A high level of prostaglandin E2 (PGE2) in the portal vein suppresses liver-associated immunity and promotes liver metastases

Abstract

Prostaglandin E2 (PGE2) is generally accepted to be an immunosuppressant produced by cancer cells and their surrounding macrophages. Although several investigators have reported detecting high concentrations of PGE2 in the portal veins of patients with colorectal cancer, the relationship between these high concentrations of PGE2 in the portal vein and liver-associated immunity remains unclear. In this study, we attempted to determine if the portal administration of PGE2 suppresses the immune function of the liver in a rat model. Donryu rats were administered PGE2 via the portal vein for 7 days, following which the cytotoxic activity of hepatic sinusoidal lymphocytes (HSL) against natural killer (NK)-sensitive YAC-1 and rat syngeneic AH60C tumor cells was assessed. Purified HSL are spontaneously cytolytic; however, the continuous administration of PGE2 dramatically suppressed the cytotoxic activity of HSLs in a dose-dependent fashion. Flow cytometric analysis showed that the large granular lymphocyte (LGL) fraction, hepatic natural killer (pit) cells, and CD4-8+ killer/suppressor T cells were mainly reduced in number in the HSLs following PGE2 infusion. In this rat AH60C metastasis model, the continuous administration of PGE2 increased the number and size of metastatic tumor nodules in the liver, suggesting that high concentrations of PGE2 in the portal vein suppress liver-associated immunity and promote the formation of hepatic metastasis.

Targeting Cyclooxygenase-2 in Hematological Malignancies: Rationale and Promise

“…This provides therapeutic potential for the use of Cox-2 selective inhibitors, which could enhance cell-mediated cytotoxic immunity to tumors of hematological origin. PGE 2 administered in vivo reduced NK cell and CTL numbers, as well as cytotoxic activity, promoting further tumor growth and metastasis [102,104]. NK cell cytolytic activity was attenuated against squamous cell carcinoma capable of producing PGE 2 , and indomethacin restored killing ability [103].…”

Lipids changes in liver cancer

“…It is probable that this effect of linoleic acid is mediated through prostaglandin E2 (PGE2). Portal PGE2 had also been shown to suppress liver-associated immunity, and promote the formation of hepatic metastases (Okuno et al, 1995). Albumin carries fatty acids and is suggested to act as an antioxidant; polyunsaturated fatty acids (linoleic, arachidonic, eicosapentaenoic and docosahexaenoic acids) inhibit growth of human hepatoma cells at low albumin concentration (0.5%) (Hostmark and Lystad, 1992).…”

Cyclooxygenases and lipoxygenases as potential targets for treatment of pancreatic cancer

“…Since the significant upregulation of the COX-2 enzyme has been reported by multiple studies, it is reasonable to speculate that pancreatic cancer cells secrete large amounts of PGs such as PGE 2 . The PGE 2 is well known to be a immunosuppressor, decreasing both the natural killer cell and Thelper lymphocyte functions [42]. Therefore, PGE 2 secreted by pancreatic cancer cells would directly block the defense mechanism against cancer and, therefore, promote pancreatic cancer growth [42,43].…”