Inhibition of ß-Catenin Activity Abolishes LKB1 Loss-Driven Pancreatic Cystadenoma in Mice.

Pancreatic cancer (PC) is the seventh leading cause of cancer death worldwide, and remains one of our most recalcitrant and dismal diseases. In contrast to many other malignancies, there has not been a significant improvement in patient survival over the past decade. Despite advances in our understanding of the genetic alterations associated with this disease, an incomplete understanding of the underlying biology and lack of suitable animal models have hampered efforts to develop more effective therapies. LKB1 is a tumor suppressor that functions as a primary upstream kinase of adenine monophosphate-activated protein kinase (AMPK), which is an important mediator in the regulation of cell growth and epithelial polarity pathways. LKB1 is mutated in a significant number of Peutz-Jeghers syndrome (PJS) patients and in a small proportion of sporadic cancers, including PC; however, little is known about how LKB1 loss contributes to PC development. Here, we report that a reduction in Wnt/ß-catenin activity is associated with LKB1 tumor-suppressive properties in PC. Remarkably, in vivo functional analyses of ß-catenin in the Pdx-1-Cre LKB1L/L ß-cateninL/L mouse model compared to LKB1 loss-driven cystadenoma demonstrate that the loss of ß-catenin impairs cystadenoma development in the pancreas of Pdx-1Cre LKB1L/L mice and dramatically restores the normal development and functions of the pancreas. This study further determined the in vivo and in vitro therapeutic efficacy of the ß-catenin inhibitor FH535 in suppressing LKB1 loss-driven cystadenoma and reducing PC progression that delineates the potential roles of Wnt/ß-catenin signaling in PC harboring LKB1 deficiency.

Mucin secreting cystic lesions of the pancreas: treatment by enucleation.

Ninety per cent of pancreatic cysts are inflammatory pseudocysts. The other 10 per cent are congenital or neoplastic and include congenital true cysts, retention cysts, lymphoepithelial cysts, the mucinous cystadenoma, mucinous cystadenocarcinoma, and serous microcystic cystadenomas and the more recently described intraductal papillary mucin-secreting neoplasms. The advent of computerized tomographic scanning, endoscopic retrograde cholangiopancreatography (ERCP), and endoscopic ultrasonography (EUS) has brought many of these lesions to light when they are minimally symptomatic or are incidentally found while investigating unrelated problems. If there is any suspicion of actual or potentially malignant disease, then total excision of the lesion with part of or the entire pancreas is indicated to achieve a likely cure, as survival is better than for the more common ductal adenocarcinomas. There are few reliable preoperative studies to distinguish accurately the etiology and prognosis of this spectrum of cystic lesions, and usually the actual diagnosis is made only at the time of operation or histopathologic examination after the cystic lesion has been biopsied or excised. If a cyst is confirmed to be totally benign, as in the congenital true cyst, lymphoepithelial cyst, or a benign mucinous cyst, they may lend themselves to nonoperative observation or excision without sacrifice of pancreatic parenchyma. However, many mucin-producing cystic lesions may evolve into a dysplastic or invasive malignant lesion requiring more aggressive resective treatment, and it is important not to miss that diagnosis early when cure is still possible. This report presents four benign mucin-secreting cysts treated by local excision. All four were in the head of the pancreas and communicated with the main pancreatic duct and lacked ovarian-type stroma, thus categorizing them as side-branch intraductal papillary mucinous neoplasms. These lesions were able to be easily dissected out of the pancreas with only one patient developing a transient pancreatic fistula. Intraoperative and final histopathology confirmed the benign status, and these patients have remained disease free 3 to 5 years postoperatively. A review of benign tumors reported to have been treated by cyst enucleation in the literature confirms the rationale of this approach in highly selected lesions.