Expression of Snail protein in tumor–stroma interface

The product of Snail gene is a repressor of E-cadherin transcription and an inductor of the epithelial-to-mesenchymal transition in several epithelial tumor cell lines. In order to examine Snail expression in animal and human tissues, we have raised a monoclonal antibody (MAb) that reacts with the regulatory domain of this protein. Analysis of murine embryos shows that Snail is expressed in extraembryonic tissues and embryonic mesoderm, in mesenchymal cells of lungs and dermis as well as in cartilage. Little reactivity was detected in adult tissues as Snail was not constitutively expressed in most mesenchymal cells. However, Snail expression was observed in activated fibroblasts involved in wound healing in mice skin. Moreover, Snail was detected in pathological conditions causing hyperstimulation of fibroblasts, such as fibromatosis. Analysis of Snail expression in tumors revealed that it was highly expressed in sarcomas and fibrosarcomas. In epithelial tumors, it presented a more limited distribution, restricted to stromal cells placed in the vicinity of the tumor and to tumoral cells in the same areas. These results demonstrate that Snail is present in activated mesenchymal cells, indicate its relevance in the communication between tumor and stroma and suggest that it can promote the conversion of carcinoma cells to stromal cells.

[1]  H. Höfler,et al.  Neoexpression of N‐cadherin in E‐cadherin positive colon cancers , 2004, International journal of cancer.

[2]  I. Puig,et al.  Phosphorylation Regulates the Subcellular Location and Activity of the Snail Transcriptional Repressor , 2003, Molecular and Cellular Biology.

[3]  Birgit Luber,et al.  Differential expression of the epithelial-mesenchymal transition regulators snail, SIP1, and twist in gastric cancer. , 2002, The American journal of pathology.

[4]  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.

[5]  A. Bernad,et al.  The transcription factor SNAIL represses vitamin D receptor expression and responsiveness in human colon cancer , 2004, Nature Medicine.

[6]  H. Beug,et al.  Molecular requirements for epithelial-mesenchymal transition during tumor progression. , 2005, Current opinion in cell biology.

[7]  M. Hung,et al.  Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition , 2004, Nature Cell Biology.

[8]  S. Frisch,et al.  Evidence for a function of CtBP in epithelial gene regulation and anoikis , 2000, Oncogene.

[9]  Francisco Portillo,et al.  The transcription factor Snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression , 2000, Nature Cell Biology.

[10]  D. Nguyen,et al.  Pak1 phosphorylation of snail, a master regulator of epithelial-to-mesenchyme transition, modulates snail's subcellular localization and functions. , 2005, Cancer research.

[11]  Carlos S. Moreno,et al.  MTA3, a Mi-2/NuRD Complex Subunit, Regulates an Invasive Growth Pathway in Breast Cancer , 2003, Cell.

[12]  G. Berx,et al.  The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. , 2001, Molecular cell.

[13]  A. Sbarbati,et al.  Mammary carcinoma provides highly tumourigenic and invasive reactive stromal cells. , 2005, Carcinogenesis.

[14]  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.

[15]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[16]  M. Nieto,et al.  A New Role for E12/E47 in the Repression ofE-cadherin Expression and Epithelial-Mesenchymal Transitions* , 2001, The Journal of Biological Chemistry.

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

[18]  R. Kalluri,et al.  Epithelial-mesenchymal transition and its implications for fibrosis. , 2003, The Journal of clinical investigation.

[19]  José Miguel García,et al.  E-cadherin and vitamin D receptor regulation by SNAIL and ZEB1 in colon cancer: clinicopathological correlations. , 2005, Human molecular genetics.

[20]  S. Weiss,et al.  Wnt-dependent Regulation of the E-cadherin Repressor Snail* , 2005, Journal of Biological Chemistry.

[21]  R. Oliver,et al.  Induction of hair growth by implantation of cultured dermal papilla cells , 1984, Nature.

[22]  M. Nieto,et al.  The snail superfamily of zinc-finger transcription factors , 2002, Nature Reviews Molecular Cell Biology.

[23]  A. Roberts,et al.  Breast cancer cells induce stromal fibroblasts to express MMP-9 via secretion of TNF-α and TGF-β , 2005, Journal of Cell Science.

[24]  M. Nieto,et al.  The Snail genes as inducers of cell movement and survival: implications in development and cancer , 2005, Development.

[25]  G. Berx,et al.  Unraveling signalling cascades for the Snail family of transcription factors. , 2005, Cellular signalling.

[26]  M. Bissell,et al.  Epithelial to mesenchymal transition in human breast cancer can provide a nonmalignant stroma. , 2003, The American journal of pathology.

[27]  Elise C. Kohn,et al.  The microenvironment of the tumour–host interface , 2001, Nature.

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

[29]  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.

[30]  W. Fiers,et al.  Genetic manipulation of E-cadherin expression by epithelial tumor cells reveals an invasion suppressor role , 1991, Cell.

[31]  Elaine Fuchs,et al.  A Signaling Pathway Involving TGF-β2 and Snail in Hair Follicle Morphogenesis , 2004, PLoS biology.

[32]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[33]  Robert D Cardiff,et al.  The transcriptional repressor Snail promotes mammary tumor recurrence. , 2005, Cancer cell.

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

[35]  K. Csiszȧr,et al.  A molecular role for lysyl oxidase‐like 2 enzyme in Snail regulation and tumor progression , 2005, The EMBO journal.

[36]  M. Quintanilla,et al.  Transforming growth factor beta-1 induces snail transcription factor in epithelial cell lines: mechanisms for epithelial mesenchymal transitions. , 2003, The Journal of biological chemistry.

[37]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[38]  H. Höfler,et al.  Expression and nuclear localization of Snail, an E-cadherin repressor, in adenocarcinomas of the upper gastrointestinal tract , 2006, Virchows Archiv.