The molecular pathogenesis of pancreatic cancer: clarifying a complex circuitry
- Departments of Medicine and Genetics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
This extract was created in the absence of an abstract.
The preponderance of pancreatic malignancies is constituted by pancreatic ductal adenocarcinomas, abbreviated as either PDA or PDAC in the literature and used interchangeably with the generic term pancreatic cancer. Other types of pancreatic malignancies, albeit uncommon and not meant to be exhaustive, include neuroendocrine tumors, acinar cell carcinomas, lymphomas, sarcomas, serous cystadenocarcinoma, and pancreatoblastoma, among other rare entities (Hruban 2006). PDAC is a disease that has a number of clinical challenges. There are ∼33,000 new cases that occur annually in the United States, with nearly the same number of deaths predominantly related to metastatic complications (Jemal et al. 2004). Overall, 5-yr survival is <5%, and this is attributable to several factors, including presentation at advanced stages of disease, thereby precluding surgical intervention, relative resistance to chemotherapy and radiation therapy, and current hurdles with other forms of therapy such as specific molecular targets, immunotherapy, and gene therapy. Meaningful therapy in the form of surgical resection is only feasible with early-stage detection, but this only applies to <20% of patients and still results in a 5-yr survival of <20% (Warshaw and Fernandez-del Castillo 1992).
Through meticulous attention to morphology and nomenclature, it is now well established that PDAC has precursor lesions, termed PanIN for pancreatic intraepithelial neoplasia (Hruban et al. 2001). PanIN lesions, delineated as PanIN-1a, PanIN-1b, PanIN-2, and PanIN-3, are associated with progressive alterations in the nuclei, epithelial polarity, and architecture, and culminate in a carcinoma in situ state (PanIN-3). Nevertheless, early PanIN lesions may be found in tissues from patients with chronic pancreatitis without PDAC or from patients at autopsy with ostensibly normal pancreata. While it is widely accepted that PanIN are the preferred precursor lesions for PDAC, this does not preclude the possibility, yet to be genetically established, that other pathways may evolve into PDAC. In the context …
