Published online before print August 7, 2008

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(American Journal of Pathology. 2008;173:865-878.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080006

Soluble Forms of the Notch Ligands Delta1 and Jagged1 Promote in Vivo Tumorigenicity in NIH3T3 Fibroblasts with Distinct Phenotypes

Sumithra Urs^*, Alice Roudabush, Christine F. O'Neill, Ilka Pinz^*, Igor Prudovsky^*, Doreen Kacer^*, Yuefang Tang^*, Lucy Liaw^* and Deena Small

From the Center for Molecular Medicine,^* Maine Medical Center Research Institute, Scarborough, Maine; Department of Animal and Nutritional Sciences and New Hampshire Veterinary Diagnostics Laboratory, University of New Hampshire, Durham, New Hampshire; Department of Biochemistry, Boston University, Boston Massachusetts; and Department of Biochemistry and Molecular Biology, University of New Hampshire, Durham, New Hampshire

We previously found that soluble forms of the Notch ligands Jagged1 and Delta1 induced fibroblast growth factor receptor-dependent cell transformation in NIH3T3 fibroblasts. However, the phenotypes of these lines differed, indicating distinct functional differences among these Notch ligands. In the present study, we used allografts to test the hypothesis that NIH3T3 fibroblasts that express soluble forms of Delta1 and Jagged1 accelerate tumorigenicity in vivo. With the exception of the full-length Jagged1 transfectant, all other cell lines, including the control, generated tumors when injected subcutaneously in athymic mice. Suppression of Notch signaling by the soluble ligands significantly increased tumor onset and growth, whereas full-length Jagged1 completely suppressed tumor development. In addition, there were striking differences in tumor pathology with respect to growth kinetics, vascularization, collagen content, size and number of necrotic foci, and invasiveness into the underlying tissue. Further, the production of angiogenic factors, including vascular endothelial growth factor, also differed among the tumor types. Lastly, both Jagged1- and Delta1-derived tumors contained phenotypically distinct populations of lipid-filled cells that corresponded with increased expression of adipocyte markers. The divergence of tumor phenotype may be attributed to ligand-specific alterations in Notch receptor responses in exogenous and endogenous cell populations within the allographs. Our findings demonstrate distinct functional properties for these Notch ligands in the promotion of tumorigenicity in vivo.