Transcriptional crosstalk between TGFβ and stem cell pathways in tumor cell invasion Role of EMT promoting Smad complexes

被引:280
作者
Fuxe, Jonas [1 ]
Vincent, Theresa [2 ]
Garcia de Herreros, Antonio [3 ]
机构
[1] Karolinska Inst, Dept Med Biochem & Biophys, Matrix Div, Stockholm, Sweden
[2] Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, New York, NY 10021 USA
[3] IMIM Hosp del Mar, Programa Recerca Canc, Barcelona, Spain
基金
瑞典研究理事会;
关键词
epithelial-mesenchymal transition; tumor cell invasion; cancer stem cells; metastasis; crosstalk; transcriptional complexes; TGF beta; Wnt; Ras; Smad; Snail; EPITHELIAL-MESENCHYMAL TRANSITION; GROWTH-FACTOR-BETA; BREAST-CANCER CELLS; E-CADHERIN EXPRESSION; NF-KAPPA-B; GLYCOGEN-SYNTHASE KINASE-3; GENE-EXPRESSION; IN-VIVO; CARCINOMA-CELLS; SNAIL TRANSCRIPTION;
D O I
10.4161/cc.9.12.12050
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Tumor cells undergoing the epithelial-mesenchymal transition (EMT) acquire the capacity to migrate, invade the stroma and metastasize. EMT cells also acquire stem cell characteristics suggesting crosstalk between EMT and pathways involved in promoting cellular stemness (stem cell pathways) and that EMT may contribute to the generation of cancer stem cells. indeed, transforming growth factor-beta (TGF beta), a major inducer of EMT, cooperates with stem cell pathways like Wnt, Ras, Hedgehog and Notch to induce EMT. A molecular basis for this cooperative signaling is indicated by recent data showing that many EMT associated transcription factors like Snail1, Zeb1/2, Twist, beta-catenin, Lef/TCF, Foxc2 and AP-1 interact with Smads and form EMT promoting Smad complexes (EPSC) engaged in either repressing epithelial genes or activating mesenchymal genes. Thus, formation and activation of EPSC represents a point of convergence between EMT and stem cell pathways. Here, we review our current understanding of the mechanisms involved in the transcriptional crosstalk between TGF beta and stem cell pathways and discuss how a fundament for the activation of these mechanisms may lead to the induction of EMT in tumors.
引用
收藏
页码:2363 / 2374
页数:12
相关论文
共 179 条
[1]   The transcription factor ZEB1 (δEF1) promotes tumour cell dedifferentiation by repressing master regulators of epithelial polarity [J].
Aigner, K. ;
Dampier, B. ;
Descovich, L. ;
Mikula, M. ;
Sultan, A. ;
Schreiber, M. ;
Mikulits, W. ;
Brabletz, T. ;
Strand, D. ;
Obrist, P. ;
Sommergruber, W. ;
Schweifer, N. ;
Wernitznig, A. ;
Beug, H. ;
Foisner, R. ;
Eger, A. .
ONCOGENE, 2007, 26 (49) :6979-6988
[2]   Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients [J].
Aktas, Bahriye ;
Tewes, Mitra ;
Fehm, Tanja ;
Hauch, Siegfried ;
Kimmig, Rainer ;
Kasimir-Bauer, Sabine .
BREAST CANCER RESEARCH, 2009, 11 (04)
[3]   Prospective identification of tumorigenic breast cancer cells [J].
Al-Hajj, M ;
Wicha, MS ;
Benito-Hernandez, A ;
Morrison, SJ ;
Clarke, MF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (07) :3983-3988
[4]   Fra-1 regulates vimentin during Ha-RAS-induced epithelial mesenchymal transition in human colon carcinoma cells [J].
Andreolas, Chrysovalantis ;
Kalogeropoulou, Margarita ;
Voulgari, Angeliki ;
Pintzas, Alexander .
INTERNATIONAL JOURNAL OF CANCER, 2008, 122 (08) :1745-1756
[5]   Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence [J].
Ansieau, Stephane ;
Bastid, Jeremy ;
Doreau, Agnes ;
Morel, Anne-Pierre ;
Bouchet, Benjamin P. ;
Thomas, Clemence ;
Fauvet, Frederique ;
Puisieux, Isabelle ;
Doglioni, Claudio ;
Piccinin, Sara ;
Maestro, Roberta ;
Voeltzel, Thibault ;
Selmi, Abdelkader ;
Valsesia-Wittmann, Sandrine ;
de Fromentel, Claude Caron ;
Puisieux, Alain .
CANCER CELL, 2008, 14 (01) :79-89
[6]   Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response [J].
Ashcroft, GS ;
Yang, X ;
Glick, AB ;
Weinstein, M ;
Letterio, JJ ;
Mizel, DE ;
Anzano, M ;
Greenwell-Wild, T ;
Wahl, SM ;
Deng, CX ;
Roberts, AB .
NATURE CELL BIOLOGY, 1999, 1 (05) :260-266
[7]   Glycogen synthase kinase-3 is an endogenous inhibitor of snail transcription: implications for the epithelial-mesenchymal transition [J].
Bachelder, RE ;
Yoon, SO ;
Franci, C ;
de Herreros, AG ;
Mercurio, AM .
JOURNAL OF CELL BIOLOGY, 2005, 168 (01) :29-33
[8]   Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer [J].
Bardeesy, Nabeel ;
Cheng, Kuang-hung ;
Berger, Justin H. ;
Chu, Gerald C. ;
Pahler, Jessica ;
Olson, Peter ;
Hezel, Aram F. ;
Horner, James ;
Lauwers, Gregory Y. ;
Hanahan, Douglas ;
DePinho, Ronald A. .
GENES & DEVELOPMENT, 2006, 20 (22) :3130-3146
[9]   The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells [J].
Batlle, E ;
Sancho, E ;
Franci, C ;
Domínguez, D ;
Monfar, M ;
Baulida, J ;
de Herreros, AG .
NATURE CELL BIOLOGY, 2000, 2 (02) :84-89
[10]   The plasminogen activator inhibitor "paradox" in cancer [J].
Binder, Bernd R. ;
Mihaly, Judit .
IMMUNOLOGY LETTERS, 2008, 118 (02) :116-124