Interleukin-10 gene transfer to peritoneal mesothelial cells suppresses peritoneal dissemination of gastric cancer cells due to a persistently high concentration in the peritoneal cavity

Abstract

Interleukin (IL)-10 has potent biological properties including an inhibitory action on the proliferation and metastasis of various cancer cells. However, it is difficult to maintain a high concentration of this cytokine as it has a short half life. In this study, we evaluated whether peritoneal mesothelial cells (PMCs) could be suitable for maintaining a high concentration of IL-10 using adenoviral gene transfer. We also evaluated the therapeutic effects of an intraperitoneal injection with adenoviral vector containing mouse IL-10 gene (Ad-mIL-10) using a mouse peritoneal dissemination model of MKN45 gastric cancer cells. We demonstrated that in vitro transfection efficiency of a recombinant adenovirus containing the bacterial b-galactosidase gene (Ad-LacZ) was approximately 10-fold higher for primarily isolated PMCs than MKN45. The entire peritoneum was transfected until 3 weeks after an intraperitoneal Ad-LacZ injection. Ad-mIL-10 treatment increased intraperitoneal IL-10 levels until 3 weeks after treatment, and then significantly inhibited peritoneal cancer growth by inhibiting angiogenesis. This treatment also improved cachexia and prolonged mice survival. We thus concluded that IL-10 gene transfer in PMCs could be a new strategy for the prevention of peritoneal dissemination of gastric cancer due to the resulting persistently high IL-10 concentration in the peritoneal cavity.

IL-10 regulation of macrophage VEGF production is dependent on macrophage polarisation and hypoxia

“…We show here, utilising an in vitro simulation to generate M1 and M2 macrophage phenotypes, that there is a phenotype dependent response to IL-10 in terms of VEGF production. This data is important as it supports the increasing challenges to the traditional paradigm for the role of M1 (NOS2 + cells) and M2 (arginase-1 + cells) phenotypes in pathological angiogenesis and moreover, the potential utilisation of IL-10 as an anti-angiogenic therapy (Silvestre et al, 2000;Tanaka et al, 2008). This current data shows that IL-10 is able to inhibit M1-stimulated VEGF (LPS/CGS21680-conditioned NOS2 + macrophages) and not M2-stimulated VEGF production (PGE2-conditioned arginase-1 + macrophages).…”

A Vaccinia Virus Armed with Interleukin-10 Is a Promising Therapeutic Agent for Treatment of Murine Pancreatic Cancer

“…Unfortunately, the half-life of IL10 is only approximately 20 minutes and it is difficult to maintain a high concentration after administration of recombinant protein (27). Nonreplicating adenovirus-mediated delivery has shown promise in retaining therapeutically effective levels of IL10 in vivo (28). Given its pleiotropic effects, IL10 may be an effective agent with which to improve the antitumor potential of vaccinia virus.…”

Gene Therapy for Gastric Diseases

“…On the other hand, Tanaka et al demonstrated that intraperitoneal IL-10 gene transfer to the peritoneal mesothelium using an adenoviral vector suppressed peritoneal dissemination of MKN45 gastric cancer cells [126]. However, IL-10 is an -17-immunosuppressive cytokine [127,128].…”