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The first experimental pancreatic tumor induction
was reported by Wilson et al. 7 who in 1941
observed pancreatic lesions, described as
hyperplastic foci, adenomas and one acinar cell
carcinoma, in approximately half of the albino rats
receiving 2-acetylaminofluorene in their diet. The
development of other models was delayed until
late 20th century. Because of the increasing
incidence of pancreatic cancer in the United
States, the development of pancreatic cancer
models was encouraged by governmental health
agencies. Since then, within a relatively short
period of time, several animal models were
developed in rodents. Although an attempt was
made to induce tumors in large animals, such as
dogs and pigs, for a better understanding and
handling of the disease, rodents, especially rats
and hamsters, were shown to be the most
responsive species. Remarkably, the biology and
morphology of tumors between these two species
varied considerably. There are significant
morphological and biological differences of
pancreatic tumors induced in different species.
Therefore, each animal model will be described
briefly and separately.
2a. Rat
Azaserine treatment of Wistar/Lewis rats has
provided one of the best characterized and widely
used model of pancreatic carcinogenesis, although
this species provided primarily acinar cell tumors,
including adenomas, atypical nodules and
eventually carcinomas with metastasis into the
8-10
liver, lymph nodes and lungs. These
morphologies are rare in humans. Although ductlike
structures were observed in some of the
lesions, the acinar phenotype was retained in the
majority of the lesions and no actual ductal
neoplasm was diagnosed . 8-10
Interestingly,
culturing and regrafting of neoplastic acinar cells in
azaserine treated rats give rise to duct-like
carcinomas. Subsequent established cell lines,
CHAPTER 2
Pancreatic Cancer Models
2
such as DSL-6A/C1, showed a loss of acinar cell 11
differentiation and an acquisition of the cytokeratin
19, a ductal cell marker 12, 13 . The unwanted effect
of Azaserine was the induction of tumors in other
sites, including the mammary gland, liver, and
kidneys 14 .
Other classes of the carcinogenic compounds,
such as 4-hydroxyaminoquinoline-1-oxide 15 ,
nafenopin 16 , clofibrate 17 , Nδ-(N-methyl-Nnitrosocarbamoyl-L-ornithine
18 and different
nitrosamines 14 also produced acinar cell, but not
ductal lesions. The sensitivity of the rat pancreas to
produce acinar cell hyperplasia and neoplasia was
highlighted by the findings that even noncarcinogenic
agents, such as raw Soya flour or
caerulein, a cholecystokinin analog, could induce
acinar cell hyperplasia and carcinoma after a
prolonged treatment 19 .
Vesselinovitch et al. induced an adenocarcinoma
in a rat by local administration of benzo(a)pyrene 20 .
When a crystalline powder of 9,10-dimethyl-1,2benzanthracene
(DMBA), a polycyclic
hydrocarbon, was implanted intra-pancreatically,
80% of the Spague-Dawley rats developed spindle
cell sarcomas and poorly differentiated
adenocarcinomas of acinar cell type. Using a
similar technique, other investigators induced
ductal cell proliferation, tubular adenocarcinomas,
acinar cell carcinomas, fibro sarcomas and
invasive ductal adenocarcinomas 21 . Some of these
tumors metastasized into the abdominal cavity, but
no distant metastases were seen 21 .
Rivera et al. exposed male Sprague-Dawley rats to
varying doses of DMBA,
methylnitronitrosoguanidine, or
ethylnitronitrosoguanidine, either through direct
implantation into the pancreas or infusion into the
pancreatic duct 22 . Additionally, near-total
pancreatectomies were performed in all but two
DMBA implantation groups. Of these carcinogens,
only DMBA caused invasive adenocarcinoma of