Journal
CANCER SCIENCE
Volume 113, Issue 10, Pages 3579-3592Publisher
WILEY
DOI: 10.1111/cas.15495
Keywords
cancer-associated fibroblasts; prostaglandin E-2; tumor microenvironment
Categories
Funding
- Japan Science and Technology Agency [JPMJFR200H]
- Japan Society for the Promotion of Science [20H03531, 20K08985, 20K09038, 21K19535]
- Naito Foundation
- Shinnihon Foundation of Advanced Medical Treatment Research
Ask authors/readers for more resources
This study found that downregulation of 15-PGDH in the tumor microenvironment enhances the accumulation of PGE2 and promotes angiogenesis and CAF expansion in fibrotic tumors.
The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E-2 (PGE2). Although inhibition of 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is reported to lead to PGE2 accumulation, the role of 15-PGDH expression in the tumor microenvironment remains unclear. We utilized Panc02 murine pancreatic cancer cells for orthotopic transplantation into wild-type and 15-pgdh(+/-) mice and found that 15-pgdh depletion in the tumor microenvironment leads to enhanced tumorigenesis accompanied by an increase in cancer-associated fibroblasts (CAFs) and the promotion of fibrosis. The fibrotic tumor microenvironment is widely considered to be hypovascular; however, we found that the angiogenesis level is maintained in 15-pgdh(+/-) mice, and these changes were also observed in a genetically engineered PDAC mouse model. Further confirmation revealed that fibroblast growth factor 1 (FGF1) is secreted by pancreatic cancer cells after PGE2 stimulation, consequently promoting CAF proliferation and vascular endothelial growth factor A (VEGFA) expression in the tumor microenvironment. Finally, in 15-pgdh(+/-)Acta2-TK mice, depletion of fibroblasts inhibited angiogenesis and cancer cell viability in orthotopically transplanted tumors. These findings highlighted the role of 15-pgdh downregulation in enhancing PGE2 accumulation in the pancreatic tumor microenvironment and in subsequently maintaining the angiogenesis level in fibrotic tumors along with CAF expansion.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available