Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways (original) (raw)

• Dick, J. E. Stem cell concepts renew cancer research. Blood 112, 4793–4807 (2008).
  Article CAS PubMed Google Scholar
• Dick, J. E. Looking ahead in cancer stem cell research. Nat. Biotechnol. 27, 44–46 (2009).
  Article CAS PubMed Google Scholar
• Johnsen, H. E. et al. Cancer stem cells and the cellular hierarchy in haematological malignancies. Eur. J. Cancer 45 (Suppl. 1), 194–201 (2009).
  Article PubMed Google Scholar
• Odoux, C. et al. A stochastic model for cancer stem cell origin in metastatic colon cancer. Cancer Res. 68, 6932–6941 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Frank, N. Y., Schatton, T. & Frank, M. H. The therapeutic promise of the cancer stem cell concept. J. Clin. Invest. 120, 41–50 (2010).
  Article CAS PubMed PubMed Central Google Scholar
• McGovern, M., Voutev, R., Maciejowski, J., Corsi, A. K. & Hubbard, E. J. A “latent niche” mechanism for tumor initiation. Proc. Natl Acad. Sci. USA 106, 11617–11622 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Peacock, C. D. et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proc. Natl Acad. Sci. USA 104, 4048–4053 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Reya, T. & Clevers, H. Wnt signalling in stem cells and cancer. Nature 434, 843–850 (2005).
  Article CAS PubMed Google Scholar
• Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells—an integrated concept of malignant tumour progression. Nat. Rev. Cancer 5, 744–749 (2005).
  Article CAS PubMed Google Scholar
• Quintana, E. et al. Efficient tumour formation by single human melanoma cells. Nature 456, 593–598 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Dieter, S. M. et al. Distinct types of human colon cancer initiating cells contribute to primary tumor and metastasis formation [abstract 9]. Proc. Am. Assoc. Cancer Res. (2010).
• Schmidt, M. et al. Polyclonal long-term repopulating stem cell clones in a primate model. Blood 100, 2737–2743 (2002).
  Article CAS PubMed Google Scholar
• Lapidot, T. et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature 367, 645–648 (1994).
  Article CAS PubMed Google Scholar
• Bonnet, D. & Dick, J. E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 3, 730–737 (1997).
  Article CAS PubMed Google Scholar
• Al-Hajj, M. et al. Prospective identification of tumorigenic breast cancer cells. Proc. Natl Acad. Sci. USA 100, 3983–3988 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Singh, S. K. et al. Identification of human brain tumour initiating cells. Nature 432, 396–401 (2004).
  Article CAS PubMed Google Scholar
• Dalerba, P. et al. Phenotypic characterization of human colorectal cancer stem cells. Proc. Natl Acad. Sci. USA 104, 10158–10163 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• O'Brien, C. A., Pollett, A., Gallinger, S. & Dick, J. E. A human colon cancer cell capable of initiating tumour growth in immunodeficient mice. Nature 445, 106–110 (2007).
  Article CAS PubMed Google Scholar
• Ricci-Vitiani, L. et al. Identification and expansion of human colon-cancer-initiating cells. Nature 445, 111–115 (2007).
  Article CAS PubMed Google Scholar
• Prince, M. E. et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc. Natl Acad. Sci. USA 104, 973–978 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Hermann, P. C. et al. Distinct populations of cancer stem cells determine tumor growth and metastatic activity in human pancreatic cancer. Cell Stem Cell 1, 313–323 (2007).
  Article CAS PubMed Google Scholar
• Li, C. et al. Identification of pancreatic cancer stem cells. Cancer Res. 67, 1030–1037 (2007).
  Article CAS PubMed Google Scholar
• Yamashita, T. et al. EpCAM-positive hepatocellular carcinoma cells are tumor-initiating cells with stem/progenitor cell features. Gastroenterology 136, 1012–1024 (2009).
  Article CAS PubMed Google Scholar
• Schatton, T. et al. Identification of cells initiating human melanomas. Nature 451, 345–349 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Yang, Z. F. et al. Significance of CD90+ cancer stem cells in human liver cancer. Cancer Cell 13, 153–166 (2008).
  Article CAS PubMed Google Scholar
• Bertolini, G. et al. Highly tumorigenic lung cancer CD133+ cells display stem-like features and are spared by cisplatin treatment. Proc. Natl Acad. Sci. USA 106, 16281–16286 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, S. et al. Identification and characterization of ovarian cancer-initiating cells from primary human tumors. Cancer Res. 68, 4311–4320 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, X. et al. A luminal epithelial stem cell that is a cell of origin for prostate cancer. Nature 461, 495–500 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Chan, K. S. et al. Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells. Proc. Natl Acad. Sci. USA 106, 14016–14021 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Suvà, M. L. et al. Identification of cancer stem cells in Ewing's sarcoma. Cancer Res. 69, 1776–1781 (2009).
  Article PubMed CAS Google Scholar
• Huang, E. 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. 69, 3382–3389 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Wang, Z. et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res. 66, 2778–2784 (2006).
  Article CAS PubMed Google Scholar
• Krivtsov, A. V. et al. Transformation from committed progenitor to leukaemia stem cell initiated by MLL-AF9. Nature 442, 818–822 (2006).
  Article CAS PubMed Google Scholar
• Reya, T., Morrison, S. J., Clarke, M. F. & Weissman, I. L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
  Article CAS PubMed Google Scholar
• Jamieson, C. H. et al. Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. N. Engl. J. Med. 351, 657–667 (2004).
  Article CAS PubMed Google Scholar
• Artavanis-Tsakonas, S., Rand, M. D. & Lake, R. J. Notch signaling: cell fate control and signal integration in development. Science 284, 770–776 (1999).
  Article CAS PubMed Google Scholar
• Dontu, G. et al. Role of Notch signaling in cell-fate determination of human mammary stem/progenitor cells. Breast Cancer Res. 6, R605–R615 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Androutsellis-Theotokis, A. et al. Notch signalling regulates stem cell numbers in vitro and in vivo. Nature 442, 823–826 (2006).
  Article CAS PubMed Google Scholar
• Rampal, R., Arboleda-Velasquez, J. F., Nita-Lazar, A., Kosik, K. S. & Haltiwanger, R. S. Highly conserved O-fucose sites have distinct effects on Notch1 function. J. Biol. Chem. 280, 32133–32140 (2005).
  Article CAS PubMed Google Scholar
• Gordon, W. R. et al. Structural basis for autoinhibition of Notch. Nat. Struct. Mol. Biol. 14, 295–300 (2007).
  Article CAS PubMed Google Scholar
• Real, P. J. et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat. Med. 15, 50–58 (2009).
  Article CAS PubMed Google Scholar
• Rizzo, P. et al. Rational targeting of Notch signaling in cancer. Oncogene 27, 5124–5131 (2008).
  Article CAS PubMed Google Scholar
• Duarte, A. et al. Dosage-sensitive requirement for mouse Dll4 in artery development. Genes Dev. 18, 2474–2478 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Suchting, S. et al. The Notch ligand Delta-like 4 negatively regulates endothelial tip cell formation and vessel branching. Proc. Natl Acad. Sci. USA 104, 3225–3230 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Ridgway, J. et al. Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis. Nature 444, 1083–1087 (2006).
  Article CAS PubMed Google Scholar
• Yan, M. et al. Chronic DLL4 blockade induces vascular neoplasms. Nature 463, E6–E7 (2010).
  Article CAS PubMed Google Scholar
• Moellering, R. E. et al. Direct inhibition of the NOTCH transcription factor complex. Nature 462, 182–188 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Sawyer, T. K. AILERON Therapeutics. Chem. Biol. Drug Des. 73, 3–6 (2009).
  Article CAS PubMed Google Scholar
• Epenetos, A., Kousparou, C. & Stylianou, S. Inhibition of Notch signaling for the treatment of human carcinomas. AACR Meeting Abstracts A5502 (2009).
• Wu, Y. et al. Therapeutic antibody targeting of individual Notch receptors. Nature 464, 1052–1057 (2010).
  Article CAS PubMed Google Scholar
• Ingham, P. W. & McMahon, A. P. Hedgehog signaling in animal development: paradigms and principles. Genes Dev. 15, 3059–3087 (2001).
  Article CAS PubMed Google Scholar
• Hahn, H. et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 85, 841–851 (1996).
  Article CAS PubMed Google Scholar
• Johnson, R. L. et al. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science 272, 1668–1671 (1996).
  Article CAS PubMed Google Scholar
• Yauch, R. L. et al. A paracrine requirement for hedgehog signalling in cancer. Nature 455, 406–410 (2008).
  Article CAS PubMed Google Scholar
• Micchelli, C. A., The, I., Selva, E., Mogila, V. & Perrimon, N. Rasp, a putative transmembrane acyltransferase, is required for Hedgehog signaling. Development 129, 843–851 (2002).
  CAS PubMed Google Scholar
• Ruiz i Altaba, A., Mas, C. & Stecca, B. The Gli code: an information nexus regulating cell fate, stemness and cancer. Trends Cell Biol. 17, 438–447 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Molofsky, A. V. et al. Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425, 962–967 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Adesina, A. M. et al. Gene expression profiling reveals signatures characterizing histologic subtypes of hepatoblastoma and global deregulation in cell growth and survival pathways. Hum. Pathol. 40, 843–853 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Zhao, C. et al. Hedgehog signaling is essential for maintenance of cancer stem cells in myeloid leukaemia. Nature 458, 776–779 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Feldmann, G. et al. Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: a new paradigm for combination therapy in solid cancers. Cancer Res. 67, 2187–2196 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Taipale, J. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000).
  Article CAS PubMed Google Scholar
• Kiselyov, A. S. Targeting the hedgehog signaling pathway with small molecules. Anticancer Agents Med. Chem. 6, 445–449 (2006).
  Article CAS PubMed Google Scholar
• Rubin, L. L. & de Sauvage, F. J. Targeting the Hedgehog pathway in cancer. Nat. Rev. Drug Discov. 5, 1026–1033 (2006).
  Article CAS PubMed Google Scholar
• Stanton, B. Z. et al. A small molecule that binds Hedgehog and blocks its signaling in human cells. Nat. Chem. Biol. 5, 154–156 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Hyman, J. M. et al. Small-molecule inhibitors reveal multiple strategies for Hedgehog pathway blockade. Proc. Natl Acad. Sci. USA 106, 14132–14137 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Olive, K. P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• LoRusso, P. M. et al. A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 26, a3516 (2008).
  Article Google Scholar
• Von Hoff, D. D. et al. Inhibition of the hedgehog pathway in advanced basal-cell carcinoma. N. Engl. J. Med. 361, 1164–1172 (2009).
  Article CAS PubMed Google Scholar
• Angers, S. & Moon, R. T. Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol. 10, 468–477 (2009).
  Article CAS PubMed Google Scholar
• Grigoryan, T., Wend, P., Klaus, A. & Birchmeier, W. Deciphering the function of canonical Wnt signals in development and disease: conditional loss- and gain-of-function mutations of beta-catenin in mice. Genes Dev. 22, 2308–2341 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Clevers, H. Wnt/beta-catenin signaling in development and disease. Cell 127, 469–480 (2006).
  Article CAS PubMed Google Scholar
• Andrade, A. C., Nilsson, O., Barnes, K. M. & Baron, J. Wnt gene expression in the post-natal growth plate: regulation with chondrocyte differentiation. Bone 40, 1361–1369 (2007).
  Article CAS PubMed PubMed Central Google Scholar
• Takada, R. et al. Monounsaturated fatty acid modification of Wnt protein: its role in Wnt secretion. Dev. Cell 11, 791–801 (2006).
  Article CAS PubMed Google Scholar
• Ching, W. & Nusse, R. A dedicated Wnt secretion factor. Cell 125, 432–433 (2006).
  Article CAS PubMed Google Scholar
• Hsieh, J. C., Rattner, A., Smallwood, P. M. & Nathans, J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl Acad. Sci. USA 96, 3546–3551 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Schulte, G. & Bryja, V. The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol. Sci. 28, 518–525 (2007).
  Article CAS PubMed Google Scholar
• de La Coste, A. et al. Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 95, 8847–8851 (1998).
  Article CAS PubMed Google Scholar
• Kim, M. S., Kim, S. S., Ahn, C. H., Yoo, N. J. & Lee, S. H. Frameshift mutations of Wnt pathway genes AXIN2 and TCF7L2 in gastric carcinomas with high microsatellite instability. Hum. Pathol. 40, 58–64 (2009).
  Article CAS PubMed Google Scholar
• Koesters, R. et al. Mutational activation of the beta-catenin proto-oncogene is a common event in the development of Wilms' tumors. Cancer Res. 59, 3880–3882 (1999).
  CAS PubMed Google Scholar
• Martin, V. et al. Epigenetic regulation of the non-canonical Wnt pathway in acute myeloid leukemia. Cancer Sci. 101, 425–432 (2010).
  Article CAS PubMed Google Scholar
• Malanchi, I. et al. Cutaneous cancer stem cell maintenance is dependent on beta-catenin signalling. Nature 452, 650–653 (2008).
  Article CAS PubMed Google Scholar
• Majeti, R. et al. Dysregulated gene expression networks in human acute myelogenous leukemia stem cells. Proc. Natl Acad. Sci. USA 106, 3396–3401 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Müller-Tidow, C. et al. Translocation products in acute myeloid leukemia activate the Wnt signaling pathway in hematopoietic cells. Mol. Cell Biol. 24, 2890–2904 (2004).
  Article PubMed PubMed Central CAS Google Scholar
• Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol. 5, 100–107 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Emami, K. H. et al. A small molecule inhibitor of beta-catenin/CREB-binding protein transcription [corrected]. Proc. Natl Acad. Sci. USA 101, 12682–12687 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Takahashi-Yanaga, F. & Kahn, M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin. Cancer Res. 16, 3153–3162 (2010).
  Article CAS PubMed Google Scholar
• Fujii, N. et al. An antagonist of dishevelled protein-protein interaction suppresses beta-catenin-dependent tumor cell growth. Cancer Res. 67, 573–579 (2007).
  Article CAS PubMed Google Scholar
• Shan, J., Shi, D. L., Wang, J. & Zheng, J. Identification of a specific inhibitor of the dishevelled PDZ domain. Biochemistry 44, 15495–15503 (2005).
  Article CAS PubMed Google Scholar
• He, B. et al. Blockade of Wnt-1 signaling induces apoptosis in human colorectal cancer cells containing downstream mutations. Oncogene 24, 3054–3058 (2005).
  Article CAS PubMed Google Scholar
• You, L. et al. An anti-Wnt-2 monoclonal antibody induces apoptosis in malignant melanoma cells and inhibits tumor growth. Cancer Res. 64, 5385–5389 (2004).
  Article CAS PubMed Google Scholar
• Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).
  Article CAS PubMed Google Scholar
• Shook, D. & Keller, R. Mechanisms, mechanics and function of epithelial-mesenchymal transitions in early development. Mech. Dev. 120, 1351–1383 (2003).
  Article CAS PubMed Google Scholar
• Kim, M. A. et al. Prognostic importance of epithelial-mesenchymal transition-related protein expression in gastric carcinoma. Histopathology 54, 442–451 (2009).
  Article PubMed Google Scholar
• Mareel, M. et al. E-cadherin/catenin/cytoskeleton complex: a regulator of cancer invasion. J. Cell Physiol. 173, 271–274 (1997).
  Article CAS PubMed Google Scholar
• Dissanayake, S. K. et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J. Biol. Chem. 282, 17259–17271 (2007).
  Article CAS PubMed Google Scholar
• Vincan, E. & Barker, N. The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin. Exp. Metastasis 25, 657–663 (2008).
  Article CAS PubMed Google Scholar
• Massagué, J. TGFbeta in cancer. Cell 134, 215–230 (2008).
  Article PubMed PubMed Central CAS Google Scholar
• Yang, J. & Weinberg, R. A. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).
  Article CAS PubMed Google Scholar
• Bailey, J. M., Singh, P. K. & Hollingsworth, M. A. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J. Cell Biochem. 102, 829–839 (2007).
  Article CAS PubMed Google Scholar
• Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).
  Article CAS PubMed Google Scholar
• Frank, N. Y. et al. ABCB5-mediated doxorubicin transport and chemoresistance in human malignant melanoma. Cancer Res. 65, 4320–4333 (2005).
  Article CAS PubMed Google Scholar
• Ambudkar, S. V., Kimchi-Sarfaty, C., Sauna, Z. E. & Gottesman, M. M. P-glycoprotein: from genomics to mechanism. Oncogene 22, 7468–7485 (2003).
  Article CAS PubMed Google Scholar
• Diehn, M. et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780–783 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Itasaki, N. & Hoppler, S. Crosstalk between Wnt and bone morphogenic protein signaling: a turbulent relationship. Dev. Dyn. 239, 16–33 (2010).
  CAS PubMed Google Scholar
• Sun, L., Tian, Z. & Wang, J. A direct cross-talk between interferon-gamma and sonic hedgehog signaling that leads to the proliferation of neuronal precursor cells. Brain Behav. Immun. 24, 220–228 (2010).
  Article CAS PubMed Google Scholar
• Vivekanand, P. & Rebay, I. Intersection of signal transduction pathways and development. Annu. Rev. Genet. 40, 139–157 (2006).
  Article CAS PubMed Google Scholar
• Ma, J. et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J. Clin. Invest. 120, 103–114 (2010).
  Article CAS PubMed Google Scholar
• Wang, Z. et al. Down-regulation of Notch-1 and Jagged-1 inhibits prostate cancer cell growth, migration and invasion, and induces apoptosis via inactivation of Akt, mTOR, and NF-kappaB signaling pathways. J. Cell. Biochem. 109, 726–736 (2010).
  CAS PubMed Google Scholar
• Meurette, O. et al. Notch activation induces Akt signaling via an autocrine loop to prevent apoptosis in breast epithelial cells. Cancer Res. 69, 5015–5022 (2009).
  Article CAS PubMed Google Scholar
• Dai, J. et al. Cross-talk between Notch and EGFR signaling in human breast cancer cells. Cancer Invest. 27, 533–540 (2009).
  Article CAS PubMed Google Scholar
• Purow, B. W. et al. Notch-1 regulates transcription of the epidermal growth factor receptor through p53. Carcinogenesis 29, 918–925 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Deb, S. P., Muñoz, R. M., Brown, D. R., Subler, M. A. & Deb, S. Wild-type human p53 activates the human epidermal growth factor receptor promoter. Oncogene 9, 1341–1349 (1994).
  CAS PubMed Google Scholar
• Mellinghoff, I. K. et al. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. N. Engl. J. Med. 353, 2012–2024 (2005).
  Article CAS PubMed Google Scholar
• Osipo, C. et al. ErbB-2 inhibition activates Notch-1 and sensitizes breast cancer cells to a gamma-secretase inhibitor. Oncogene 27, 5019–5032 (2008).
  Article CAS PubMed Google Scholar
• Hirose, H. et al. Notch pathway as candidate therapeutic target in Her2/Neu/ErbB2 receptor-negative breast tumors. Oncol. Rep. 23, 35–43 (2010).
  CAS PubMed Google Scholar
• Guo, X. & Wang, X. F. Signaling cross-talk between TGF-beta/BMP and other pathways. Cell Res. 19, 71–88 (2009).
  Article CAS PubMed Google Scholar
• Zavadil, J., Cermak, L., Soto-Nieves, N. & Böttinger, E. P. Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO J. 23, 1155–1165 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• He, J. et al. Suppressing Wnt signaling by the hedgehog pathway through sFRP-1. J. Biol. Chem. 281, 35598–35602 (2006).
  Article CAS PubMed Google Scholar
• Bhagwandin, V. J. & Shay. J. W. Pancreatic cancer stem cells: fact or fiction? Biochim. Biophys. Acta 1792, 248–259 (2009).
  Article CAS PubMed PubMed Central Google Scholar
• Deangelo, D. J. et al. A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias [abstract]. J. Clin. Oncol. 24, a6585 (2006).
  Google Scholar
• Peters, J. U. et al. Novel orally active, dibenzazepinone-based gamma-secretase inhibitors. Bioorg Med. Chem. Lett. 17, 5918–5923 (2007).
  Article CAS PubMed Google Scholar
• Kopan, R. & Ilagan, M. X. Gamma-secretase: proteasome of the membrane? Nat. Rev. Mol. Cell Biol. 5, 499–504 (2004).
  Article CAS PubMed Google Scholar
• Li, K. et al. Modulation of Notch signaling by antibodies specific for the extracellular negative regulatory region of NOTCH3. J. Biol. Chem. 283, 8046–8054 (2006).
  Article CAS Google Scholar
• Hoey, T. et al. DLL4 blockade inhibits tumor growth and reduces tumor-initiating cell frequency. Cell Stem Cell 5, 168–177 (2009).
  Article CAS PubMed Google Scholar
• Noguera-Troise, I. et al. Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis. Nature 444, 1032–1037 (2006).
  Article CAS PubMed Google Scholar
• Garcés, C. et al. Notch-1 controls the expression of fatty acid-activated transcription factors and is required for adipogenesis. J. Biol. Chem. 272, 29729–29734 (1997).
  Article PubMed Google Scholar
• Nickoloff, B. J. et al. Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. Cell Death Differ. 9, 842–855 (2002).
  Article CAS PubMed Google Scholar
• Rudin, C. M., Hann, C. L., Peacock, C. D. & Watkins, D. N. Novel systemic therapies for small cell lung cancer. J. Natl Compr. Canc. Netw. 6, 315–322 (2008).
  Article CAS PubMed PubMed Central Google Scholar
• Barginear, M. F., Leung, M. & Budman, D. R. The hedgehog pathway as a therapeutic target for treatment of breast cancer. Breast Cancer Res. Treat. 116, 239–246 (2009).
  Article CAS PubMed Google Scholar
• Fukukawa, C. Katagiri, T., Nakatsuru, S. & Nakamura, Y. Therapeutic potential of antibodies against frizzled homologue 10, a cell-surface protein, for synovial sarcoma [abstract]. Proc. Amer. Assoc. Cancer Res. 47, 1975 (2006).
  Google Scholar
• Yoshizumi, T. et al. Thiazolidinedione, a peroxisome proliferator-activated receptor-gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int. J. Oncol. 25, 631–639 (2004).
  CAS PubMed Google Scholar
• Arber, N. et al. Celecoxib for the prevention of colorectal adenomatous polyps. N. Engl. J. Med. 355, 885–895 (2006).
  Article CAS PubMed Google Scholar
• van Stolk, R. et al. Phase I trial of exisulind (sulindac sulfone, FGN-1) as a chemopreventive agent in patients with familial adenomatous polyposis. Clin. Cancer Res. 6, 78–89 (2000).
  CAS PubMed Google Scholar
• Cong, F., Zhang, J., Pao, W., Zhou, P. & Varmus, H. A protein knockdown strategy to study the function of beta-catenin in tumorigenesis. BMC Mol. Biol. 4, 10 (2003).
  Article PubMed PubMed Central Google Scholar
• Liu, J., Stevens, J., Matsunami, N. & White, R. L. Targeted degradation of beta-catenin by chimeric F-box fusion proteins. Biochem. Biophys. Res. Commun. 313, 1023–1029 (2004).
  Article CAS PubMed Google Scholar
• Nagao, R. et al. A novel β-catenin inhibitor, AV65 suppresses the growth of CML cell lines which acquire imatinib-resistance because of Abl kinase domain mutations including T315I and hypoxia-adaptation. 50 th ASH Annual Meeting and Exposition Abstracts, 1081 (2008).
  Google Scholar
• Su, Y., Ishikawa, S., Kojima, M. & Liu, B. Eradication of pathogenic beta-catenin by Skp1/Cullin/F box ubiquitination machinery. Proc. Natl Acad. Sci. USA 100, 12729–12734 (2003).
  Article CAS PubMed PubMed Central Google Scholar