Pten constrains centroacinar cell expansion and malignant transformation in the pancreas

Abstract

To determine the role of the phosphatidylinositol 3-kinase (PI3-K) pathway in pancreas development, we generated a pancreas-specific knockout of Pten, a negative regulator of PI3-K signaling. Knockout mice display progressive replacement of the acinar pancreas with highly proliferative ductal structures that contain abundant mucins and express Pdx1 and Hes1, two markers of pancreatic progenitor cells. Moreover, a fraction of these mice develop ductal malignancy. We provide evidence that ductal metaplasia results from the expansion of centroacinar cells rather than transdifferentiation of acinar cells. These results indicate that Pten actively maintains the balance between different cell types in the adult pancreas and that misregulation of the PI3-K pathway in centroacinar cells may contribute to the initiation of pancreatic carcinoma in vivo.

Akt activation by arachidonic acid metabolism occurs via oxidation and inactivation of PTEN tumor suppressor

“…Pancreas-restricted knockout of PTEN leads to ductal malignancy in mice (Stanger et al, 2005), and the expression of PTEN is significantly decreased in a number of pancreatic cancer cells and tumor tissues (Asano et al, 2004). These investigations show that PTEN downregulation is relevant to multistage tumor progression in the pancreas.…”

Murine Embryonic Stem Cell–Derived Pancreatic Acinar Cells Recapitulate Features of Early Pancreatic Differentiation

“…This fully differentiated state may include a higher potential of cell plasticity in vitro. An alternate explanation is that in vivo metaplasia occurs because of expansion of duct like cells without de/transdifferentiation of acinar cells (37).…”

“…5G). By contrast, Dolichos biflorus agglutinin (DBA) -which selectively recognizes ductal cells (37) -was restricted to very few cells (1.8 ± 1.82%) that were β-galactosidase-negative (Fig. 5J).…”

Pancreas organogenesis: From bud to plexus to gland

“…Some reports even suggest that they represent a thin internal sheath of cells lining the inside surface of the acinar cap, such that acini do not actually contact the duct lumen. CAC express several common duct-specific TFs, such as Sox9 (Seymour et al, 2007), HNF1b (Solar et al, 2009), and Hes1 (Stanger et al, 2005;Kopinke et al, 2011). Prior findings suggest that, under injury conditions, CAC in the adult pancreas may act as facultative progenitors competent to produce all three pancreatic cell types (Leeson and Leeson, 1986;Gasslander et al, 1992;Hayashi et al, 2003;Nagasao et al, 2003).…”