c-fos-induced Osteosarcoma Formation in Transgenic Mice: Cooperativity with c-jun and the Role of Endogenous c-fos

ZQ Wang, J Liang, K Schellander, EF Wagner… - Cancer research, 1995 - AACR
ZQ Wang, J Liang, K Schellander, EF Wagner, AE Grigoriadis
Cancer research, 1995AACR
Transgenic mice overexpressing the c-fos proto-oncogene in bone develop osteosarcomas,
whereas mice overexpressing c-Jun are normal. In this study, we investigated whether Fos
and Jun would cooperate in vivo and whether the threshold levels of Fos are important in
osteosarcoma formation. Fos-Jun double-transgenic mice develop osteosarcomas at a
higher frequency than single-Fos transgenic mice with no differences in the time of onset of
tumor formation. Histological and histochemical analyses indicated that Fos-Jun tumors …
Abstract
Transgenic mice overexpressing the c-fos proto-oncogene in bone develop osteosarcomas, whereas mice overexpressing c-Jun are normal. In this study, we investigated whether Fos and Jun would cooperate in vivo and whether the threshold levels of Fos are important in osteosarcoma formation. Fos-Jun double-transgenic mice develop osteosarcomas at a higher frequency than single-Fos transgenic mice with no differences in the time of onset of tumor formation. Histological and histochemical analyses indicated that Fos-Jun tumors contained greater quantities of neoplastic bone, were more remodeled, and contained a greater number of multinucleated osteoclast-like cells than tumors isolated from agematched, single transgenic littermates. In contrast, overexpression of Fos in knockout mice that lack endogenous Fos resulted in a decrease in the number of tumor-bearing mice; osteosarcomas were almost absent in c-fos -/-; mice, whereas tumor incidence was reduced to ∼50% in c-fos +/- mice.
Cell lines isolated from Fos-Jun transgenic tumors expressed high levels of both transgenes but significantly lower levels of the jun-related gene junB compared with cells expressing only a c-fos transgene. Osteoblastic marker genes were expressed at varying levels in different cell lines, but expression of interstitial collagenase (matrix metalloproteinase-1) was enhanced in cells derived from Fos-Jun tumors. These studies demonstrate that coexpression of a c-jun transgene can enhance Fos-induced oncogenesis in vivo and suggest that a critical level of Fos is necessary for osteosarcoma development.
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