From the AGA Journals

Loss of pancreatic E-cadherin contributes to carcinogenesis

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Loss of pancreatic E-cadherin contributes to carcinogenesis

E-cadherins have remained an enigma in cancer biology. Initially thought to be modulators of organism growth, studies in the past several years have established their role in tumor growth and metastasis. Cadherins are a large family of glycoproteins that mediate specific cell-cell adhesion in a calcium-dependent manner. Among this family, E-cadherins were among the first ones to be discovered almost 50 years back. During embryonic development, the spatiotemporal regulation of E-cadherin regulates cell migration and morphogenesis. In malignant cells, loss of E-cadherin leads to metastasis.
This has spurred studying of E-cadherin as a tumor suppressor. Loss of E-cadherin–mediated cell adhesion often correlates with loss of epithelial morphology and acquisition of metastatic properties. In the pancreas specific context as described by Kaneta et al, loss of E-cadherin leads to loss of acinar cells, elevated serum amylase accompanied with increased inflammation, showing a pancreatitis like phenotype. In the presence of activated oncogenic K-Ras, however, deletion of E-cadherin showed abundant desmoplasia resembling aggressive tumors in the early postnatal stage.

This is also reflected in the patient population. Studies have shown that 43% of the pancreatic adenocarcinomas analyzed had partial or complete loss of E-cadherin expression. Patients with a complete loss of this protein showed ~5.5 months median survival whereas those with partial loss had a survival of 12.7 months, indicating that loss of E-cadherin had a trend toward correlating with poor outcome (Modern Pathol. 2011;24:1237-47). Similarly, Epithelial-mesenchymal transition orchestrated by loss of E-cadherin has been shown to be a driver of tumor initiation (Nat Rev Cancer. 2013;13:97-110). Thus, the study by Kaneta et al. demonstrating the loss of E-cadherin is a step forward in understanding the role of this protein in light of not only pancreatic carcinogenesis but pancreatic pathology in general.

Sulagna Banerjee, PhD is associate professor, department of surgery, University of Miami. She is a consultant with Minneamrita Therapeutics LLC.


 

FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY

Loss of pancreatic E-cadherin may interfere with normal growth and maintenance of the pancreas while contributing to multiple pathological processes, based on evidence from mouse models.

In the presence of an oncogene, E-cadherin may play a pivotal role in pancreatic tumor formation, according to lead author Yoshihiro Kaneta, of Yokohama (Japan) City University in Japan, and colleagues. These findings could lead to new treatment strategies for patients with pancreatic cancer who lack E-cadherin, they noted.

Previous studies have shown that E-cadherin is involved in tissue homeostasis, although exact mechanisms vary by organ, and have remained unclear in the pancreas, the investigators explained in Cellular and Molecular Gastroenterology and Hepatology.

According to the investigators, E-cadherin expression is up-regulated in chemically induced acute pancreatitis, while in chronic pancreatitis, which is associated with an increased risk of pancreatic adenocarcinoma, E-cadherin expression is either low or absent. Other research has pointed to a link between dysregulated E-cadherin expression and cancer progression, with a loss of E-cadherin implicated in development of diffuse-type gastric cancer; however, evidence of a similar process in pancreatic cancer has not been reported, the investigators wrote.

To determine the role of E-cadherin in pancreatic function and tumor development, the investigators conducted experiments with knockout mice lacking pancreatic E-cadherin.

For the first 2 days after birth, knockout mice were similar both phenotypically and histologically to control mice. But over time, differences became apparent. Starting at day 3, control mice were comparatively larger than knockout mice, and by day 12, knockout mice began to die, with none surviving beyond day 28. Starting at day 6, histologic changes were observed in the pancreatic tissue of knockout mice, specifically, with aberrant epithelial tubules that resembled acinar-to-ductal metaplasia (ADM). Moreover, acinar cells were dilated and lacked surface expression of E-cadherin.

“These results suggested that E-cadherin was not required for pancreatic development at the embryonic stage but was required for growth and maintenance of the pancreas in the postnatal stage,” the investigators wrote.

Additional analyses revealed further differences between pancreatic tissue from knockout mice and control mice. A variety of aberrant processes were observed in knockout mice, including replacement of acini with alpha-smooth muscle actin–positive fibrotic cells, an increased number of ductal-like structures, a reduced number of amylase-positive cells, and an increased number of cytokeratin-19–positive and CD45-positive cells. Messenger RNA expression levels were also abnormal in pancreatic tissue of knockout mice, with shifts across a variety of cytokines and chemokines. These trends toward inflammation and fibrosis were described by the investigators as pancreatitis-like changes, although they observed no pancreatic intraepithelial neoplasia (PanIN), which is a precursor of pancreatic ductal adenocarcinoma.

In the presence of an oncogene, however, loss of pancreatic E-cadherin did contribute to the development of pancreatic cancer. In the presence of a Kras mutation, knockout mice began to develop PanINs and ADMs as soon as day 4. By day 7, PanINs stained partially positive for E-cadherin, showed structural abnormalities, and exhibited decreased amylase and increased cytokeratin-19. Within a similar time frame, pancreatic tissue began to adhere to the intestine, resulting in ascites and death. No metastases to other organs were observed.

Further testing showed that pancreatic stroma contained tumor cells. While DNA double-strand breaks were scarce, the investigators pointed out that chemotherapy and radiotherapy are typically responsible for DNA damage. Based on previous research linking stem cell conversion with Kras-acquired resistance, the investigators tested markers of stem cells in pancreatic tissue of knockout mice, finding that CD44, KLF4, and KLF5 were increased.

“These observations suggested that loss of E-cadherin provided tumorigenic activity to pancreatic cells and contributed to PanIN formation,” the investigators wrote.

Additional experiments with cell lines supported the above results and added further insight. Of clinical relevance, the investigators suggested that targeting Hdac1 with histone deacetylase inhibitors may be a viable treatment strategy for patients lacking pancreatic E-cadherin.

The study was funded by the Japan Society for the Promotion of Science KAKENHI grant JP17K09465 and the Yokohama City University Kamome project. The investigators declared no conflicts of interest.

SOURCE: Kaneta Y et al. Cell Mol Gastroenterol Hepatol. 2019 Sep 14. doi: 10.1016/j.jcmgh.2019.09.001.

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