Acinar‐to‐ductal metaplasia accompanies c‐myc‐induced exocrine pancreatic cancer progression in transgenic rodents

Abstract

Several important characteristics of exocrine pancreatic tumor pathogenesis remain incompletely defined, including identification of the cell of origin. Most human pancreatic neoplasms are ductal adenocarcinomas. However, acinar cells have been proposed as the source of some ductal neoplasms through a process of acinar-to-ductal metaplasia. The oncogenic transcription factor c-myc is associated with human pancreatic neoplasms. Transgenic mice overexpressing c-myc under control of acinar cell-specific elastase (Ela) gene regulatory elements not only develop acinar cell carcinomas but also mixed neoplasms that display both acinar-like neoplastic cells and duct-like neoplastic cells. In this report, we demonstrate that, first, c-myc is sufficient to induce acinar hyperplasia, though neoplastic lesions develop focally. Second, cell proliferation remains elevated in the neoplastic duct cell compartment of mixed neoplasms. Third, the proliferation/apoptosis ratio in cells from all lesion types remains constant, suggesting that differential regulation of these processes is not a feature of cancer progression in this model. Fourth, before the development of mixed neoplasms, there is transcriptional activation of the duct cell-specific cytokeratin-19 gene promoter in multicellular foci of amylase-positive acinar neoplasms. This observation provides direct evidence for metaplasia as the mechanism underlying development of ductal neoplastic cells within the context of an acinar neoplasm and suggests that the stimulus for this transformation acts over a multicellular domain or field within a neoplasm. Finally, focal ductal elements develop in some acinar cell carcinomas in Ela-c-myc transgenic rats, indicating that myc-associated acinar-to-ductal metaplasia is not restricted to the mouse.The hallmark of cancer is excessive tissue growth, but neoplastic tissue also can differ from normal tissue in other ways. Anaplasia, or loss of cellular and tissue differentiation, is observed commonly in malignant neoplasms and their metastases. In other neoplasms, the pattern of differentiation may be redirected. The result is metaplasia, the replacement of one type of differentiated cell by another. Both anaplasia and metaplasia can obscure the identity of the neoplasm's cell of origin.We and other workers have reported that c-myc-induced transformation of transgenic mouse acinar cells produces both acinar and mixed acinar/ductal neoplasms.1-4 The latter were unexpected, given the transgene targeting strategy, which used the acinar cell-specific elastase (Ela) enhancer/ promoter. Neoplastic duct-like cells first were identified in small foci associated with localized fibrosis within Ela-c-myc acinar cell carcinomas. Eventually, large neoplasms developed that were composed of cytokeratin-19 (CK19)-positive ductal epithelial cells embedded in a fibrous stroma and that contained focal collections of amylase-positive acinar-like neoplastic cells. These observations supported suggestions that acinar-to-ductal metaplasia could develop within ...

c-Myc downregulation is required for preacinar to acinar maturation and pancreatic homeostasis

“…Starting at day 1 after birth (P1) until 8 weeks, prior to tumour development, Ela1-Myc mice display progressive acinar dilation, acinoductal metaplasia (ADM) and acinar dysplasia. By 5 months, all mice develop cancer with mixed areas of acinar and ductal differentiation 30 33. Expression of the c-Myc transgene led to a threefold upregulation of total c-Myc mRNA at all stages analysed with reduced levels of endogenous c-Myc mRNA likely resulting from a negative feedback regulation34 (figure 2A).…”

“…The loss of acinar differentiation is often associated with activation of ADM,38 thought to contribute to the development of pancreatic cancer 33. The incomplete acinar differentiation at late embryonic stages raised the question of whether high c-Myc expression provides a permissive genomic context allowing the acquisition of alternative differentiation potentials.…”

Acinar cell plasticity and development of pancreatic ductal adenocarcinoma

“…In addition to the previously discussed molecules, MYC and KLF4 are other factors that are required to initiate the ADM process in mice 70,71 . Moreover, ectopic expression of hepatocyte nuclear factor 6 (HNF6) in mouse or human acinar cells represses acinar genes and upregulates ductal genes 48 .…”

Galectin-1 Drives Pancreatic Carcinogenesis through Stroma Remodeling and Hedgehog Signaling Activation

“…In this study, using Ela-myc mice, a well characterized model of pancreatic cancer (16-18) and Gal1 knockout mice, we define a novel Gal1-driven mechanism controlling desmoplasia in these tumors. Our data show that partial or complete depletion of Gal1 reduces in vivo tumorigenicity, leading to a significant increase in Ela-myc mice survival.…”