Site-Dependent E-Cadherin Cleavage and Nuclear Translocation in a Metastatic Colorectal Cancer Model

• DOI: 10.2353/ajpath.2010.100079
• Publication Date: 2010-09-03T02:33:02Z
• Authors: María Virtudes Cé...; María Jesús Larriba; Miguel Angel Pavón; Patricia Álamo; Isolda Casanova; Matilde Parreño; Anna Feliu; Francesc Josep Sa...; Alberto Muñoz; Ramón Mangues
• Keywords: Fluorescent Antibody Technique; transcription factor Snail; cancer model; Immunoenzyme Techniques; Mice; protein cleavage; Peritoneal Neoplasms; 0303 health sciences; lymph node metastasis; Reverse Transcriptase Polymerase Chain Reaction; article; signet ring carcinoma; Cadherins; 3. Good health; Protein Transport; tumor growth; priority journal; Lymphatic Metastasis; beta catenin; protein degradation; Colorectal Neoplasms; Lymphoid Enhancer-Binding Factor 1; animal experiment; Blotting, Western; Mice, Nude; colorectal cancer; survival; uvomorulin; animal tissue; peritoneum metastasis; 03 medical and health sciences; presenilin 1; Presenilin-1; metastasis; Animals; Humans; controlled study; human; RNA, Messenger; protein expression; mouse; Cell Nucleus; nonhuman; animal model; human cell; Fibronectins; Lymph Nodes; Carcinoma, Signet Ring Cell

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.