Notch and Wnt inhibitors as potential new drugs for intestinal neoplastic disease.

Colorectal cancer is a major cause of death in the western world. Recent advances in treatment comprise variations on the classical themes of surgical resection combined with chemotherapy using cytotoxic drugs and radiation therapy. Because this therapy is only moderately successful, novel approaches to the treatment of colorectal cancer are required. Our rapidly increasing knowledge of molecular signalling pathways that are deregulated in colorectal cancer might provide a platform from which to develop new rational cancer therapies. Here, we give an update on the roles of the Wnt and Notch signalling pathways in the self renewal of the intestinal epithelium and the consequences of Wnt deregulation in colorectal cancer. We focus on the potential of recently identified small-molecule inhibitors of the Wnt pathway and gamma-secretase inhibitors of the Notch pathway as novel colon cancer therapeutics.

[1]  A. Gossler,et al.  Expression of Notch pathway components in fetal and adult mouse small intestine. , 2002, Gene expression patterns : GEP.

[2]  D. Roberts,et al.  Molecular mechanisms of development of the gastrointestinal tract , 2000, Developmental dynamics : an official publication of the American Association of Anatomists.

[3]  Randall T. Moon,et al.  The transcriptional coactivator CBP interacts with beta-catenin to activate gene expression. , 2000, The Journal of cell biology.

[4]  Tony Pawson,et al.  β-Catenin and TCF Mediate Cell Positioning in the Intestinal Epithelium by Controlling the Expression of EphB/EphrinB , 2002, Cell.

[5]  Pauline Chu,et al.  Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1 , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[6]  Inke S Näthke,et al.  The adenomatous polyposis coli protein: the Achilles heel of the gut epithelium. , 2004, Annual review of cell and developmental biology.

[7]  Sandipan Chatterjee,et al.  Wnt/wingless Signaling Requires Bcl9/legless-mediated Recruitment of Pygopus to the Nuclear Beta-catenin-tcf Complex , 2022 .

[8]  S. Artavanis-Tsakonas,et al.  Notch Signaling : Cell Fate Control and Signal Integration in Development , 1999 .

[9]  T. Honjo,et al.  Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. , 2002, International immunology.

[10]  Hans Clevers,et al.  Notch/γ-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells , 2005, Nature.

[11]  T. Pawson,et al.  EphB receptor activity suppresses colorectal cancer progression , 2005, Nature.

[12]  Larry Kedes,et al.  HES and HERP families: Multiple effectors of the notch signaling pathway , 2003, Journal of cellular physiology.

[13]  H. Clevers,et al.  Wnt signalling in stem cells and cancer , 2005, Nature.

[14]  M. W. Young,et al.  kuzbanian-mediated cleavage of Drosophila Notch. , 2002, Genes & development.

[15]  J. Behrens,et al.  The Wnt connection to tumorigenesis. , 2004, The International journal of developmental biology.

[16]  David I. Smith,et al.  Mutations in AXIN2 cause colorectal cancer with defective mismatch repair by activating β-catenin/TCF signalling , 2000, Nature Genetics.

[17]  M. Baron,et al.  An overview of the Notch signalling pathway. , 2003, Seminars in cell & developmental biology.

[18]  S. Artavanis-Tsakonas,et al.  Notch signals control the fate of immature progenitor cells in the intestine , 2005, Nature.

[19]  H. Zoghbi,et al.  Requirement of Math1 for Secretory Cell Lineage Commitment in the Mouse Intestine , 2001, Science.

[20]  Hans Clevers,et al.  Expression pattern of Wnt signaling components in the adult intestine. , 2005, Gastroenterology.

[21]  R. Nusse,et al.  The Wnt signaling pathway in development and disease. , 2004, Annual review of cell and developmental biology.

[22]  Ryoichiro Kageyama,et al.  Control of endodermal endocrine development by Hes-1 , 2000, Nature Genetics.

[23]  A. Xu,et al.  Chaperone Activity of Protein O-Fucosyltransferase 1 Promotes Notch Receptor Folding , 2005, Science.

[24]  A. Goate,et al.  A common enzyme connects notch signaling and Alzheimer's disease. , 2000, Genes & development.

[25]  Mariann Bienz,et al.  A new nuclear component of the Wnt signalling pathway , 2002, Nature Cell Biology.

[26]  K. Kinzler,et al.  Erratum: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene , 1992, Science.

[27]  Xi He,et al.  Control of β-Catenin Phosphorylation/Degradation by a Dual-Kinase Mechanism , 2002, Cell.

[28]  A. Wynshaw-Boris,et al.  The canonical Wnt pathway in early mammalian embryogenesis and stem cell maintenance/differentiation. , 2004, Current opinion in genetics & development.

[29]  Hans Clevers,et al.  Signaling pathways in intestinal development and cancer. , 2004, Annual review of cell and developmental biology.

[30]  A Cumano,et al.  A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE. , 2000, Molecular cell.

[31]  A. Sparks,et al.  Identification of c-MYC as a target of the APC pathway. , 1998, Science.

[32]  W. H. Jordan,et al.  Adipsin, a Biomarker of Gastrointestinal Toxicity Mediated by a Functional γ-Secretase Inhibitor* , 2003, Journal of Biological Chemistry.

[33]  Stephen J. Elledge,et al.  The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro , 1999 .

[34]  H Clevers,et al.  The chromatin remodelling factor Brg‐1 interacts with β‐catenin to promote target gene activation , 2001, The EMBO journal.

[35]  H. Clevers,et al.  Wnt signalling induces maturation of Paneth cells in intestinal crypts , 2005, Nature Cell Biology.

[36]  I. Weissman,et al.  Wnt proteins are lipid-modified and can act as stem cell growth factors , 2003, Nature.

[37]  Hans Clevers,et al.  The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors , 1998, Nature.

[38]  Neil Vargesson,et al.  Delta-Notch signalling controls commitment to a secretory fate in the zebrafish intestine , 2005, Development.

[39]  M. von Knebel Doeberitz,et al.  Wnt/β‐catenin‐pathway as a molecular target for future anti‐cancer therapeutics , 2005 .

[40]  Frank Petersen,et al.  Small-molecule antagonists of the oncogenic Tcf/β-catenin protein complex , 2004 .

[41]  Hans Clevers,et al.  Canonical Wnt signals are essential for homeostasis of the intestinal epithelium. , 2003, Genes & development.

[42]  B. Vogelstein,et al.  A genetic model for colorectal tumorigenesis , 1990, Cell.

[43]  Matthias Mann,et al.  Axin-mediated CKI phosphorylation of beta-catenin at Ser 45: a molecular switch for the Wnt pathway. , 2002, Genes & development.

[44]  Isabelle Duluc,et al.  Neurogenin3 is differentially required for endocrine cell fate specification in the intestinal and gastric epithelium , 2002, The EMBO journal.

[45]  Hans Clevers,et al.  Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4 , 1998, Nature Genetics.

[46]  D. W. Green,et al.  β-Catenin Antisense Treatment Decreases β-Catenin Expression and Tumor Growth Rate in Colon Carcinoma Xenografts☆ , 2001 .

[47]  S. Artavanis-Tsakonas,et al.  Intracellular Cleavage of Notch Leads to a Heterodimeric Receptor on the Plasma Membrane , 1997, Cell.

[48]  Raphael Kopan,et al.  Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain , 1998, Nature.

[49]  Jay S. Fine,et al.  Chronic Treatment with the γ-Secretase Inhibitor LY-411,575 Inhibits β-Amyloid Peptide Production and Alters Lymphopoiesis and Intestinal Cell Differentiation* , 2004, Journal of Biological Chemistry.

[50]  Hans Clevers,et al.  XTcf-3 Transcription Factor Mediates β-Catenin-Induced Axis Formation in Xenopus Embryos , 1996, Cell.

[51]  Michael Kühl,et al.  Functional interaction of β-catenin with the transcription factor LEF-1 , 1996, Nature.

[52]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[53]  Francois Pognan,et al.  Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. , 2004, Toxicological sciences : an official journal of the Society of Toxicology.

[54]  Hans Clevers,et al.  Drosophila Tcf and Groucho interact to repress Wingless signalling activity , 1998, Nature.

[55]  Hans Clevers,et al.  Activation of β-Catenin-Tcf Signaling in Colon Cancer by Mutations in β-Catenin or APC , 1997, Science.

[56]  A. Xu,et al.  Modulation of Notch-Ligand Binding by Protein O-Fucosyltransferase 1 and Fringe* , 2003, Journal of Biological Chemistry.

[57]  Mariann Bienz,et al.  The APC tumour suppressor has a nuclear export function , 2000, Nature.

[58]  Hans Clevers,et al.  The β-Catenin/TCF-4 Complex Imposes a Crypt Progenitor Phenotype on Colorectal Cancer Cells , 2002, Cell.

[59]  M. Kitagawa,et al.  An F‐box protein, FWD1, mediates ubiquitin‐dependent proteolysis of β‐catenin , 1999, The EMBO journal.

[60]  K. Kinzler,et al.  Targeted inactivation of CTNNB1 reveals unexpected effects of β-catenin mutation , 2002, Proceedings of the National Academy of Sciences of the United States of America.