Transgenic mice harboring oncogenes under control of tissue specific promoters are useful animal models for experimental analysis of tumor development. Preliminary experiments with two different transgenic models have revealed a possible role for fibroblast growth factor (FGF) receptors in tumorigenic progression. Transgenic mice that express SV40 large T antigen under transcriptional control of the insulin promoter develop tumors of the pancreatic beta cell. FGF receptor 4 gene expression is up- regulated in late stage beta cell tumors. Beta tumor cells also express acidic FGF, a known ligand for FGF receptor 4, suggesting a possible autocrine loop or tumor proliferation. A second group of transgenic mice express the early region of the human papilloma virus type 16 genome in basal keratinocytes and develop squamous cell carcinoma. FGF receptor 1 gene expression is up-regulated in poorly differentiated squamous cell carcinoma. Tumor cells also express acidic FGF and basic FGF, both known to be high affinity ligands for FGF receptor 1. In two cancer models both FGF ligands and FGF receptors are coexpressed, implicating FGF receptor signaling in autocrine stimulation of tumorigenesis. It is striking that this mechanism may act in two very different tumor types, and suggests that a comparative study of the two models may highlight mechanisms common to progression of many tumor types. Expression and activity of FGF receptors in cells derived from these mouse tumors will be examined to assess the response of tumor cells to FGF ligands. Genes that encode dominant-negative mutant FGF receptors will be introduced into tumor cells and transgenic mice to explore the impact of disrupted FGF receptor signaling on tumor formation and metastatic progression. Collectively, the experiments described in this proposal will provide new and meaningful insight into the importance of FGF receptor signaling for tumor formation.
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