aP2-Cre-mediated expression activation of an oncogenic PLAG1 transgene results in cavernous angiomatosis in mice.

ABSTRACT

The developmentally regulated PLAG1 proto-oncogene has been implicated in the development of various human tumor types, such as pleomorphic salivary gland adenomas, lipoblastomas, hepatoblastomas and AML. In previous studies, we generated two independent PLAG1 transgenic founder strains, PTMS1 and PTMS2, in which PLAG1 could be activated via Cre-mediated excision of a stop cassette. With these founders, PLAG1-induced tumor formation in salivary and mammary glands of mice was studied. To further delineate the oncogenic spectrum of PLAG1 in mice, we induced aP2-Cre-mediated overexpression of PLAG1 in offspring from crossbreeding PTMS1 mice with aP2-Cre transgenic mice. More than 80% of aP2-Cre(+/-)/PLAG1(+/-) (P1-ACre) mice developed a vascular tumor type within one year, which could be classified histopathologically as cavernous angiomatosis. The lesions occurred in various regions of the mouse body but almost exclusively in the immediate surrounding of fat cells. Validation of available PLAG1-induced gene expression profiling data, using targeted tissues, revealed that expression activation of PLAG1 is functional because it leads to elevated levels of PLAG1 target gene transcripts in those tissues, such as for instance those of H19, Dlk1, and Igf-2, similarly as observed in PLAG1-induced salivary and mammary gland tumors. In conclusion, we present the first evidence that links PLAG1 to the molecular pathogenesis of vascular tumorigenesis, known as cavernous angiomatosis, with the possible involvement of Igf signaling and, moreover, further delineate the oncogenic spectrum of PLAG1 in mice, increasing the potential of this transgenic mouse tumor model system for research and therapeutic drug testing.