Expression of L1-CAM and ADAM10 in Human Colon Cancer Cells Induces Metastasis

Nancy Gavert,Shani Raveh,Francis Barany,Thomas Brabletz,Michal Sheffer,Phillip Paty,Avri Ben-Ze'Ev,Daniel Notterman,Michael Shtutman,Eytan Domany,Simone Spaderna

doi:10.1158/0008-5472.can-07-0991

Abstract

L1-CAM, a neuronal cell adhesion receptor, is also expressed in a variety of cancer cells. Recent studies identified L1-CAM as a target gene of beta-catenin-T-cell factor (TCF) signaling expressed at the invasive front of human colon cancer tissue. We found that L1-CAM expression in colon cancer cells lacking L1-CAM confers metastatic capacity, and mice injected in their spleen with such cells form liver metastases. We identified ADAM10, a metalloproteinase that cleaves the L1-CAM extracellular domain, as a novel target gene of beta-catenin-TCF signaling. ADAM10 overexpression in colon cancer cells displaying endogenous L1-CAM enhanced L1-CAM cleavage and induced liver metastasis, and ADAM10 also enhanced metastasis in colon cancer cells stably transfected with L1-CAM. DNA microarray analysis of genes induced by L1-CAM in colon cancer cells identified a cluster of genes also elevated in a large set of human colon carcinoma tissue samples. Expression of these genes in normal colon epithelium was low. These results indicate that there is a gene program induced by L1-CAM in colon cancer cells that is also present in colorectal cancer tissue and suggest that L1-CAM can serve as target for colon cancer therapy.

Highlights

Colorectal cancer (CRC) is one of the most prevalent cancers in the Western world with f150,000 new cases and 60,000 deaths each year in the United States alone [1]
We identified genes coding for members of the neuronal L1-CAM family of immunoglobulin-like cell adhesion receptors (L1-CAM and Nr-CAM) as targets of h-catenin/T-cell factor (TCF) signaling in colon cancer cells [23, 24] and detected L1-CAM and the metalloproteinase ADAM10, which cleaves the L1-CAM ectodomain, in a subpopulation of CRC cells at the invasive front of tumors [24]
We investigated whether L1CAM and ADAM10 expression in human CRC cells promotes the metastatic capacity of these cells and compared the gene expression pattern elicited by L1-CAM expression in cultured CRC cells to changes in the profile of genes expressed in human CRC tissue

Summary

Introduction

Colorectal cancer (CRC) is one of the most prevalent cancers in the Western world with f150,000 new cases and 60,000 deaths each year in the United States alone [1]. Because evolution of the adenoma-carcinoma sequence takes between 5 and 15 years, there is ample opportunity for early intervention. Studies on both sporadic and inherited CRC revealed that, in the great majority of such cancer patients, the primary mutation targets a single signaling pathway, the Wnt pathway [3,4,5,6]. A key component in the Wnt pathway is h-catenin that plays a dual role in the cell: it is a major structural component of cell-cell adhesions It can function as an activator of gene transcription in the nucleus together with T-cell factor (TCF)/ lymphocyte enhancer factor (LEF) transcription factors [7, 8]. As is the case in CRC, h-catenin is an oncogene, constitutively activating genes that contribute to CRC development

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