even though the results of this study have not yet been reported.

These PDX1 Cre/RASG12D animals develop commonly, but develop harmless precursor lesions named pancreatic intraepithelial neoplasms that can, with long latency, progress to form PDAC. As demonstrated previously, these neoplastic lesions stain absolutely for markers of Dasatinib senescence, including expression of p53 and p21CIP1 and SA W woman. However, they generally lack markers of incorporation, specifically Ki67, MCM2 expression and proliferation of BrdU. To try the effect of PIK3CA/AKT pathway activation with this activated RAS induced in vivo senescence like state, the PDX1 Cre/RASG12D animals were crossed to animals that have one or both PTEN alleles flanked by Cre recombination sites, to drive simultaneous activation of RAS and partial or biallelic inactivation of PTEN in the pancreas. Considerably, complete inactivation of PTEN in the mouse pancreas does not stimulate senescence. Comparing PanINs inside the pancreata of 6 week old PDX1 Cre/RASG12D and PDX1 Cre/RASG12D/PTEN animals, we discovered that inactivation of PTEN mainly Metastatic carcinoma abolished expression of p21, p53, senescence markers and SA B gal. As measured by a rise in immunohistochemical staining of incoporation, MCM2 and Ki67 of BrdU, In line with the theory that inactivation of PTEN encourages the senescence to an entire bypass like state, we identified the PanINs of the PDX1 Cre/RASG12D/PTEN animals to become extremely proliferative. Senescence bypass was associated with phosphorylation of GSK3 on serine 9, like the in vitro model. Consistent with this senescence like state being an effective tumor suppression mechanism in this in vivo model, expression of activated RAS and concurrent inactivation of PTEN resulted in rapid development of PanINs into PDAC, as reported recently. Previously, Decitabine we have claimed that inactivation of p21CIP1 boosts tumorigenesis in this design, likely although inactivation of senescence. Notably, scarcity of p21CIP1 didn't further accelerate tumorigenesis in PDX1 Cre/RASG12D/ PTENfl/ animals, indicating that loss of p21CIP1 and PTEN accelerate PDAC via the exact same pathway, further implicating loss of PTEN in abrogation of senescence in this model. IHC analysis of PTEN indicated that tumors due to PDX1 Cre/RASG12D/PTENfl/ mice had lost the next allele of PTEN. Also, the ramifications of PTEN disruption were more marked when both, as opposed to one, alleles of PTEN were engineered for inactivation within the pancreas. Loss of two alleles of PTEN resulted in a remarkably dangerous velocity of tumorigenesis, leading inevitably to quick death and a mean survival of 15 days. In these mice, almost the complete pancreas was replaced by neoplastic tissue, with very little normal tissue remaining. Neoplastic structure covered popular mitoses, including some aberrant results. In places, there was loss of the normal pancreatic architecture with angulated glands, indicating invasive carcinoma.