Chemoradiotherapy Resistance in Colorectal Cancer Cells is Mediated by Wnt/β-catenin Signaling.
Georg Emons,Melanie Spitzner,Sebastian Reineke,Janneke Möller,Noam Auslander,Frank Kramer,Yue Hu,Tim Beissbarth,Hendrik A. Wolff,Margret Rave-Fränk,Elisabeth Heßmann,Jochen Gaedcke,B. Michael Ghadimi,Steven A. Johnsen,Thomas Ried,Marian Grade +15 more
Reads0
Chats0
TLDR
Aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Abstract:
Activation of Wnt/β-catenin signaling plays a central role in the development and progression of colorectal cancer. The Wnt-transcription factor, TCF7L2, is overexpressed in primary rectal cancers that are resistant to chemoradiotherapy and TCF7L2 mediates resistance to chemoradiotherapy. However, it is unclear whether the resistance is mediated by a TCF7L2 inherent mechanism or Wnt/β-catenin signaling in general. Here, inhibition of β-catenin by siRNAs or a small-molecule inhibitor (XAV-939) resulted in sensitization of colorectal cancer cells to chemoradiotherapy. To investigate the potential role of Wnt/β-catenin signaling in controlling therapeutic responsiveness, nontumorigenic RPE-1 cells were stimulated with Wnt-3a, a physiologic ligand of Frizzled receptors, which increased resistance to chemoradiotherapy. This effect could be recapitulated by overexpression of a degradation-resistant mutant of β-catenin (S33Y), also boosting resistance of RPE-1 cells to chemoradiotherapy, which was, conversely, abrogated by siRNA-mediated silencing of β-catenin. Consistent with these findings, higher expression levels of active β-catenin were observed as well as increased TCF/LEF reporter activity in SW1463 cells that evolved radiation resistance due to repeated radiation treatment. Global gene expression profiling identified several altered pathways, including PPAR signaling and other metabolic pathways, associated with cellular response to radiation. In summary, aberrant activation of Wnt/β-catenin signaling not only regulates the development and progression of colorectal cancer, but also mediates resistance of rectal cancers to chemoradiotherapy.Implications: Targeting Wnt/β-catenin signaling or one of the downstream pathways represents a promising strategy to increase response to chemoradiotherapy. Mol Cancer Res; 15(11); 1481-90. ©2017 AACR.read more
Citations
More filters
Journal ArticleDOI
A rectal cancer organoid platform to study individual responses to chemoradiation.
Karuna Ganesh,Chao Wu,Kevin P. O’Rourke,Bryan C. Szeglin,Youyun Zheng,Charles Etienne Gabriel Sauvé,Mohammad Adileh,Isaac Wasserman,Michael R. Marco,Amanda S. Kim,Maha Shady,Francisco Sanchez-Vega,Wouter R. Karthaus,Helen Won,Seo Hyun Choi,Raphael Pelossof,Afsar Barlas,Peter Ntiamoah,Emmanouil P. Pappou,Arthur E. Elghouayel,James S. Strong,Chin Tung Chen,Jennifer W. Harris,Martin R. Weiser,Garrett M. Nash,Jose G. Guillem,Iris H Wei,Richard Kolesnick,Harini Veeraraghavan,Eduardo J. Ortiz,Iva Petkovska,Andrea Cercek,Katia Manova-Todorova,Leonard B. Saltz,Jessica A. Lavery,Ronald P. DeMatteo,Joan Massagué,Philip B. Paty,Rona Yaeger,Xi Chen,Sujata Patil,Hans Clevers,Michael F. Berger,Scott W. Lowe,Jinru Shia,Paul B. Romesser,Lukas E. Dow,Julio Garcia-Aguilar,Charles L. Sawyers,J. Joshua Smith +49 more
TL;DR: The biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals.
Journal ArticleDOI
WNT Signaling in Cancer Immunosurveillance.
TL;DR: The molecular and cellular mechanisms through which WNT signaling influences cancer immunosurveillance are discussed and potential therapeutic avenues to harness currently available WNT modulators for cancer immunotherapy are presented.
Journal ArticleDOI
Wnt Signaling and Drug Resistance in Cancer
Zheng Zhong,David M. Virshup +1 more
TL;DR: Recent studies extend understanding of this ancient signaling pathway and describe the development and improvement of anti-Wnt therapeutic modalities for cancer.
Journal ArticleDOI
Functions and mechanisms of circular RNAs in cancer radiotherapy and chemotherapy resistance
TL;DR: This review summarizes recent progress and mechanisms of circRNAs in cancer resistance to radiation and chemotherapy, and it discusses the limitations of available knowledge and potential future directions.
Journal ArticleDOI
TRIB3 Interacts With β-Catenin and TCF4 to Increase Stem Cell Features of Colorectal Cancer Stem Cells and Tumorigenesis
Fang Hua,Shuang Shang,Yang Yuwei,Haizeng Zhang,Tian-lei Xu,Jiao-jiao Yu,Dan-dan Zhou,Bing Cui,Ke Li,Xiaoxi Lv,Xiaowei Zhang,Shan-Shan Liu,Jin-mei Yu,Feng Wang,Cheng Zhang,Bo Huang,Zhuo-Wei Hu +16 more
TL;DR: This investigation investigated whether increased TRIB3 expression promotes stem cell features of CRC cells and tumor progression by interacting with the Wnt signaling pathway and derived organoids from human and mouse colorectal tumors to analyze the function of TRIB 3 and test the effect of a peptide inhibitor.
References
More filters
Journal ArticleDOI
Cancer statistics, 2012
TL;DR: The reduction in overall cancer death rates since 1990 in men and 1991 in women translates to the avoidance of about 1,024,400 deaths from cancer, which can be accelerated by applying existing cancer control knowledge across all segments of the population, with an emphasis on those groups in the lowest socioeconomic bracket.
Journal ArticleDOI
Comprehensive molecular characterization of human colon and rectal cancer
Donna M. Muzny,Matthew N. Bainbridge,Kyle Chang,Huyen Dinh,Jennifer Drummond,Gerald R. Fowler,Christie Kovar,Lora Lewis,Margaret Morgan,Irene Newsham,Jeffrey G. Reid,Jireh Santibanez,Eve Shinbrot,Lisa R. Trevino,Yuan Qing Wu,Min Wang,Preethi H. Gunaratne,Preethi H. Gunaratne,Lawrence A. Donehower,Chad J. Creighton,David A. Wheeler,Richard A. Gibbs,Michael S. Lawrence,Douglas Voet,Rui Jing,Kristian Cibulskis,Andrey Sivachenko,Andrey Sivachenko,Petar Stojanov,Aaron McKenna,Eric S. Lander,Eric S. Lander,Stacey Gabriel,Li Ding,Robert S. Fulton,Daniel C. Koboldt,Todd Wylie,Jason Walker,David J. Dooling,Lucinda Fulton,Kim D. Delehaunty,Catrina Fronick,Ryan Demeter,Elaine R. Mardis,Richard K. Wilson,Andy Chu,Hye Jung E. Chun,Andrew J. Mungall,Erin Pleasance,A. Gordon Robertson,Dominik Stoll,Miruna Balasundaram,Inanc Birol,Yaron S.N. Butterfield,Eric Chuah,Robin J.N. Coope,Noreen Dhalla,Ranabir Guin,Carrie Hirst,Martin Hirst,Robert A. Holt,Darlene Lee,Haiyan I. Li,Michael Mayo,Richard A. Moore,Jacqueline E. Schein,Jared R. Slobodan,Angela Tam,Nina Thiessen,Richard Varhol,Thomas Zeng,Yongjun Zhao,Steven J.M. Jones,Marco A. Marra,Adam J. Bass,Alex H. Ramos,Gordon Saksena,Andrew D. Cherniack,Stephen E. Schumacher,Barbara Tabak,Scott L. Carter,Nam Pho,Huy V. Nguyen,Robert C. Onofrio,Andrew Crenshaw,Kristin G. Ardlie,Rameen Beroukhim,Wendy Winckler,Matthew Meyerson,Alexei Protopopov,Angela Hadjipanayis,Eunjung Lee,Ruibin Xi,Lixing Yang,Xiaojia Ren,Narayanan Sathiamoorthy,Peng Chieh Chen,Psalm Haseley,Yonghong Xiao,Semin Lee,Jonathan G. Seidman,Lynda Chin,Peter J. Park,Raju Kucherlapati,J. Todd Auman,Katherine A. Hoadley,Ying Du,Matthew D. Wilkerson,Yan Shi,Christina Liquori,Shaowu Meng,Ling Li,Yidi J. Turman,Michael D. Topal,Donghui Tan,Scot Waring,Elizabeth Buda,Jesse Walsh,Corbin D. Jones,Piotr A. Mieczkowski,Darshan Singh,Junyuan Wu,Anisha Gulabani,Peter Dolina,Tom Bodenheimer,Alan P. Hoyle,Janae V. Simons,Matthew G. Soloway,Lisle E. Mose,Stuart R. Jefferys,Saianand Balu,Brian O'Connor,Jan F. Prins,Derek Y. Chiang,D. Neil Hayes,Charles M. Perou,Toshinori Hinoue,Daniel J. Weisenberger,Dennis T. Maglinte,Fei Pan,Benjamin P. Berman,David Van Den Berg,Hui Shen,Timothy J. Triche,Stephen B. Baylin,Peter W. Laird,Gad Getz,Michael S. Noble,Doug Voat,Nils Gehlenborg,Daniel DiCara,Juinhua Zhang,Hailei Zhang,Chang-Jiun Wu,Spring Yingchun Liu,Sachet A. Shukla,Lihua Zhou,Pei Lin,Richard W. Park,Marc Danie Nazaire,James A. Robinson,Helga Thorvaldsdottir,Jill P. Mesirov,Vesteinn Thorsson,Sheila Reynolds,Brady Bernard,Richard Kreisberg,Jake Lin,Lisa Iype,Ryan Bressler,Timo Erkkilä,Madhumati Gundapuneni,Yuexin Liu,Adam Norberg,Thomas Robinson,Da Yang,Wei Zhang,Ilya Shmulevich,Jorma J. de Ronde,Jorma J. de Ronde,Nikolaus Schultz,Ethan Cerami,Giovanni Ciriello,Arthur P. Goldberg,Benjamin Gross,Anders Jacobsen,Jianjiong Gao,Bogumil Kaczkowski,Rileen Sinha,B. Arman Aksoy,Yevgeniy Antipin,Boris Reva,Ronglai Shen,Barry S. Taylor,Marc Ladanyi,Chris Sander,Rehan Akbani,Nianxiang Zhang,Bradley M. Broom,Tod D. Casasent,Anna K. Unruh,Chris Wakefield,Stanley R. Hamilton,R. Craig Cason,Keith A. Baggerly,John N. Weinstein,David Haussler,Christopher C. Benz,Joshua M. Stuart,Stephen C. Benz,J. Zachary Sanborn,Charles J. Vaske,Jingchun Zhu,Christopher Szeto,Gary K. Scott,Christina Yau,Sam Ng,Theodore C. Goldstein,Kyle Ellrott,Eric A. Collisson,Aaron E. Cozen,Daniel R. Zerbino,Christopher Wilks,Brian Craft,Paul T. Spellman,Robert Penny,Troy Shelton,Martha Hatfield,Scott Morris,Peggy Yena,Candace Shelton,Mark Sherman,Joseph Paulauskis,Julie M. Gastier-Foster,Julie M. Gastier-Foster,Jay Bowen,Nilsa C. Ramirez,Nilsa C. Ramirez,Aaron D. Black,Robert E. Pyatt,Robert E. Pyatt,Lisa Wise,Peter White,Peter White,Monica M. Bertagnolli,Jen Brown,Timothy A. Chan,Gerald C. Chu,Christine Czerwinski,Fred Denstman,Rajiv Dhir,Arnulf Dörner,Charles S. Fuchs,Jose G. Guillem,Mary Iacocca,Hartmut Juhl,Andrew Kaufman,Bernard Kohl,Xuan Van Le,Maria C. Mariano,Elizabeth N. Medina,Michael Meyers,Garrett M. Nash,P. Paty,Nicholas J. Petrelli,Brenda Rabeno,William G. Richards,David B. Solit,Pat Swanson,Larissa K. Temple,Joel E. Tepper,Richard Thorp,Efsevia Vakiani,Martin R. Weiser,Joseph Willis,Gary Witkin,Zhaoshi Zeng,Michael J. Zinner,Carsten Zornig,Mark A. Jensen,Robert Sfeir,Ari B. Kahn,Anna L. Chu,Prachi Kothiyal,Zhining Wang,Eric E. Snyder,Joan Pontius,Todd Pihl,Brenda Ayala,Mark Backus,Jessica Walton,Jon Whitmore,Julien Baboud,Dominique L. Berton,Matthew C. Nicholls,Deepak Srinivasan,Rohini Raman,Stanley Girshik,Peter A. Kigonya,Shelley Alonso,Rashmi N. Sanbhadti,Sean P. Barletta,John M. Greene,David Pot,Kenna R. Mills Shaw,Laura A.L. Dillon,Kenneth H. Buetow,Tanja Davidsen,John A. Demchok,Greg Eley,Martin L. Ferguson,Peter Fielding,Carl F. Schaefer,Margi Sheth,Liming Yang,Mark S. Guyer,Bradley A. Ozenberger,Jacqueline D. Palchik,Jane Peterson,Heidi J. Sofia,Elizabeth J. Thomson +320 more
TL;DR: Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role for MYC-directed transcriptional activation and repression.
Journal ArticleDOI
Extension of life-span by introduction of telomerase into normal human cells
Andrea G. Bodnar,Michel M. Ouellette,Maria Frolkis,Shawn E. Holt,Choy-Pik Chiu,Gregg B. Morin,Calvin B. Harley,Jerry W. Shay,Serge Lichtsteiner,Woodring E. Wright +9 more
TL;DR: In this article, two telomerase-negative normal human cell types, retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomere catalytic subunit.
Journal ArticleDOI
Wnt/β-catenin signaling and disease.
Hans Clevers,Roel Nusse +1 more
TL;DR: An update of the core Wnt/β-catenin signaling pathway is provided, how its various components contribute to disease, and outstanding questions to be addressed in the future are discussed.
Journal ArticleDOI
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.
Roel Nusse,Hans Clevers +1 more
TL;DR: The core Wnt/β-catenin signaling pathway is described, how it controls stem cells, and contributes to disease, and strategies for Wnt-based therapies are discussed.
Related Papers (5)
Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities.
Roel Nusse,Hans Clevers +1 more
Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling
Shih Min A Huang,Yuji Mishina,Shanming Liu,Atwood K. Cheung,Frank Stegmeier,Gregory A. Michaud,Olga Charlat,Elizabeth Wiellette,Yue Zhang,Stephanie Wiessner,Marc Hild,Xiaoying Shi,Christine D. Wilson,Craig Mickanin,Vic E. Myer,Aleem Fazal,Ronald Tomlinson,Fabrizio C. Serluca,Wenlin Shao,Hong Cheng,Michael Shultz,Christina Rau,Markus Schirle,Judith Schlegl,Sonja Ghidelli,Stephen Fawell,Chris Lu,Daniel Curtis,Marc W. Kirschner,Christoph Lengauer,Peter Finan,John A. Tallarico,Tewis Bouwmeester,Jeffery A. Porter,Andreas Bauer,Feng Cong +35 more
Wnt addiction of genetically defined cancers reversed by PORCN inhibition
Babita Madan,Zhiyuan Ke,Nathan Harmston,Soo Yei Ho,A O Frois,Jenefer Alam,Duraiswamy Athisayamani Jeyaraj,Vishal Pendharkar,Kakaly Ghosh,I H Virshup,Vithya Manoharan,Esther Hq Ong,Kanda Sangthongpitag,Jeffrey Hill,Enrico Petretto,Thomas H. Keller,May Ann Lee,Alex Matter,David M. Virshup,David M. Virshup +19 more