br Discussion br The pancreas
The pancreas is an organ in which inflammation, fibrosis and atrophy are easily induced because most of the pancreatic parenchyma is composed of acini that produce digestive enzymes . However, the significance of the changes in acinar morphology within the sur-rounding microenvironment of the tumor during the development and progression of pancreatic cancer are unknown. In this study, we have found that the border between the tumor and the acini is largely di-vided into two histopathologically distinct regions, the invasive front and the non-invasive front. In the invasive front, cancer Y-27632 and/or CAFs demonstrate extensive invasion of the pancreatic parenchyma that is accompanied by desmoplastic changes and acinar atrophy. In the
non-invasive front, cancer cells and areas of desmoplasia are en-capsulated by fibrosis. We also found extensive ADM-like lesions in areas of CAA observed within the invasive front of pancreatic tumors in both humans and KPC mice. In the orthotopic transplantation model, we also observed extensive ADM-like lesions and desmoplastic changes within the invasive front of tumors in the pancreas of mice. Further-
more, tumor volumes were also significantly larger, possibly because of the extensive ADM found in KrasG12D/+ mice. These results suggest that
ADM-like lesions within CAA regions of the invasive front enhance tumor invasion into the local pancreatic parenchyma.
Pancreatic acinar cells show plasticity termed ADM [12–14]. In previous reports, ADM has been described in humans and mice, espe-cially regarding carcinogenesis [17,18], [32,33]. In our study, ADM-like lesions were observed in the invasive front, especially where acinar atrophy and invasion into the pancreatic parenchyma were extensive. In addition, a strong desmoplastic reaction was observed around these ADM-like lesions. When we induced temporary acute pancreatitis by administration of caerulein in KPC mice that had already formed palpable invasive cancer, tumor progression was accelerated (data not shown). This is possibly a consequence of the Kras mutation, which promotes ADM within the pancreas around the established tumor. Changes in the physical structural of the surrounding tumor micro-environment, including collagen matrix remodeling within regions of desmoplasia, are known to contribute to the process of cancer invasion [20,34]. These data suggest that ADM-like lesions with acinar atrophy and associated areas of desmoplasia within the invasive front of the tumor contribute to the formation of a microenvironment that favors local invasion in pancreatic cancer.
Several mechanisms linking ADM to carcinogenesis have been de-scribed [18,35], but the significance of ADM within the invasive front of the tumor has remained unclear. It has been reported that factors secreted by cancer cells, such as TGFα and TGFβ, are involved in ADM formation [17,36]. Our immunohistochemical analysis revealed that ADM lesions within the invasive front of the tumor were positive for TGFα expression. In addition, when PACs were stimulated with TGFα in an in vitro 3D explant culture model, they formed ADM-like structures. ADM can also be induced following pancreatic inflammation  and in response to macrophage-secreted cytokines . Our present find-ings suggest that ADM can be classified according to three distinct phenotypical profiles that are dependent upon the properties of the local pancreatic microenvironment.
The Klf4 gene, which is known to be essential for the induction of ADM [35,38], was up-regulated in all three subtypes of ADM. In CA-ADM, growth factor, cytokine, and secretory factor-related genes, such as Bmp, Fgf, Il, Tnf and Mmp, were up-regulated. Bone morphogenetic protein belongs to the TGFβ superfamily and has been implicated in the invasion and metastasis of cancer cells during epithelial–mesenchymal transition . Fibroblast growth factor and Interleukin are