Cooperative action of germ-line mutations in decorin and p53 accelerates lymphoma tumorigenesis

Ectopic expression of decorin in a wide variety of transformed cells result s in growth arrest and the inability to generate tumors in nude mice, This process is caused by a decorin-mediated activation of the epidermal growth factor receptor, which leads to a sustained induction of endogenous p21(WAF 1.CIP1) (the cyclin-dependent kinase inhibitor p21) and growth arrest. Howe ver, mice harboring a targeted disruption of the decorin gene do not develo p spontaneous tumors, To test the role of decorin in tumorigenesis, we gene rated mice lacking both decorin and p53, an established tumor-suppressor ge ne. Mice lacking both genes showed a faster rate of tumor development and s uccumbed almost uniformly to thymic lymphomas within 6 months [mean surviva l age (T-50) similar to 4 months], Mice harboring one decorin allele and no p53 gene developed the same spectrum of tumors as the double knockout anim als, but had a survival rate similar to the p53 nub animals (T-50 similar t o 6 months). Ectopic expression of decorin in thymic lymphoma cells isolate d from double mutant animals markedly suppressed their colony-forming abili ty. When these lymphoma cells were cocultured wit fibroblasts derived from either wild-type or decorin null embryos, the cells grew faster in the abse nce of decorin, Moreover, exogenous decorin proteoglycan or its protein cor e significantly retarded their growth in vitro. These results indicate that the lack of decorin is permissive for lymphoma tumorigenesis in a mouse mo del predisposed to cancer and suggest that germ-line mutations in decorin a nd p53 may cooperate in the transformation of lymphocytes and ultimately le ad to a more aggressive phenotype by shortening the tumor latency.