title: The receptor tyrosine kinase EPHB4 has tumor suppressor activities in intestinal tumorigenesis.
abstract: 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.
authors.affiliation: Group of Molecular Oncology, Biochemistry Research Center (CIBBIM-Nanomedicine) and Department of Pathology, Vall d'Hebron Hospital, Barcelona, Spain.
authors.forename: Higinio
authors.initials: H
authors.lastname: Dopeso
authors.forename: Silvia
authors.initials: S
authors.lastname: Mateo-Lozano
authors.forename: Rocco
authors.initials: R
authors.lastname: Mazzolini
authors.forename: Paulo
authors.initials: P
authors.lastname: Rodrigues
authors.forename: Laura
authors.initials: L
authors.lastname: Lagares-Tena
authors.forename: Julian
authors.initials: J
authors.lastname: Ceron
authors.forename: Jordi
authors.initials: J
authors.lastname: Romero
authors.forename: Marielle
authors.initials: M
authors.lastname: Esteves
authors.forename: Stefania
authors.initials: S
authors.lastname: Landolfi
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.forename: Julio
authors.initials: J
authors.lastname: Castaño
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Santiago
authors.initials: S
authors.lastname: Ramon y Cajal
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
authors.forename: Simo
authors.initials: S
authors.lastname: Schwartz
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D015179:Colorectal Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D036224:Receptor, EphB4 / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D036224:Receptor, EphB4