ABSTRACT
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.
Subject(s)
Calcium-Binding Proteins/metabolism , Cell Transformation, Neoplastic/metabolism , Intercellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Neoplasms, Experimental/metabolism , Phenotype , Animals , Blotting, Western , Calcium-Binding Proteins/genetics , Cell Line , Enzyme-Linked Immunosorbent Assay , Fibroblasts/metabolism , Immunohistochemistry , In Situ Nick-End Labeling , Intercellular Signaling Peptides and Proteins/genetics , Intracellular Signaling Peptides and Proteins , Jagged-1 Protein , Magnetic Resonance Imaging , Male , Membrane Proteins/genetics , Mice , Mice, Nude , Neoplasm Transplantation , Neovascularization, Pathologic/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Serrate-Jagged Proteins , TransfectionABSTRACT
A 10.8-year-old, spayed female toy poodle presented with an esophageal foreign body. The foreign body was removed endoscopically, and a gastrostomy tube was placed to provide nutritional support during esophageal healing. The gastrostomy tube was later removed by endoscopic retrieval of the bulb through the esophagus. Immediately afterward, the dog developed hemothorax and eventually died. It was determined that many small arterial branches were avulsed from the aorta. The involved sections of aorta histopathogically evidenced medial necrosis, which was believed to be related to a prior disruption of blood flow through the vasa vasorum.
