Snail1-driven plasticity of epithelial and mesenchymal cells sustains cancer malignancy.

The transcription factor Snail1 induces epithelial-to-mesenchymal transition (EMT) in tumor epithelial cells, a process associated with the emergence of stemness, invasion and cancer malignancy. Here, we review recent reports indicating that Snail1 also regulates mesenchymal plasticity and paracrine signaling and propose that Snail1 orchestrates the generation of cancer stem cells (CSCs) and cancer-associated fibroblasts (CAFs). Our view supports the current models for tumorigenesis that consider stemness and tumor microenvironment as retroactive actors for metastasis formation, revealing Snail1 as a regulator of these metastatic forces. This view offers new perspectives for understanding and targeting metastasis.

[1]  Hao Wang,et al.  Acquisition of epithelial-mesenchymal transition phenotype and cancer stem cell-like properties in cisplatin-resistant lung cancer cells through AKT/β-catenin/Snail signaling pathway. , 2014, European journal of pharmacology.

[2]  I. Malanchi,et al.  The EMT universe: space between cancer cell dissemination and metastasis initiation. , 2014, Critical reviews in oncogenesis.

[3]  N. Dave,et al.  Expression of Snail protein in tumor–stroma interface , 2006, Oncogene.

[4]  E. Cukierman,et al.  Physico-mechanical aspects of extracellular matrix influences on tumorigenic behaviors. , 2010, Seminars in cancer biology.

[5]  G. Longmore,et al.  Transient SNAIL1 expression is necessary for metastatic competence in breast cancer. , 2014, Cancer research.

[6]  Maximilian Reichert,et al.  EMT and Dissemination Precede Pancreatic Tumor Formation , 2012, Cell.

[7]  R. Aft,et al.  Temporal and Spatial Cooperation of Snail1 and Twist1 during Epithelial–Mesenchymal Transition Predicts for Human Breast Cancer Recurrence , 2011, Molecular Cancer Research.

[8]  Chun-Hung Chou,et al.  Acetylation of snail modulates the cytokinome of cancer cells to enhance the recruitment of macrophages. , 2014, Cancer cell.

[9]  Ya-jie Liu,et al.  Snail1 is involved in de novo cardiac fibrosis after myocardial infarction in mice. , 2012, Acta biochimica et biophysica Sinica.

[10]  G. Moreno-Bueno,et al.  Correlation of Snail expression with histological grade and lymph node status in breast carcinomas , 2002, Oncogene.

[11]  A. G. de Herreros,et al.  The p65 subunit of NF-κB and PARP1 assist Snail1 in activating fibronectin transcription , 2011, Journal of Cell Science.

[12]  E. Cukierman,et al.  Stroma-derived three-dimensional matrices are necessary and sufficient to promote desmoplastic differentiation of normal fibroblasts. , 2005, The American journal of pathology.

[13]  Thomas Kirchner,et al.  Migrating cancer stem cells — an integrated concept of malignant tumour progression , 2005, Nature Reviews Cancer.

[14]  Javier Silva,et al.  Protumorigenic effects of Snail‐expression fibroblasts on colon cancer cells , 2014, International journal of cancer.

[15]  M. H. Chui.  Insights into cancer metastasis from a clinicopathologic perspective: Epithelial‐Mesenchymal Transition is not a necessary step , 2013, International journal of cancer.

[16]  Benjamin Bonavida,et al.  Central role of Snail1 in the regulation of EMT and resistance in cancer: a target for therapeutic intervention , 2014, Journal of experimental & clinical cancer research : CR.

[17]  H. Nakano,et al.  β-Catenin and Smad3 regulate the activity and stability of myocardin-related transcription factor during epithelial–myofibroblast transition , 2011, Molecular biology of the cell.

[18]  E. Carver,et al.  The Mouse Snail Gene Encodes a Key Regulator of the Epithelial-Mesenchymal Transition , 2001, Molecular and Cellular Biology.

[19]  K. Chan,et al.  RUNX1 is essential for mesenchymal stem cell proliferation and myofibroblast differentiation , 2014, Proceedings of the National Academy of Sciences.

[20]  E. Hay.  An overview of epithelio-mesenchymal transformation. , 1995, Acta anatomica.

[21]  B. Hinz,et al.  Tissue stiffness, latent TGF-β1 Activation, and mechanical signal transduction: Implications for the pathogenesis and treatment of fibrosis , 2009, Current rheumatology reports.

[22]  P. Brun,et al.  Snail1 transcription factor is a critical mediator of hepatic stellate cell activation following hepatic injury. , 2011, American journal of physiology. Gastrointestinal and liver physiology.

[23]  A. Degnim,et al.  Diagnostic utility of snail in metaplastic breast carcinoma , 2010, Diagnostic pathology.

[24]  B. Hinz,et al.  The myofibroblast: paradigm for a mechanically active cell. , 2010, Journal of biomechanics.

[25]  Dong Wang,et al.  Breast Cancer Stem Cells Transition between Epithelial and Mesenchymal States Reflective of their Normal Counterparts , 2013, Stem cell reports.

[26]  J. Nesland,et al.  Snail, Slug, and Smad‐interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma , 2005, Cancer.

[27]  A. G. Herreros,et al.  The transcription factor Snail is a repressor of E-cadherin gene expression in epithelial tumour cells , 2000, Nature Cell Biology.

[28]  M. Klymkowsky,et al.  Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. , 2009, The American journal of pathology.

[29]  Christopher S. Chen,et al.  Matrix rigidity regulates a switch between TGF-β1–induced apoptosis and epithelial–mesenchymal transition , 2012, Molecular biology of the cell.

[30]  A. Lekkerkerker,et al.  Cellular players in lung fibrosis. , 2012, Current pharmaceutical design.

[31]  C. McCulloch,et al.  Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. , 2004, The American journal of pathology.

[32]  Eleftherios P. Diamandis,et al.  Cancer-Associated Fibroblasts Drive the Progression of Metastasis through both Paracrine and Mechanical Pressure on Cancer Tissue , 2012, Molecular Cancer Research.

[33]  Jan Paul Medema,et al.  Cancer stem cells: The challenges ahead , 2013, Nature Cell Biology.

[34]  Robert A. Weinberg,et al.  Autocrine TGF-β and stromal cell-derived factor-1 (SDF-1) signaling drives the evolution of tumor-promoting mammary stromal myofibroblasts , 2010, Proceedings of the National Academy of Sciences.

[35]  F. Alameda,et al.  Snail1 Protein in the Stroma as a New Putative Prognosis Marker for Colon Tumours , 2009, PloS one.

[36]  A. Mannermaa,et al.  Transcription factor snail1 expression and poor survival in pharyngeal squamous cell carcinoma. , 2011, Histology and histopathology.

[37]  S. Dedhar,et al.  Regulation of Snail transcription during epithelial to mesenchymal transition of tumor cells , 2004, Oncogene.

[38]  J. Whitsett,et al.  Foxm1 transcription factor is required for lung fibrosis and epithelial‐to‐mesenchymal transition , 2013, The EMBO journal.

[39]  E. Cukierman,et al.  FAP-overexpressing fibroblasts produce an extracellular matrix that enhances invasive velocity and directionality of pancreatic cancer cells , 2011, BMC Cancer.

[40]  Y. Koyama,et al.  The types of hepatic myofibroblasts contributing to liver fibrosis of different etiologies , 2014, Front. Pharmacol..

[41]  B. Alman,et al.  Prestress in the extracellular matrix sensitizes latent TGF-β1 for activation , 2014, The Journal of cell biology.

[42]  Roman Mezencev,et al.  SNAIL‐induced epithelial‐to‐mesenchymal transition produces concerted biophysical changes from altered cytoskeletal gene expression , 2015, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[43]  C. McCulloch,et al.  Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. , 2004, The American journal of pathology.

[44]  A. García de Herreros,et al.  Cooperation, amplification, and feed-back in epithelial-mesenchymal transition. , 2012, Biochimica et biophysica acta.

[45]  V. Díaz,et al.  Regulation of the protein stability of EMT transcription factors , 2014, Cell adhesion & migration.

[46]  M. Mack,et al.  Origin of myofibroblasts and cellular events triggering fibrosis. , 2015, Kidney international.

[47]  John T. Powers,et al.  The Epithelial-Mesenchymal Transition Factor SNAIL Paradoxically Enhances Reprogramming , 2014, Stem cell reports.

[48]  Esther W. Gomez,et al.  Matrix Rigidity Mediates TGFβ1‐induced Epithelial‐Myofibroblast Transition by Controlling Cytoskeletal Organization and MRTF‐A Localization , 2015, Journal of cellular physiology.

[49]  D. Navajas,et al.  Snail1-expressing fibroblasts in the tumor microenvironment display mechanical properties that support metastasis. , 2015, Cancer research.

[50]  Shoichiro Tsukita,et al.  Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail , 2003, Journal of Cell Science.

[51]  S. Weiss,et al.  Hepatocyte-Derived Snail1 Propagates Liver Fibrosis Progression , 2011, Molecular and Cellular Biology.

[52]  A. G. de Herreros,et al.  Functional Heterogeneity of Cancer-Associated Fibroblasts from Human Colon Tumors Shows Specific Prognostic Gene Expression Signature , 2013, Clinical Cancer Research.

[53]  F. Rojo,et al.  Snail1 Expression Is Required for Sarcomagenesis12 , 2014, Neoplasia.

[54]  G. Adler,et al.  Collagen type I induces disruption of E-cadherin-mediated cell-cell contacts and promotes proliferation of pancreatic carcinoma cells. , 2006, Cancer research.

[55]  J. Schwarzbauer,et al.  Assembly of fibronectin extracellular matrix. , 2010, Annual review of cell and developmental biology.

[56]  H. Moses,et al.  Transforming growth factor-beta1 mediates epithelial to mesenchymal transdifferentiation through a RhoA-dependent mechanism. , 2001, Molecular biology of the cell.

[57]  J. Martı́n-Caballero,et al.  Snail1 controls TGF-β responsiveness and differentiation of Mesenchymal Stem Cells , 2012, Oncogene.

[58]  Sendurai A Mani,et al.  The Epithelial-to-Mesenchymal Transition and Cancer Stem Cells: A Coalition Against Cancer Therapies , 2009, Journal of Mammary Gland Biology and Neoplasia.

[59]  C. Heldin,et al.  Induction of epithelial-mesenchymal transition by transforming growth factor β. , 2012, Seminars in cancer biology.

[60]  Kevin W. Eliceiri,et al.  The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis , 2013, Nature Cell Biology.

[61]  P. Savagner.  The epithelial-mesenchymal transition (EMT) phenomenon. , 2010, Annals of oncology : official journal of the European Society for Medical Oncology.

[62]  B. Turk,et al.  An AMPK-independent signaling pathway downstream of the LKB1 tumor suppressor controls Snail1 and metastatic potential. , 2014, Molecular cell.

[63]  Lucila Ohno-Machado,et al.  Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. , 2011, Cancer research.

[64]  Eshel Ben-Jacob,et al.  Towards elucidating the connection between epithelial–mesenchymal transitions and stemness , 2014, Journal of The Royal Society Interface.

[65]  Y. Tokura,et al.  Expression of Snail1 in the fibrotic dermis of postmenopausal frontal fibrosing alopecia: possible involvement of an epithelial–mesenchymal transition and a review of the Japanese patients , 2010, The British journal of dermatology.

[66]  Cathrin Brisken,et al.  Epithelial‐Mesenchymal Transition‐Derived Cells Exhibit Multilineage Differentiation Potential Similar to Mesenchymal Stem Cells , 2010, Stem cells.

[67]  S. Akunuru,et al.  Non-small cell lung cancer stem/progenitor cells are enriched in multiple distinct phenotypic subpopulations and exhibit plasticity , 2012, Cell Death and Disease.

[68]  Yin-hua Yu,et al.  Transformation of Epithelial Ovarian Cancer Stemlike Cells into Mesenchymal Lineage via EMT Results in Cellular Heterogeneity and Supports Tumor Engraftment , 2012, Molecular medicine.

[69]  Eduard Batlle,et al.  Snail Induction of Epithelial to Mesenchymal Transition in Tumor Cells Is Accompanied by MUC1 Repression andZEB1 Expression* , 2002, The Journal of Biological Chemistry.

[70]  A. Oloumi,et al.  Integrin‐linked kinase regulates E‐cadherin expression through PARP‐1 , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[71]  Wenjun Guo,et al.  The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells , 2008, Cell.

[72]  Michael Gibson,et al.  Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes , 2013, Molecular Cancer.