One of the major obstacles in studying tumorigenesis in vivo is the lack of a sensitive and non-invasive imaging system which would allow us to monitor genetic changes, such as oncogene activation or tumor suppressor gene deletion, in a living individual.
The aim of this proposal is to design and test a PET imaging system which will allow us to follow PTEN tumor suppressor gene deletion in an animal tumor model that we have recently established. PTEN/MMAC1 is the first phosphatase identified as a major tumor suppressor. Deletions and mutations in the PTEN gene are found at high frequency in many primary human cancers, including glioblastoma, endometrial tumors, prostate and breast cancers. In addition, germline mutations of PTEN have been identified in three related, autosomal dominant familial cancer predisposition disorders. Very recently, inactivation of PTEN in a mouse model has confirmed the role of PTEN as a tumor suppressor. Pten+/- mice spontaneously develop tumors in many tissues. However, due to multiple tumor formation in the heterozygous mice and early embryonic lethality of Pten-/- mice, the exact formation of PTEN in regulation of cell growth and tumorigenesis remains unclear. To study the function of PTEN in cancer development in vivo, a conditional knock-out strategy was undertaken. The conditional mutagenesis approach will inactivate the Pten gene only upon co- expression of Cre recombinase. The Cre cleavable sequences, loxp, have been introduced into the mouse Pten gene, and mice homozygous for this modified Pten allele (Ptenloxp/loxp) have been obtained recently. In this proposal, a REAPER (for recombinationally activated PET reporter) mice strain will be generated. By cross the REAPER mice with the Ptenloxp/loxP mice, the PET reporter gene will be """"""""turned on"""""""" in very cell carrying Pten deletion upon exposure to the Cre recombinase. This methodology will allow us, for the firs time, to mark with a PET reporter gene those cells with a genetic deletion and to repetitively monitor the progression, metastasis, and regression of resulting tumors in response to therapy in a living individual.
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