Chenodeoxycholic acid stimulates the progression of human esophageal cancer cells: A possible mechanism of angiogenesis in patients with esophageal cancer.
Bile acids are known to promote the growth of gastrointestinal cancer. However, the underlying mechanism remains unclear. We examined whether bile acids induce tumor growth via the cyclooxygenase (COX)-2 angiogenic pathway. In vitro, esophageal squamous cell carcinoma (ESCC) cells and esophageal adenocarcinoma cells were studied. Production of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) in response to treatment with chenodeoxycholic acid (CDCA) was assessed by enzyme-linked immunosorbent assay (ELISA). COX-2 protein and VEGF protein were measured by immunoblot analysis, and COX-2 activity was measured by ELISA. In vivo, CDCA was administered to ESCC cell-bearing mice. Tumor tissues were analyzed immunohistochemically, and microvessel density was evaluated. Clinically, 134 patients with ESCC who underwent esophagectomy were studied. In vitro, CDCA induced the production of PGE2 and VEGF in dose- and time-dependent manners, and these effects were attenuated by a selective COX-2 inhibitor, mitogen-activated protein kinases inhibitor, or epidermal growth factor receptor inhibitor. CDCA-induced COX-2 in the cell lysate increased the secretion of VEGF into the culture medium. In vivo, CDCA markedly enhanced tumor growth and increased vascularization. Clinically, patients whose tumors expressed both COX-2 and VEGF had poor outcomes. Our results suggest that bile acids, important constituents of duodenal fluid, stimulate the development of human esophageal cancer by promoting angiogenesis via the COX-2 pathway.
Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Toshiya
T
Soma
Junichi
J
Kaganoi
Atsushi
A
Kawabe
Kan
K
Kondo
Shigeru
S
Tsunoda
Masayuki
M
Imamura
Yutaka
Y
Shimada
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000096:biosynthesis; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
D015850:Interleukin-6; D042461:Vascular Endothelial Growth Factor A; D002635:Chenodeoxycholic Acid; D051546:Cyclooxygenase 2; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D015232:Dinoprostone