Avian leukosis virus (ALV) rapidly induces metastatic bursal lymphomas in lymphoma-susceptible chicken strains, after clonal expansion of B cells harboring a proviral c-myc gene integration within transformed follicles. Pulse-chase labelling measurements of proliferation and bursal emigration will examine how c-myc overexpression induces rapid expansion of these transformed follicles. The same analysis will determine why transformed follicles from lymphoma-resistant chicken strains fail to expand and form tumors. Transplantation of bursal progenitors overexpressing exogenous myc from retroviral vectors will test whether this resistance results from reduced ALF LTR-driven myc expression, or altered target cell response to myc expression. Immunohistochemical studies of the effects of myc in lymphoma-susceptible birds revealed angiogenesis at early stages within c-myc or v-myc-transformed follicles and tumors. The angiogenic activity induced by myc overexpression in B cells will be characterized using in vitro and in vivo assays of endothelial proliferation, migration, and vessel growth. Angiogenesis will be manipulated during bursal lymphomagenesis by transplantation of bursal progenitors expressing myc and/or angiogenic inhibitors from retroviral vectors, to determine whether inhibition of angiogenesis prevents early growth of myc-transformed follicles or their ability to form metastatic lymphomas. Bursal lymphocytes overexpressing myc show increased vascular endothelial growth factor (VEGF) production. The contribution of this endothelial growth factor to myc-induced angiogenesis will be assessed by overexpressing or underexpressing VEGF in B cells. The effects of VEGF overexpression in low myc B cell lines will be characterized by endothelial proliferation, migration, and angiogenesis assays, and bursal progenitors overexpressing VEGF will be assessed for their ability to induce angiogenesis in vivo. The VEGF gene will be deleted from myc-overexpressing B cell lines by homologous recombination, to determine whether this reduces angiogenic activity in vitro, and formation of angiogenic tumors in vivo. These studies will give insight to the role of myc- and VEGF-induced angiogenesis during the generation of lymphomas. Findings from the experimental model will be applied to studies of angiogenesis in human lymphomas and other cancers involving de-regulated c-myc expression, to determine whether myc-induced angiogenesis contributes to the common association of myc overexpression with human cancers.
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