Rat embryo fibroblasts transformed by c-Jun display highly metastatic and angiogenic activities in vivo and deregulate gene expression of both angiogenic and antiangiogenic factors

The comparative tumorigenicity in rats and nude mice of cell lines derived from FR3T3 and transformed by either c-jun, ras, SV40 It, or bovine papillo ma virus type 1 (BPV1) oncogenes was investigated. c-Jun-transformed cells were as tumorigenic and metastatic as Ras-transformed cells. Latencies were short, and numerous pulmonary metastases were observed in all injected ani mals, In contrast, tumors induced by s.c. injection of SV40-transformed cel ls developed slower, and none of the animals who received injections i.v. p resented with metastases, BPV1-transformed cells had an intermediate tumori genic and metastatic activity. Microvessels present in the different tumors were revealed by immunostaining with Griffonia (Bandeiraea) Simplicifolia lectin 1, Tumors obtained with c-Jun-transformed cells exhibited more neova scularization than those induced by the other oncogenes, By comparison to F R3T3 cells or SV40- or BPV1-transformed cells, c-Jun-transformed fibroblast s repress the antiangiogenic thrombospondin-1 and SPARC genes, whereas we f ound that they express higher levels of gene expression of the angiogenic v ascular endothelial growth factor, Finally, as compared with cells before p assage in animals, thrombospondin-l, SPARC, and VEGF gene expression was al so deregulated in cell lines isolated from primary tumors induced by BPV1-t ransformants. Our results indicate that the high transforming potential of c-Jun, evidenced as soon as transformation is established in vitro, correla tes with deregulation of gene expression of both angiogenic and antiangioge nic factors leading to rapid neovascularization of tumors.