Site-dependent E-cadherin cleavage and nuclear translocation in a metastatic colorectal cancer model.
Metastases are frequently found during colorectal cancer diagnoses and are the main determinants of clinical outcome. The lack of reliable models of metastases has precluded their mechanistic understanding and our capacity to improve outcome. We studied the effect of E-cadherin and Snail1 expression on metastagenesis in a colorectal cancer model. We microinjected SW480-ADH human colorectal cancer cells, transfected with an empty vector (Mock) or overexpressing Snail1 (Snail1(OE)) or E-cadherin (E-cadherin(OE)), in the ceca of nude mice (eight per group) and analyzed tumor growth, dissemination, and Snail1, E-cadherin, β-catenin, and Presenilin1 (PS1) expression in local tumors and/or metastatic foci. Snail1(OE) cells disseminated only to lymph nodes, whereas Mock or E-cadherin(OE) cells spread to lymph nodes and peritoneums. Peritoneal tumor foci developed by E-cadherin(OE) cells presented an increase in E-cadherin proteolysis and nuclear translocation, and enhanced expression of proteolytically active PS1, which was linked to increased tumor growth and shortened mouse survival. Interestingly, local and lymph node tumors in mice bearing E-cadherin(OE) cells overexpressed E-cadherin, but they did not show E-cadherin proteolysis or nuclear translocation. Remarkably, E-cadherin nuclear translocation and enhanced expression of active PS1 were found in a patient with colorectal signet-ring cell carcinoma. In conclusion, we have established a colorectal cancer metastasis model in which E-cadherin proteolyis and nuclear translocation associates with aggressive foci growth only in the peritoneal microenvironment.
Céspedes
María Virtudes
MV
Grup d'Oncogènesi i Antitumorals of the Centro de Investigación Biomédica en Red en Bioingenieria, Hospital de Sant Pau, Barcelona, Spain.
Larriba
María Jesús
MJ
Pavón
Miguel Angel
MA
Alamo
Patricia
P
Casanova
Isolda
I
Parreño
Matilde
M
Feliu
Anna
A
Sancho
Francesc Josep
FJ
Muñoz
Alberto
A
Mangues
Ramón
R
D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics / Q000378:metabolism*; D018279:Carcinoma, Signet Ring Cell; D002467:Cell Nucleus / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005353:Fibronectins; D005455:Fluorescent Antibody Technique; D006801:Humans; D007124:Immunoenzyme Techniques; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D008207:Lymphatic Metastasis; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008819:Mice, Nude; D010534:Peritoneal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000556:secondary*; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D005353:Fibronectins; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D053764:Presenilin-1; D012333:RNA, Messenger; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D051176:beta Catenin
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