학술논문
Tumor microenvironmental 15‐PGDH depletion promotes fibrotic tumor formation and angiogenesis in pancreatic cancer
Document Type
Report
Author
Bu, Luke; Yonemura, Atsuko; Yasuda‐Yoshihara, Noriko; Uchihara, Tomoyuki; Ismagulov, Galym; Takasugi, Sanae; Yasuda, Tadahito; Okamoto, Yuya; Kitamura, Fumimasa; Akiyama, Takahiko; Arima, Kota; Itoyama, Rumi; Zhang, Jun; Fu, Lingfeng; Hu, Xichen; Wei, Feng; Arima, Yuichiro; Moroishi, Toshiro; Nishiyama, Koichi; Sheng, Guojun; Mukunoki, Toshifumi; Otani, Jun; Baba, Hideo; Ishimoto, Takatsugu
Source
Cancer Science. October 2022, Vol. 113 Issue 10, p3579, 14 p.
Subject
Language
English
ISSN
1347-9032
Abstract
Abbreviations INTRODUCTION Pancreatic ductal adenocarcinoma (PDAC) is one of the most serious malignant diseases.[sup.1] Despite the development of anticancer treatments in recent decades, PDAC remains the seventh leading cause of [...]
: The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E[sub.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[sup.+/−] 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[sup.+/−] 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[sup.+/−]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.
: The arachidonic acid cascade is a major inflammatory pathway that produces prostaglandin E[sub.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[sup.+/−] 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[sup.+/−] 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[sup.+/−]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.