Osaka, Japan - Chronic inflammation of the pancreas is a debilitating disease with poorly understood causative factors. Now, researchers at Osaka University have identified the disturbed molecular pathways and revealed the underlying mechanisms that may inform an effective and much-needed therapeutic strategy.
The pancreas is an important organ with a dual role in digestion and the production of various hormones including insulin and glucagon that fine-tune blood sugar levels.
Chronic pancreatitis (CP) is characterized by inflammation of the gland causing shrinkage, replacement of glandular elements with fibrous tissue (fibrosis) and loss of function. Patients suffer abdominal symptoms, poor digestion and consequent nutritional disorders. They can also develop diabetes mellitus and, in some cases, even pancreatic cancer. The roles of alcohol abuse and digestive enzyme gene mutations in triggering CP are known, yet the underlying molecular mechanisms remain unclear.
The research team's suspicions fell on two molecular channels of cellular communication, called the PI3K and the Hippo signaling pathways, that have been implicated in the development of pancreatic cancer. Takeshi Tamura, co-first author, explains the research strategy: "In experimental mouse models of CP, we showed that the expression of two molecular components of the PI3K and Hippo signaling pathways, PTEN and SAV1, is decreased in the pancreatic tissues. Additionally, we generated mice that lack pancreas-specific genes for these two molecules and observed that they spontaneously developed CP."
Co-first author Takahiro Kodama elaborates: "In laboratory experiments, we were able to establish the pivotal role of Connective Tissue Growth Factor (CTGF) in the development of CP. Inhibition of PTEN and SAV1 increases CTGF which, in turn, induces a pathological transformation of glandular cell types called acinar-to-ductal metaplasia (ADM). It also activates pancreatic stellate cells and macrophages, both of which promote fibrosis in CP." These are hallmarks of chronic inflammation in the pancreas with a potential to trigger carcinogenesis. Furthermore, the researchers were able to show that CTGF inhibition in animal models alleviated the inflammation, fibrosis and ADM formation of CP, and they could confirm these experimental findings by analysis of human pancreatic tissue.
These findings elaborate the molecular mechanisms that underpin the development and progression of chronic inflammation in the pancreas, suggesting that CTGF may be a fruitful new therapeutic target in the quest for effective therapy against chronic pancreatitis.
The article, "Dysregulation of PI3K and hippo signaling pathways synergistically induces chronic pancreatitis via Ctgf upregulation" was published in the Journal of Clinical Investigation at DOI: https://doi.org/10.1172/JCI143414
About Osaka University
Osaka University was founded in 1931 as one of the seven imperial universities of Japan and is now one of Japan's leading comprehensive universities with a broad disciplinary spectrum. This strength is coupled with a singular drive for innovation that extends throughout the scientific process, from fundamental research to the creation of applied technology with positive economic impacts. Its commitment to innovation has been recognized in Japan and around the world, being named Japan's most innovative university in 2015 (Reuters 2015 Top 100) and one of the most innovative institutions in the world in 2017 (Innovative Universities and the Nature Index Innovation 2017). Now, Osaka University is leveraging its role as a Designated National University Corporation selected by the Ministry of Education, Culture, Sports, Science and Technology to contribute to innovation for human welfare, sustainable development of society, and social transformation.
Journal of Clinical Investigation