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Sarcomas are a family of tumors of mesenchymal origin representing <1% of all human cancers. A subgroup of soft-tissue sarcomas is associated to defined chromosomal translocations and simple karyotypes, whereas the rest (including leiomyosarcomas) is characterized by complex genotypes and numerous chromosomal aberrations. To date, both the underlying genetic defects and the cell of origin of most human sarcomas remain unknown. Recently, alterations in the PI3K-Akt pathway have been identified in certain sarcoma subtypes. For instance, loss of heterozygosity of 10q23 (containing the PTEN genomic locus) has been frequently observed in human leiomyosarcomas. To determine the role of aberrant PI3K-Akt signaling in leiomyosarcoma pathogenesis, we have genetically inactivated PTEN in the smooth muscle lineage by crossing PTENlox/lox and SM22α-cre mice. Resultant animals carrying homozygous deletion of both PTEN alleles developed widespread smooth muscle hyperplasia, particularly affecting the urinary tract and the intestinal wall. Furthermore, we observed a very rapid onset (2-3 months of age) and elevated incidence of abdominal leiomyosarcomas. Importantly, some of them originate from the blood vessel walls, consistent with one of the sites of origin of these tumors in humans. We confirmed the smooth-muscle origin of these lesions by positive staining of well-established markers, such as desmin and smooth muscle actin. As expected, tumors display high levels of p-Akt and downstream effectors, indicative of constitutive Akt-mTOR signaling. In addition, we found a significant induction of p53 expression, confirming the p53-mediated anti-proliferative response subsequent to PTEN inactivation found in other tissue types. Taken together, our data reveal a novel critical role for the PTEN-Akt pathway in mesenchymal transformation and sarcomagenesis. These newly generated sarcoma models may enable the identification of secondary genetic or phenotypic events required for sarcoma progression and/or metastasis. Finally, we are currently performing pre-clinical studies in this model with new therapeutic compounds that target the Akt-mTOR pathway.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]