Journal
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY
Volume 321, Issue 4, Pages G378-G388Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpgi.00120.2021
Keywords
Nrf2; oxidative stress; pancreatic fibrosis; pancreatic stellate cell; stroma
Categories
Funding
- JSPS KAKENHI [19H03631, 20K08300]
- Smoking Research Foundation
- Grants-in-Aid for Scientific Research [20K08300, 19H03631] Funding Source: KAKEN
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Systemic Nrf2 deletion decreases pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model, with pancreatic stellate cells (PSCs) playing a role in this process. Nrf2-deleted PSCs exhibit lower proliferative and migration capacity, and show reduced growth-stimulating effects on pancreatic cancer cells.
It was previously identified that systemic Nrf2 deletion attenuates pancreatic cancer progression in a mutant K-ras/p53-expressing mouse model (KPC mouse). In this study, the type of cell that is responsible for the retarded cancer progression was elucidated. Human pancreatic cancers were first examined, and elevated expression of NRF2-target gene products in a-smooth muscle actin-positive cells was found, suggesting that pancreatic stellate cells (PSCs) are involved in this process. Closer examination of primary cultured PSCs from Nrf2-deleted mice revealed that the cells were less proliferative and retained a lower migration capacity. The conditioned medium of Nrf2-deleted PSCs exhibited reduced growth-stimulating effects in pancreatic cancer cells. KPC mouse-derived pancreatic cancer cells coinjected with wild-type PSCs developed significantly larger subcutaneous tumors in immunodeficient mice than those coinjected with Nrf2-deleted PSCs. These results demonstrate that Nrf2 actively contributes to the function of PSCs to sustain KPC cancer progression, thus, suggesting that Nrf2 inhibition in PSCs may be therapeutically important in pancreatic cancer.
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