Acinar-to-ductal metaplasia in pancreatic cancer development.

Ductal adenocarcinoma is by far the most frequent tumor of the pancreas. Although pancreatic cancer cells share substantial characteristics with pancreatic duct cells, the origin of these cancer cells is still a matter of debate. Progressive changes in the ductal epithelium range from non-papillary to papillary hyperplasia, with little or no development of atypical or dysplastic epithelial lesions. These ductal changes have been classified as “pancreatic intraepithelial neoplasia” (PanIN) (1). Studies examining the loss of heterozygosity at loci associated with pancreatic cancer have demonstrated the clonal evolution of the regions of PanINs (2). Some have proposed that pancreatic cancer develops from acinar cells, and indeed, acinar cell hyperplasia has been described in the human pancreas (3). Moreover, in TGF-α transgenic mice, an animal model for pancreatic cancer, acinar cells are the primary sites of pancreatic neoplasms (4). In this model, acinar cells lose their characteristic zymogen granules and become transitional cells, which subsequently acquire the features of duct cells. In animals older than one year, tumors develop from acinar-to-ductal metaplasia. In this issue of the JCI, Crawford et al. present data linking the development of acinar-to-ductal metaplasia to expression of the matrix metalloproteinase MMP-7 and the Fas ligand FasL (5). They found MMP-7 to be upregulated in human pancreatic cancer and PanINs, in metaplastic ducts of TGFα transgenic mice, and in metaplastic changes following pancreatic ductal ligation. Following up on this observation, Crawford and colleagues ligated the ducts of control and MMP-7–/– mice. Remarkably, they observed acinar cell loss, caspase-3 activation, and subsequent metaplastic conversion in wild-type mice, but almost no such responses in the mutants. MMP-7 in apoptosis Previously, MMP-7 has been shown in vitro to cleave several substrates including FasL, a transmembrane stimulator of the death receptor Fas. To test the possibility that FasL mediates the effects of MMP-7 in apoptosis, Crawford et al. took advantage of a naturally occurring FasL mutation in the gld mouse strain. They found that ductal ligation caused relatively modest acinar cell loss and metaplastic duct formation in gld mice. Likewise, these pathogenic changes are not evident in Mmp-7–/– mice, where FasL is present mainly in its unprocessed form. These data suggest that the proapoptotic effect of MMP-7 is mediated largely by FasL and is responsible for ductal metaplasia. One fundamental role of the apoptotic response is to protect animals from cancer, as seen in the increased tumorigenesis following experimental inhibition of apoptosis. In addition,