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Review
. 2008:3:157-88.
doi: 10.1146/annurev.pathmechdis.3.121806.154305.

Pancreatic cancer

Anirban Maitra  1 , Ralph H Hruban
Affiliations
Review

Pancreatic cancer

Anirban Maitra et al. Annu Rev Pathol. 2008.

Abstract

The past two decades have witnessed an explosion in our understanding of pancreatic cancer, and it is now clear that pancreatic cancer is a disease of inherited (germ-line) and somatic gene mutations. The genes mutated in pancreatic cancer include KRAS2, p16/CDKN2A, TP53, and SMAD4/DPC4, and these are accompanied by a substantial compendium of genomic and transcriptomic alterations that facilitate cell cycle deregulation, cell survival, invasion, and metastases. Pancreatic cancers do not arise de novo, and three distinct precursor lesions have been identified. Experimental models of pancreatic cancer have been developed in genetically engineered mice, which recapitulate the multistep progression of the cognate human disease. Although the putative cell of origin for pancreatic cancer remains elusive, minor populations of cells with stem-like properties have been identified that appear responsible for tumor initiation, metastases, and resistance of pancreatic cancer to conventional therapies.

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Figures

Figure 1
Figure 1
Pathology of pancreatic adenocarcinoma and its precursor lesions. (a) Gross photograph of an infiltrating adenocarcinoma. Note the dramatic narrowing of the pancreatic duct associated with the poorly defined white neoplasm. (b) Low-power photomicrograph of an infiltrating adenocarcinoma. Note the haphazard arrangement of the glands and the associated non-neoplastic desmoplastic stroma. (c) High-power photomicrograph of an infiltrating adenocarcinoma. Note the desmoplastic stroma and the marked pleomorphism in the cancer relative to the trapped non-neoplastic duct. (d) High-grade pancreatic intraepithelial neoplasia.
Figure 2
Figure 2
Genetic progression model of pancreatic adenocarcinoma. The progression from histologically normal epithelium to low-grade pancreatic intraepithelial neoplasia (PanIN), to high-grade PanIN, to invasive carcinoma (left to right) is associated with the accumulation of specific genetic alterations. On the basis of their temporal appearance in this progression model, the molecular abnormalities can be classified as early (KRAS2 mutation, telomere shortening), intermediate (p16/CDKN2A loss), or late (mutations of DPC4/SMAD4, TP53, BRCA2). These signature genomic alterations are accompanied by a multitude of expression abnormalities that are not illustrated (see text for details). Note that this progression model is specific for PanINs, and other recognized precursor lesions of adenocarcinoma (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) likely harbor a distinct compendium of genetic alterations in their path to invasive cancer. The state of the field does not definitively establish the cellular origin for PanIN and pancreatic cancer. On the basis of genetically engineered models, two candidates have emerged as the most likely cell of origin for ductal neoplasia in the pancreas: facultative progenitors within the acinar compartment and centroacinar cells. Both competing hypotheses are illustrated to the far left of the figure to underscore the current uncertainty in the literature. Rigorous lineage-tracing experiments have confirmed the ability of differentiated acinar cells to undergo acinar-to-ductal transdifferentiation, via generation of nestin-positive intermediates. This process, known as acinar-to-ductal metaplasia, is a frequent accompaniment of pancreatic neoplasia in experimental models, and is also observed in the setting of human pancreatic cancers. The second putative source of neoplastic ductal cells is centroacinar cells, which are found at the junction of acini and ducts. These are the only cell types in the mature exocrine pancreas with retained Notch activation, as determined via persistent nuclear Hes1 expression. Loss of regulatory signals (e.g., inactivation of PTEN) that lead to uncontrolled centroacinar cell expansion culminates in pancreatic adenocarcinoma. In addition to these putative candidates, this model does not exclude the possibility of a rare, as yet undefined, pancreatic stem cell as the source of ductal neoplasia. See Cellular Origins of Pancreatic Cancer for further details.
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