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The Receptor Tyrosine Kinase EPHB4 Has Tumor Suppressor Activities in Intestinal Tumorigenesis

Groups of ¹ Molecular Oncology, ² Functional Genomics and Genetics, and ³ Drug Delivery and Targeting, Molecular Biology and Biochemistry Research Center (CIBBIM-Nanomedicine) and ⁴ Department of Pathology, Vall d'Hebron Hospital; ⁵ CIBER de Bioingeniería, Biomateriales y Nanomedicina, Barcelona, Spain; ⁶ Department of Obstetrics and Gynecology, Vanderbilt University Medical Center, Nashville, Tennessee; and ⁷ Ludwig Institute for Cancer Research, Melbourne Centre for Clinical Sciences, Austin Health, Heidelberg, Victoria, Australia

Requests for reprints: Diego Arango, Group of Molecular Oncology, Molecular Biology and Biochemistry Research Center (CIBBIM-Nanomedicine), Vall d'Hebron Hospital Research Institute, Passeig Vall d'Hebron 119-129, Barcelona 08035, Spain. Phone: 34-93-274-6739; Fax: 34-93-489-3893; E-mail: darango{at}ir.vhebron.net.

Key Words: colorectal cancer • EPHB4 • mouse model

Colorectal cancer is the second cause of cancer-related death in the western world, and although the genetic and molecular mechanisms involved in the initiation and progression of these tumors are among the best characterized, there are significant gaps in our understanding of this disease. The role of EPHB signaling in colorectal cancer has only recently been realized. Here, we use animal models to investigate the role of EphB4 in intestinal tumorigenesis. Modulation of EPHB4 levels in colon cancer cell lines resulted in significant differences in tumor growth in a xenograft model, with low levels of EPHB4 associated with faster growth. In addition, using a genetic model of intestinal tumorigenesis where adenomatous polyposis coli (Apc) mutations lead to initiation of the tumorigenic process (Apc^min mice), we show that inactivation of a single allele of EphB4 results in higher proliferation in both the normal epithelium and intestinal tumors, significantly larger tumors in the small intestine, and a 10-fold increase in the number of tumors in the large intestine. This was associated with a 25% reduction in the lifespan of Apc^min mice (P < 0.0001). Gene expression analysis showed that EphB4 mutations result in a profound transcriptional reprogramming, affecting genes involved in cell proliferation, remodeling of the extracellular matrix, and cell attachment to the basement membrane among other functional groups of genes. Importantly, in agreement with the expression profiling experiments, using an in vitro assay, we show that loss of EPHB4 in colon cancer cells results in a significantly increased potential to invade through a complex extracellular matrix. Collectively, these results indicate that EphB4 has tumor suppressor activities and that regulation of cell proliferation, extracellular matrix remodeling, and invasive potential are important mechanisms of tumor suppression. [Cancer Res 2009;69(18):7430–8]