Carlos Fernandez-Del Castillo, MD
Sonic Hedgehog May Play a Critical Role as an Initiator of Pancreatic Cancer
Cancer cells subvert these signaling and developmental pathways to alter phenotype or proliferative cues. One key factor in pancreatic development that may also be important in human pancreatic neoplasia is Sonic hedgehog (Shh). Shh is a secreted signaling protein essential in regional specialization of the foregut endoderm, where restriction of Shh is functionally critical for normal pancreatic development. We find that Shh is abnormally expressed in pancreatic adenocarcinoma and its precursor lesions. The role of Shh misexpression was better defined in transgenic mice in which Shh was misexpressed in the pancreatic endoderm. These mice developed abnormal tubular structures that resembled human precursor lesions with high-grade dysplasia. Moreover, these tubular structures also contain mutations in K-ras and overexpress Her-2/neu, two genetic mutations found in the early progression of human pancreatic cancer. These data suggest that Shh may have an early and critical role in the genesis of this cancer.
Shh May Play an Important Role in Maintenance of Human Pancreatic Cancer
Hedgehog signaling also remains active in pancreatic cancer cell lines. Inhibition of the Hedgehog pathway in xenografts made from freshly resected human pancreatic cancer specimens in vivo induced apoptosis and blocked proliferation. These data suggest that Shh and its pathway are important in the maintenance of aberrant proliferation and tumorigenesis, and may provide a novel therapeutic target.
Evaluation of Progressive Genomic Alterations in Intraductal Papillary Mucinous Neoplasms of the Pancreas Intraductal papillary mucinous neoplasms of the pancreas (IPMNs) are increasingly recognized cystic tumors characterized by mucin production, a prominent intraductal component, and by malignant potential. Histologically, IPMNs may demonstrate a spectrum of cellular atypia ranging from minimal mucinous hyperplasia to frank invasive carcinoma. Although they have been clinically well described as a unique entity of pancreatic tumors, the molecular and genetic background underlying this disease is not completely understood. We are currently identifying chromosomal aberrations which may contribute to neoplastic developments in IPMNs.
Shh, Inflammation, and Cancer
Our laboratory has an ongoing interest in linking inflammatory states such as pancreatitis to pancreatic cancer formation. Inflammatory states have been linked causally to many cancers, including pancreatic cancer. Shh appears to be activated early in response to inflammation. We are investigating the role of NFkB and other proinflammatory mediators in Shh activation.
Lineage Analysis of Pancreatic Cancer
In collaboration with Yuval Dor of the Melton Laboratory, Harvard University, we have been looking to identify the progenitor cells for pancreatic adenocarcinoma. Ductal adenocarcinoma is the most common type of primary malignancy of the pancreas. Despite the ductal phenotype of most human pancreatic carcinomas, there is still considerable debate regarding the cell origin of this tumor, and it remains an important unanswered question. Recent advances in conditional transgenic technology have provided tools for conclusively determining the cell lineage in mice using targeted gene recombination. Genomically tagged mice will be subjected to pancreatic cancer induction. Cell-type-specific tags will finally allow determination of initiator cells for pancreatic cancer.
Identification of a Novel Kindred with Familial Pancreatitis and Pancreatic Cancer
Hereditary pancreatic cancer comprises up to 10% of pancreatic cancer cases. Prior work has identified multiple mutations that are associated with hereditary pancreatic cancer, including those forms associated with pancreatitis. We have identified a unique family, Family Pancreatitis/Pancreatic Cancer (Family (P/PC), which demonstrates pancreatitis and pancreatic cancer due to a previously uncharacterized genetic mutation. The mutation is transmitted in an autosomal dominant fashion, has a high penetrance, and places affected members at a significantly greater risk of developing pancreatic cancer. Current studies include characterization of the family and their diseases, identification of methods with which to risk stratify those affected members, create a screening protocol in order to identify tumors in their resectable and preneoplastic stages, and identification of the locus and gene resulting in disease.
Challenging the Role of the p16 Mutation in the Development of Pancreatic Adenocarcinoma
In mice Shh misexpression in the pancreas results in the formation of mucinous atypical epithelial structures that resemble certain features of PanINs; however, in this model no cancers were identified. These early studies suggest that Shh may be sufficient for initiation, but insufficient for progression to cancer. Inactivation of p16 is found in virtually all pancreatic cancers. The role of p16 is thought to involve progression but not initiation since p16-/- mice have normal pancreata. While we hypothesized that the combined effect of Shh overexpression and the p16 knockout would result in progression of the pancreatic neoplastic phenotype, we instead discovered that the PdxShh;p16-/- mice displayed normalization of the acinar, epithelial and endocrine compartments. These changes are associated with an increase in progenitor marker expression, suggesting that the combination of overexpression and the p16 knockout might stimulate or maintain a progenitor population.