The P.I.'s long term goal is to the understand the molecular basis of Murine Leukemia (MoMuLV) and Sarcoma Virus (MoMuSV) induced pathogenesis. The MoMuSVs comprise a family of mos containing viruses that rapidly induces solid tumors in infected mice. Preliminary, studies made on three different MoMuSV isolates, confirmed that MPSV induces fibromatous lesions and myeloproliferation. In contrast, MuSV349, and SV7 induced angiomatous lesions that histologically resemble acute Kaposi's sarcoma (KS) found in AIDS patients. In these murine lesions, endothelium of vessels are transformed and preliminary evidence indicates that the spindle-like cell component of the lesion may also be of endothelial cell origin. In addition, while SV7 also caused proliferation of erythroid and myeloid cells, MuSV349 failed to do so. It was also demonstrated that SV7 in the absence of helper virus induced KS-like lesions in vivo after a significantly longer latent period. To date the etiology of KS in humans remains unknown. However, the possibility that the spindle-like cells of KS is of lymphatic endothelial cell origin has been suggested. The induction of fibrosarcomas and KS-like lesions by MuSV may be used to investigate how endothelial cells become transformed. These findings may help us understand the pathogenesis of KS. Therefore, we specifically propose to: (i) Characterize and compare in detail the pathogenesis of helper-free ml, MuSVI24, MPSV, SV7, and MuSV349 and compare the development of KS-like lesions induced by helper-free SV7 and SV7 rescued with MoMuLV-TB. Light and electron microscopy together with histochemical staining will be used; (ii) Identify the genetic determinant(s) in SV7 that is responsible for the transformation of endothelial cells by genomic fragment exchange between SV7 and MPSV genomic DNA and/or site-directed mutagenesis; (iii) Establish and characterize endothelial cell populations from tumors induced by helper-free SV7 or SV7 rescued by MoMuLV-TB. These cell populations will be used to determine whether activation of other oncogenes is involved in the transformation of endothelial cells.
| Yuen, P H; Matherne, C M; Molinari-Storey, L M (1991) SV7, a molecular clone of Moloney murine sarcoma virus 349, transforms vascular endothelial cells. Am J Pathol 139:1449-61 |
