted therapy: mechanisms of anti-tumour activity. Nat Rev Cancer 8(8):579–591

    CAS  PubMed  Google Scholar 

  • Emami KH, Nguyen C, Ma H, Kim DH, Jeong KW, Eguchi M et al (2004) A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc Natl Acad Sci USA 101(34):12682–12687

    PubMed Central  CAS  PubMed  Google Scholar 

  • Erler JT, Bennewith KL, Cox TR, Lang G, Bird D, Koong A et al (2009) Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15(1):35–44

    PubMed Central  CAS  PubMed  Google Scholar 

  • Espinoza I, Pochampally R, Xing F, Watabe K, Miele L (2013) Notch signaling: targeting cancer stem cells and epithelial-to-mesenchymal transition. Onco Targets Ther 6:1249–1259

    PubMed Central  PubMed  Google Scholar 

  • Fan X, Khaki L, Zhu TS, Soules ME, Talsma CE, Gul N et al (2010) NOTCH pathway blockade depletes CD133-positive glioblastoma cells and inhibits growth of tumor neurospheres and xenografts. Stem Cells 28(1):5–16

    PubMed Central  CAS  PubMed  Google Scholar 

  • Fantozzi A, Gruber DC, Pisarsky L, Heck C, Kunita A, Yilmaz M et al (2014) VEGF-mediated angiogenesis links EMT-induced cancer stemness to tumor initiation. Cancer Res 74(5):1566–1575

    CAS  PubMed  Google Scholar 

  • Fischer M, Yen WC, Kapoun AM, Wang M, O’Young G, Lewicki J et al (2011) Anti-DLL4 inhibits growth and reduces tumor-initiating cell frequency in colorectal tumors with oncogenic KRAS mutations. Cancer Res 71(5):1520–1525

    CAS  PubMed  Google Scholar 

  • Folkins C, Man S, Xu P, Shaked Y, Hicklin DJ, Kerbel RS (2007) Anticancer therapies combining antiangiogenic and tumor cell cytotoxic effects reduce the tumor stem-like cell fraction in glioma xenograft tumors. Cancer Res 67(8):3560–3564

    CAS  PubMed  Google Scholar 

  • Folkman J (1971) Tumor angiogenesis: therapeutic implications. N Engl J Med 285(21):1182–1186

    CAS  PubMed  Google Scholar 

  • Gao H, Chakraborty G, Lee-Lim AP, Mo Q, Decker M, Vonica A et al (2012) The BMP inhibitor Coco reactivates breast cancer cells at lung metastatic sites. Cell 150(4):764–779

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ginestier C, Wicinski J, Cervera N, Monville F, Finetti P, Bertucci F et al (2009) Retinoid signaling regulates breast cancer stem cell differentiation. Cell Cycle 8(20):3297–3302

    PubMed Central  CAS  PubMed  Google Scholar 

  • Goel HL, Mercurio AM (2013) VEGF targets the tumour cell. Nat Rev Cancer 13(12):871–882

    PubMed Central  CAS  PubMed  Google Scholar 

  • Goel HL, Chang C, Pursell B, Leav I, Lyle S, Xi HS et al (2012) VEGF/neuropilin-2 regulation of Bmi-1 and consequent repression of IGF-IR define a novel mechanism of aggressive prostate cancer. Cancer Discov 2(10):906–921

    PubMed Central  CAS  PubMed  Google Scholar 

  • Goel HL, Pursell B, Chang C, Shaw LM, Mao J, Simin K et al (2013) GLI1 regulates a novel neuropilin-2/alpha6beta1 integrin based autocrine pathway that contributes to breast cancer initiation. EMBO Mol Med 5(4):488–508

    PubMed Central  CAS  PubMed  Google Scholar 

  • Goel HL, Gritsko T, Pursell B, Chang C, Shultz LD, Greiner DL et al (2014) Regulated splicing of the alpha6 integrin cytoplasmic domain determines the fate of breast cancer stem cells. Cell Rep 7(3):747–761

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gordan JD, Bertout JA, Hu CJ, Diehl JA, Simon MC (2007) HIF-2alpha promotes hypoxic cell proliferation by enhancing c-myc transcriptional activity. Cancer Cell 11(4):335–347

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gupta PB, Onder TT, Jiang G, Tao K, Kuperwasser C, Weinberg RA et al (2009) Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138(4):645–659

    CAS  PubMed  Google Scholar 

  • Gupta SC, Patchva S, Aggarwal BB (2013) Therapeutic roles of curcumin: lessons learned from clinical trials. AAPS J 15(1):195–218

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L et al (2012) Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA 109(29):11717–11722

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hamerlik P, Lathia JD, Rasmussen R, Wu Q, Bartkova J, Lee M et al (2012) Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med 209(3):507–520

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hammerle B, Yanez Y, Palanca S, Canete A, Burks DJ, Castel V et al (2013) Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor. PLoS One 8(10), e76761

    PubMed Central  CAS  PubMed  Google Scholar 

  • Harikumar KB, Kunnumakkara AB, Sethi G, Diagaradjane P, Anand P, Pandey MK et al (2010) Resveratrol, a multitargeted agent, can enhance antitumor activity of gemcitabine in vitro and in orthotopic mouse model of human pancreatic cancer. Int J Cancer 127(2):257–268

    PubMed Central  CAS  PubMed  Google Scholar 

  • Harris AL (2002) Hypoxia–a key regulatory factor in tumour growth. Nat Rev Cancer 2(1):38–47

    CAS  PubMed  Google Scholar 

  • Heiss MM, Murawa P, Koralewski P, Kutarska E, Kolesnik OO, Ivanchenko VV et al (2010) The trifunctional antibody catumaxomab for the treatment of malignant ascites due to epithelial cancer: results of a prospective randomized phase II/III trial. Int J Cancer 127(9):2209–2221

    PubMed Central  CAS  PubMed  Google Scholar 

  • 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

    CAS  PubMed  Google Scholar 

  • Herrmann I, Baeuerle PA, Friedrich M, Murr A, Filusch S, Ruttinger D et al (2010) Highly efficient elimination of colorectal tumor-initiating cells by an EpCAM/CD3-bispecific antibody engaging human T cells. PLoS One 5(10), e13474

    PubMed Central  PubMed  Google Scholar 

  • Hoey T, Yen WC, Axelrod F, Basi J, Donigian L, Dylla S et al (2009) DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5(2):168–177

    CAS  PubMed  Google Scholar 

  • Hsiao HT, Xing L, Deng X, Sun X, Ling CC, Li GC (2014) Hypoxia-targeted triple suicide gene therapy radiosensitizes human colorectal cancer cells. Oncol Rep 32(2):723–729

    PubMed Central  PubMed  Google Scholar 

  • Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LM (2002) Hsp90 regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-degradative pathway. J Biol Chem 277(33):29936–29944

    CAS  PubMed  Google Scholar 

  • Ishimoto T, Nagano O, Yae T, Tamada M, Motohara T, Oshima H et al (2011) CD44 variant regulates redox status in cancer cells by stabilizing the xCT subunit of system xc(-) and thereby promotes tumor growth. Cancer Cell 19(3):387–400

    CAS  PubMed  Google Scholar 

  • Jager M, Schoberth A, Ruf P, Hess J, Hennig M, Schmalfeldt B et al (2012) Immunomonitoring results of a phase II/III study of malignant ascites patients treated with the trifunctional antibody catumaxomab (anti-EpCAM x anti-CD3). Cancer Res 72(1):24–32

    PubMed  Google Scholar 

  • Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307(5706):58–62

    CAS  PubMed  Google Scholar 

  • Jimeno A, Weiss GJ, Miller WH Jr, Gettinger S, Eigl BJ, Chang AL et al (2013) Phase I study of the Hedgehog pathway inhibitor IPI-926 in adult patients with solid tumors. Clin Cancer Res 19(10):2766–2774

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jin L, Hope KJ, Zhai Q, Smadja-Joffe F, Dick JE (2006) Targeting of CD44 eradicates human acute myeloid leukemic stem cells. Nat Med 12(10):1167–1174

    PubMed  Google Scholar 

  • Jin L, Lee EM, Ramshaw HS, Busfield SJ, Peoppl AG, Wilkinson L et al (2009) Monoclonal antibody-mediated targeting of CD123, IL-3 receptor alpha chain, eliminates human acute myeloid leukemic stem cells. Cell Stem Cell 5(1):31–42

    CAS  PubMed  Google Scholar 

  • Jung JW, Park SB, Lee SJ, Seo MS, Trosko JE, Kang KS (2011) Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 expression. PLoS One 6(11), e28068

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kakarala M, Brenner DE, Korkaya H, Cheng C, Tazi K, Ginestier C et al (2010) Targeting breast stem cells with the cancer preventive compounds curcumin and piperine. Breast Cancer Res Treat 122(3):777–785

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kaluz S, Kaluzova M, Stanbridge EJ (2006) Proteasomal inhibition attenuates transcriptional activity of hypoxia-inducible factor 1 (HIF-1) via specific effect on the HIF-1alpha C-terminal activation domain. Mol Cell Biol 26(15):5895–5907

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kang Y, Hu W, Ivan C, Dalton HJ, Miyake T, Pecot CV et al (2013) Role of focal adhesion kinase in regulating YB-1-mediated paclitaxel resistance in ovarian cancer. J Natl Cancer Inst 105(19):1485–1495

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kaur B, Khwaja FW, Severson EA, Matheny SL, Brat DJ, Van Meir EG (2005) Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro Oncol 7(2):134–153

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ketola K, Hilvo M, Hyotylainen T, Vuoristo A, Ruskeepaa AL, Oresic M et al (2012) Salinomycin inhibits prostate cancer growth and migration via induction of oxidative stress. Br J Cancer 106(1):99–106

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim G, Ouzounova M, Quraishi AA, Davis A, Tawakkol N, Clouthier SG et al (2014) SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene 34(6):671–680

    PubMed Central  PubMed  Google Scholar 

  • Kondratyev M, Kreso A, Hallett RM, Girgis-Gabardo A, Barcelon ME, Ilieva D et al (2012) Gamma-secretase inhibitors target tumor-initiating cells in a mouse model of ERBB2 breast cancer. Oncogene 31(1):93–103

    CAS  PubMed  Google Scholar 

  • Koo KH, Kim H, Bae YK, Kim K, Park BK, Lee CH et al (2013) Salinomycin induces cell death via inactivation of Stat3 and down regulation of Skp2. Cell Death Dis 4:e693

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kreso A, Dick JE (2014) Evolution of the cancer stem cell model. Cell Stem Cell 14(3):275–291

    CAS  PubMed  Google Scholar 

  • Kreso A, van Galen P, Pedley NM, Lima-Fernandes E, Frelin C, Davis T et al (2014) Self-renewal as a therapeutic target in human colorectal cancer. Nat Med 20(1):29–36

    CAS  PubMed  Google Scholar 

  • Kung AL, Zabludoff SD, France DS, Freedman SJ, Tanner EA, Vieira A et al (2004) Small molecule blockade of transcriptional coactivation of the hypoxia-inducible factor pathway. Cancer Cell 6(1):33–43

    CAS  PubMed  Google Scholar 

  • Lathia JD, Gallagher J, Heddleston JM, Wang J, Eyler CE, Macswords J et al (2010) Integrin alpha 6 regulates glioblastoma stem cells. Cell Stem Cell 6(5):421–432

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lee K, Qian DZ, Rey S, Wei H, Liu JO, Semenza GL (2009) Anthracycline chemotherapy inhibits HIF-1 transcriptional activity and tumor-induced mobilization of circulating angiogenic cells. Proc Natl Acad Sci USA 106(7):2353–2358

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lee HJ, Zhuang G, Cao Y, Du P, Kim HJ, Settleman J (2014) Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells. Cancer Cell 26(2):207–221

    CAS  PubMed  Google Scholar 

  • Li F, Sonveaux P, Rabbani ZN, Liu S, Yan B, Huang Q et al (2007) Regulation of HIF-1alpha stability through S-nitrosylation. Mol Cell 26(1):63–74

    PubMed Central  PubMed  Google Scholar 

  • Li Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S et al (2009) Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells. Cancer Cell 15(6):501–513

    PubMed Central  CAS  PubMed  Google Scholar 

  • Li L, Hao X, Qin J, Tang W, He F, Smith A et al (2014) Antibody against CD44s inhibits pancreatic tumor initiation and postradiation recurrence in mice. Gastroenterology 146(4):1108–1118

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lin TL, Wang QH, Brown P, Peacock C, Merchant AA, Brennan S et al (2010) Self-renewal of acute lymphocytic leukemia cells is limited by the hedgehog pathway inhibitors cyclopamine and IPI-926. PLoS One 5(12):e15262

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liu J, Pan S, Hsieh MH, Ng N, Sun F, Wang T et al (2013) Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc Natl Acad Sci USA 110(50):20224–20229

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lombardo Y, Scopelliti A, Cammareri P, Todaro M, Iovino F, Ricci-Vitiani L et al (2011) Bone morphogenetic protein 4 induces differentiation of colorectal cancer stem cells and increases their response to chemotherapy in mice. Gastroenterology 140(1):297–309

    CAS  PubMed  Google Scholar 

  • Lu X, Kang Y (2010) Hypoxia and hypoxia-inducible factors: master regulators of metastasis. Clin Cancer Res 16(24):5928–5935

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lu W, Li Y (2014) Salinomycin suppresses LRP6 expression and inhibits both Wnt/beta-catenin and mTORC1 signaling in breast and prostate cancer cells. J Cell Biochem 115(10):1799–1807

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lu D, Choi MY, Yu J, Castro JE, Kipps TJ, Carson DA (2011) Salinomycin inhibits Wnt signaling and selectively induces apoptosis in chronic lymphocytic leukemia cells. Proc Natl Acad Sci USA 108(32):13253–13257

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D et al (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22(1):21–35

    PubMed Central  CAS  PubMed  Google Scholar 

  • Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD Jr et al (2009) CD47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell 138(2):286–299

    PubMed Central  CAS  PubMed  Google Scholar 

  • Malik SM, Maher VE, Bijwaard KE, Becker RL, Zhang L, Tang SW et al (2014) U.S. food and drug administration approval: crizotinib for treatment of advanced or metastatic non-small cell lung cancer that is anaplastic lymphoma kinase positive. Clin Cancer Res 20(8):2029–2034

    CAS  PubMed  Google Scholar 

  • Marangoni E, Lecomte N, Durand L, de Pinieux G, Decaudin D, Chomienne C et al (2009) CD44 targeting reduces tumour growth and prevents post-chemotherapy relapse of human breast cancers xenografts. Br J Cancer 100(6):918–922

    PubMed Central  CAS  PubMed  Google Scholar 

  • Masuko K, Okazaki S, Satoh M, Tanaka G, Ikeda T, Torii R et al (2012) Anti-tumor effect against human cancer xenografts by a fully human monoclonal antibody to a variant 8-epitope of CD44R1 expressed on cancer stem cells. PLoS One 7(1):e29728

    PubMed Central  CAS  PubMed  Google Scholar 

  • Maugeri-Sacca M, Vigneri P, De Maria R (2011) Cancer stem cells and chemosensitivity. Clin Cancer Res 17(15):4942–4947

    CAS  PubMed  Google Scholar 

  • Medema JP (2013) Cancer stem cells: the challenges ahead. Nat Cell Biol 15(4):338–344

    CAS  PubMed  Google Scholar 

  • Mendes-Pereira AM, Martin SA, Brough R, McCarthy A, Taylor JR, Kim JS et al (2009) Synthetic lethal targeting of PTEN mutant cells with PARP inhibitors. EMBO Mol Med 1(6–7):315–322

    PubMed Central  CAS  PubMed  Google Scholar 

  • Mie Lee Y, Kim SH, Kim HS, Jin Son M, Nakajima H, Jeong Kwon H et al (2003) Inhibition of hypoxia-induced angiogenesis by FK228, a specific histone deacetylase inhibitor, via suppression of HIF-1alpha activity. Biochem Biophys Res Commun 300(1):241–246

    PubMed  Google Scholar 

  • Moeller BJ, Cao Y, Li CY, Dewhirst MW (2004) Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell 5(5):429–441

    CAS  PubMed  Google Scholar 

  • Morel AP, Lievre M, Thomas C, Hinkal G, Ansieau S, Puisieux A (2008) Generation of breast cancer stem cells through epithelial-mesenchymal transition. PLoS One 3(8), e2888

    PubMed Central  PubMed  Google Scholar 

  • Naujokat C (2014) Monoclonal antibodies against human cancer stem cells. Immunotherapy 6(3):290–308

    CAS  PubMed  Google Scholar 

  • Nautiyal J, Kanwar SS, Yu Y, Majumdar AP (2011) Combination of dasatinib and curcumin eliminates chemo-resistant colon cancer cells. J Mol Signal 6:7

    PubMed Central  CAS  PubMed  Google Scholar 

  • Olive KP, Jacobetz MA, Davidson CJ, Gopinathan A, McIntyre D, Honess D et al (2009) Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324(5933):1457–1461

    PubMed Central  CAS  PubMed  Google Scholar 

  • Oliveras-Ferraros C, Vazquez-Martin A, Cuyas E, Corominas-Faja B, Rodriguez-Gallego E, Fernandez-Arroyo S et al (2014) Acquired resistance to metformin in breast cancer cells triggers transcriptome reprogramming toward a degradome-related metastatic stem-like profile. Cell Cycle 13(7):1132–1144

    PubMed Central  CAS  PubMed  Google Scholar 

  • Onnis B, Rapisarda A, Melillo G (2009) Development of HIF-1 inhibitors for cancer therapy. J Cell Mol Med 13(9A):2780–2786

    PubMed Central  CAS  PubMed  Google Scholar 

  • O’Shaughnessy J, Osborne C, Pippen JE, Yoffe M, Patt D, Rocha C et al (2011) Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N Engl J Med 364(3):205–214

    PubMed  Google Scholar 

  • Pan Q, Chanthery Y, Liang WC, Stawicki S, Mak J, Rathore N et al (2007) Blocking neuropilin-1 function has an additive effect with anti-VEGF to inhibit tumor growth. Cancer Cell 11(1):53–67

    CAS  PubMed  Google Scholar 

  • Pannuti A, Foreman K, Rizzo P, Osipo C, Golde T, Osborne B et al (2010) Targeting notch to target cancer stem cells. Clin Cancer Res 16(12):3141–3152

    PubMed Central  CAS  PubMed  Google Scholar 

  • Park JE, Chen HH, Winer J, Houck KA, Ferrara N (1994) Placenta growth factor. Potentiation of vascular endothelial growth factor bioactivity, in vitro and in vivo, and high affinity binding to Flt-1 but not to Flk-1/KDR. J Biol Chem 269(41):25646–25654

    CAS  PubMed  Google Scholar 

  • Patel A, Sun W (2014) Ziv-aflibercept in metastatic colorectal cancer. Biol 8:13–25

    CAS  Google Scholar 

  • Pattabiraman DR, Weinberg RA (2014) Tackling the cancer stem cells – what challenges do they pose? Nat Rev Drug Discov 13(7):497–512

    PubMed Central  CAS  PubMed  Google Scholar 

  • Patterson AV, Williams KJ, Cowen RL, Jaffar M, Telfer BA, Saunders M et al (2002) Oxygen-sensitive enzyme-prodrug gene therapy for the eradication of radiation-resistant solid tumours. Gene Ther 9(14):946–954

    CAS  PubMed  Google Scholar 

  • Peacock CD, Wang Q, Gesell GS, Corcoran-Schwartz IM, Jones E, Kim J et al (2007) Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc Natl Acad Sci USA 104(10):4048–4053

    PubMed Central  CAS  PubMed  Google Scholar 

  • Peters S, Adjei AA (2012) MET: a promising anticancer therapeutic target. Nat Rev Clin Oncol 9(6):314–326

    CAS  PubMed  Google Scholar 

  • Phan VT, Wu X, Cheng JH, Sheng RX, Chung AS, Zhuang G et al (2013) Oncogenic RAS pathway activation promotes resistance to anti-VEGF therapy through G-CSF-induced neutrophil recruitment. Proc Natl Acad Sci USA 110(15):6079–6084

    PubMed Central  CAS  PubMed  Google Scholar 

  • Poon E, Harris AL, Ashcroft M (2009) Targeting the hypoxia-inducible factor (HIF) pathway in cancer. Expert Rev Mol Med 11, e26

    PubMed  Google Scholar 

  • Qian DZ, Kachhap SK, Collis SJ, Verheul HM, Carducci MA, Atadja P et al (2006) Class II histone deacetylases are associated with VHL-independent regulation of hypoxia-inducible factor 1 alpha. Cancer Res 66(17):8814–8821

    CAS  PubMed  Google Scholar 

  • Rattan R, Ali Fehmi R, Munkarah A (2012) Metformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis. J Oncol 2012:928127

    PubMed Central  PubMed  Google Scholar 

  • Ravi R, Mookerjee B, Bhujwalla ZM, Sutter CH, Artemov D, Zeng Q et al (2000) Regulation of tumor angiogenesis by p53-induced degradation of hypoxia-inducible factor 1alpha. Genes Dev 14(1):34–44

    PubMed Central  CAS  PubMed  Google Scholar 

  • Riccioni R, Dupuis ML, Bernabei M, Petrucci E, Pasquini L, Mariani G, Cianfriglia M, Testa U (2010) The cancer stem cell selective inhibitor salinomycin is a p-glycoprotein inhibitor. Blood Cells Mol Dis 45(1):86–92

    CAS  PubMed  Google Scholar 

  • Ricci-Vitiani L, Pallini R, Biffoni M, Todaro M, Invernici G, Cenci T et al (2010) Tumour vascularization via endothelial differentiation of glioblastoma stem-like cells. Nature 468(7325):824–828

    CAS  PubMed  Google Scholar 

  • Santoni M, Conti A, Massari F, Arnaldi G, Iacovelli R, Rizzo M et al (2014) Treatment-related fatigue with sorafenib, sunitinib and pazopanib in patients with advanced solid tumors: an up-to-date review and meta-analysis of clinical trials. Int J Cancer 136(1):1–10

    PubMed  Google Scholar 

  • Sato A, Okada M, Shibuya K, Watanabe E, Seino S, Suzuki K et al (2013) Resveratrol promotes proteasome-dependent degradation of nanog via p53 activation and induces differentiation of glioma stem cells. Stem Cell Res 11(1):601–610

    CAS  PubMed  Google Scholar 

  • Scheel C, Eaton EN, Li SH, Chaffer CL, Reinhardt F, Kah KJ et al (2011) Paracrine and autocrine signals induce and maintain mesenchymal and stem cell states in the breast. Cell 145(6):926–940

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schepers AG, Snippert HJ, Stange DE, van den Born M, van Es JH, van de Wetering M et al (2012) Lineage tracing reveals Lgr5+ stem cell activity in mouse intestinal adenomas. Science 337(6095):730–735

    CAS  PubMed  Google Scholar 

  • Schmid T, Zhou J, Kohl R, Brune B (2004) p300 relieves p53-evoked transcriptional repression of hypoxia-inducible factor-1 (HIF-1). Biochem J 380(Pt 1):289–295

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schober M, Fuchs E (2011) Tumor-initiating stem cells of squamous cell carcinomas and their control by TGF-beta and integrin/focal adhesion kinase (FAK) signaling. Proc Natl Acad Sci USA 108(26):10544–10549

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schott AF, Landis MD, Dontu G, Griffith KA, Layman RM, Krop I et al (2013) Preclinical and clinical studies of gamma secretase inhibitors with docetaxel on human breast tumors. Clin Cancer Res 19(6):1512–1524

    PubMed Central  CAS  PubMed  Google Scholar 

  • Semenza GL (2003) Targeting HIF-1 for cancer therapy. Nat Rev Cancer 3(10):721–732

    CAS  PubMed  Google Scholar 

  • Shankar S, Davis R, Singh KP, Kurzrock R, Ross DD, Srivastava RK (2009) Suberoylanilide hydroxamic acid (Zolinza/vorinostat) sensitizes TRAIL-resistant breast cancer cells orthotopically implanted in BALB/c nude mice. Mol Cancer Ther 8(6):1596–1605

    CAS  PubMed  Google Scholar 

  • Shankar S, Nall D, Tang SN, Meeker D, Passarini J, Sharma J et al (2011) Resveratrol inhibits pancreatic cancer stem cell characteristics in human and KrasG12D transgenic mice by inhibiting pluripotency maintaining factors and epithelial-mesenchymal transition. PLoS One 6(1), e16530

    PubMed Central  CAS  PubMed  Google Scholar 

  • Shishido Y, Ueno S, Yamazaki R, Nagaoka M, Matsuzaki T (2013) ABCG2 inhibitor YHO-13351 sensitizes cancer stem/initiating-like side population cells to irinotecan. Anticancer Res 33(4):1379–1386

    CAS  PubMed  Google Scholar 

  • Singh BN, Fu J, Srivastava RK, Shankar S (2011) Hedgehog signaling antagonist GDC-0449 (Vismodegib) inhibits pancreatic cancer stem cell characteristics: molecular mechanisms. PLoS One 6(11), e27306

    PubMed Central  CAS  PubMed  Google Scholar 

  • Snuderl M, Batista A, Kirkpatrick ND, Ruiz de Almodovar C, Riedemann L, Walsh EC et al (2013) Targeting placental growth factor/neuropilin 1 pathway inhibits growth and spread of medulloblastoma. Cell 152(5):1065–1076

    PubMed Central  CAS  PubMed  Google Scholar 

  • Soker S, Takashima S, Miao HQ, Neufeld G, Klagsbrun M (1998) Neuropilin-1 is expressed by endothelial and tumor cells as an isoform-specific receptor for vascular endothelial growth factor. Cell 92(6):735–745

    CAS  PubMed  Google Scholar 

  • Song Z, Yue W, Wei B, Wang N, Li T, Guan L et al (2011) Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One 6(3), e17687

    PubMed Central  CAS  PubMed  Google Scholar 

  • Sulzmaier FJ, Jean C, Schlaepfer DD (2014) FAK in cancer: mechanistic findings and clinical applications. Nat Rev Cancer 14(9):598–610

    PubMed Central  CAS  PubMed  Google Scholar 

  • Takahashi-Yanaga F, Kahn M (2010) Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin Cancer Res 16(12):3153–3162

    CAS  PubMed  Google Scholar 

  • Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ et al (2000) The expression and distribution of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 157(2):411–421

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tate CM, Pallini R, Ricci-Vitiani L, Dowless M, Shiyanova T, D’Alessandris GQ et al (2012) A BMP7 variant inhibits the tumorigenic potential of glioblastoma stem-like cells. Cell Death Differ 19(10):1644–1654

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tentori L, Ricci-Vitiani L, Muzi A, Ciccarone F, Pelacchi F, Calabrese R et al (2014) Pharmacological inhibition of poly(ADP-ribose) polymerase-1 modulates resistance of human glioblastoma stem cells to temozolomide. BMC Cancer 14:151

    PubMed Central  PubMed  Google Scholar 

  • Tewari KS, Sill MW, Long HJ 3rd, Penson RT, Huang H, Ramondetta LM et al (2014) Improved survival with bevacizumab in advanced cervical cancer. N Engl J Med 370(8):734–743

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC et al (1991) The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem 266(18):11947–11954

    CAS  PubMed  Google Scholar 

  • To K, Fotovati A, Reipas KM, Law JH, Hu K, Wang J et al (2010) Y-box binding protein-1 induces the expression of CD44 and CD49f leading to enhanced self-renewal, mammosphere growth, and drug resistance. Cancer Res 70(7):2840–2851

    PubMed Central  CAS  PubMed  Google Scholar 

  • Todaro M, Gaggianesi M, Catalano V, Benfante A, Iovino F, Biffoni M et al (2014) CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis. Cell Stem Cell 14(3):342–356

    CAS  PubMed  Google Scholar 

  • Tremblay MR, Lescarbeau A, Grogan MJ, Tan E, Lin G, Austad BC et al (2009) Discovery of a potent and orally active hedgehog pathway antagonist (IPI-926). J Med Chem 52(14):4400–4418

    CAS  PubMed  Google Scholar 

  • Valent P, Bonnet D, De Maria R, Lapidot T, Copland M, Melo JV et al (2012) Cancer stem cell definitions and terminology: the devil is in the details. Nat Rev Cancer 12(11):767–775

    CAS  PubMed  Google Scholar 

  • Vanner RJ, Remke M, Gallo M, Selvadurai HJ, Coutinho F, Lee L et al (2014) Quiescent sox2(+) cells drive hierarchical growth and relapse in sonic hedgehog subgroup medulloblastoma. Cancer Cell 26(1):33–47

    PubMed Central  CAS  PubMed  Google Scholar 

  • Varga AC, Wrana JL (2005) The disparate role of BMP in stem cell biology. Oncogene 24(37):5713–5721

    CAS  PubMed  Google Scholar 

  • Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA (2010) Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial-mesenchymal transition (EMT) status. Cell Cycle 9(18):3807–3814

    CAS  PubMed  Google Scholar 

  • Venere M, Hamerlik P, Wu Q, Rasmussen RD, Song LA, Vasanji A et al (2014) Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ 21(2):258–269

    PubMed Central  CAS  PubMed  Google Scholar 

  • Wilson WR, Hay MP (2011) Targeting hypoxia in cancer therapy. Nat Rev Cancer 11(6):393–410

    CAS  PubMed  Google Scholar 

  • Wouters BG, Koritzinsky M (2008) Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer 8(11):851–864

    CAS  PubMed  Google Scholar 

  • Xia X, Yang J, Li F, Li Y, Zhou X, Dai Y et al (2010) Image-based chemical screening identifies drug efflux inhibitors in lung cancer cells. Cancer Res 70(19):7723–7733

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang QC, Zeng BF, Shi ZM, Dong Y, Jiang ZM, Huang J et al (2006) Inhibition of hypoxia-induced angiogenesis by trichostatin A via suppression of HIF-1a activity in human osteosarcoma. J Exp Clin Cancer Res 25(4):593–599

    CAS  PubMed  Google Scholar 

  • Yang J, Ahmed A, Poon E, Perusinghe N, de Haven BA, Box G et al (2009) Small-molecule activation of p53 blocks hypoxia-inducible factor 1alpha and vascular endothelial growth factor expression in vivo and leads to tumor cell apoptosis in normoxia and hypoxia. Mol Cell Biol 29(8):2243–2253

    PubMed Central  CAS  PubMed  Google Scholar 

  • Yang YP, Chang YL, Huang PI, Chiou GY, Tseng LM, Chiou SH et al (2012) Resveratrol suppresses tumorigenicity and enhances radiosensitivity in primary glioblastoma tumor initiating cells by inhibiting the STAT3 axis. J Cell Physiol 227(3):976–993

    CAS  PubMed  Google Scholar 

  • Yu Y, Kanwar SS, Patel BB, Nautiyal J, Sarkar FH, Majumdar AP (2009) Elimination of colon cancer stem-like cells by the combination of curcumin and FOLFOX. Transl Oncol 2(4):321–328

    PubMed Central  PubMed  Google Scholar 

  • Zhang B, Strauss AC, Chu S, Li M, Ho Y, Shiang KD et al (2010) Effective targeting of quiescent chronic myelogenous leukemia stem cells by histone deacetylase inhibitors in combination with imatinib mesylate. Cancer Cell 17(5):427–442

    PubMed Central  PubMed  Google Scholar 

  • Zhang XH, Jin X, Malladi S, Zou Y, Wen YH, Brogi E et al (2013) Selection of bone metastasis seeds by mesenchymal signals in the primary tumor stroma. Cell 154(5):1060–1073

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhou GB, Zhao WL, Wang ZY, Chen SJ, Chen Z (2005) Retinoic acid and arsenic for treating acute promyelocytic leukemia. PLoS Med 2(1), e12

    PubMed Central  PubMed  Google Scholar 

  • Zhou D, Shao L, Spitz DR (2014) Reactive oxygen species in normal and tumor stem cells. Adv Cancer Res 122:1–67

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhu Z, Khan MA, Weiler M, Blaes J, Jestaedt L, Geibert M et al (2014) Targeting self-renewal in high-grade brain tumors leads to loss of brain tumor stem cells and prolonged survival. Cell Stem Cell 15(2):185–198

    CAS  PubMed  Google Scholar 

  • Zhuang W, Long L, Zheng B, Ji W, Yang N, Zhang Q et al (2012) Curcumin promotes differentiation of glioma-initiating cells by inducing autophagy. Cancer Sci 103(4):684–690

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The present study was supported by grants from AIRC to G. Stassi and M. Todaro. A. Turdo is a PhD student in “International Immunopharmacology Course” at University of Palermo. Special thanks go to Tatiana Terranova for her critical review of the manuscript. The authors disclose no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Surgical and Oncological Sciences, Laboratory of Cellular and Molecular Pathophysiology, University of Palermo, Via Liborio Giuffrè, 5., 90127, Palermo, Italy

    Alice Turdo, Matilde Todaro & Giorgio Stassi

Authors
  1. Alice Turdo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matilde Todaro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giorgio Stassi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giorgio Stassi .

Editor information

Editors and Affiliations

  1. Faculty of Biol. Scs. Dept. of Mol. Gen., Tarbiat Modares University , Tehran, Iran

    Sadegh Babashah

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Turdo, A., Todaro, M., Stassi, G. (2015). Targeting Cancer Stem Cells and the Tumor Microenvironment. In: Babashah, S. (eds) Cancer Stem Cells: Emerging Concepts and Future Perspectives in Translational Oncology. Springer, Cham. https://doi.org/10.1007/978-3-319-21030-8_16

Download citation

Publish with us

Policies and ethics

Search

Navigation