Prevention of intrahepatic metastasis of liver cancer by suicide gene therapy and chemokine ligand 2/monocyte chemoattractant protein‐1 delivery in mice

Abstract

Background The prognosis of patients with hepatocellular carcinoma (HCC) remains poor, largely as a result of intrahepatic metastasis. Using a mouse model of intrahepatic metastasis, we investigated whether chemokine ligand 2/monocyte chemoattractant protein‐1 (CCL2/MCP‐1) could potentiate the antitumor effects of the herpes simplex virus thymidine kinase/ganciclovir (HSV‐tk/GCV) system. Methods Mouse hepatoma cells infected with recombinant adenovirus vectors expressing HSV‐tk, CCL2/MCP‐1 and LacZ at multiplicities of infection of Ad‐tk/Ad‐MCP1 = 3/0.03 (T/MLow), 3/3 (T/MHigh) and Ad‐tk/Ad‐LacZ = 3/3 (T/L) were injected into BALB/c mice. Results Intrahepatic tumor growth was significantly lower in T/MLow mice. By contrast, no tumor suppression was observed in T/MHigh mice. The tumor‐specific cytolytic activities of splenocytes from T/MLow and T/MHigh mice were comparable. Immunohistochemical analysis of liver tissues showed similar infiltration by Mac‐1+ and T cells in these animals, whereas the proportions of classical activated (M1) monocytes/macrophages were significantly higher in T/MLow mice. In addition, interleukin‐12 production was elevated in these tissues. Vascular endothelial growth factor‐A expression and CD31+ microvessels were increased in T/MHigh mice. Conclusions Collectively, these results demonstrate that an adequate amount of CCL2/MCP‐1, together with the HSV‐tk/GCV system, may induce T helper 1‐polarized antitumor effects without inducing tumor angiogenesis in the microenvironment of intrahepatic HCC progression. Copyright © 2010 John Wiley & Sons, Ltd.

Membrane-bound form of monocyte chemoattractant protein-1 enhances antitumor effects of suicide gene therapy in a model of hepatocellular carcinoma

“…4 Consistently, we further demonstrated that the delivery of an optimal amount of rAd expressing MCP-1 enhanced the antitumor effects of the HSV-tk/GCV system in a model of HCC. 16,18 Infection with Ad-mMCP-1 can sustain MCP-1 expression in tumor tissues more efficiently than that with Ad-sMCP-1 as evidenced by an immunohistochemical analysis on the infected tumor tissues. The sustained MCP-1 expression can potentiate suicide gene therapy more efficiently.…”

“…The systemic administration of recombinant MCP-1 rather enhanced tumor growth ( Figure 4b). As we previously demonstrated that MCP-1 can promote tumor growth in a context-dependent manner by recruiting macrophages, which can secrete an angiogenic factor, the vascular endothelial growth factor, 16,18 systemic MCP-1 injection may promote tumor growth by its pro-angiogenic activities.…”

Chemokines, chemokine receptors and the gastrointestinal system

“…In a model of HCC, coupling adenovirus-based CCL2 and the thymidine kinase/ganciclovir expression was shown to prevent intrahepatic metastasis in vivo. This combination was also shown to induce an innate immune response involving monocytes/macrophages and NK cells, leading to prolongation of anti-metastatic effects [144][145][146] . CCL2 was also identified by Chen et al [147] as a potential target for development of future HCC treatment.…”

“…Application to prevent metastasis, application to prevent HCC by deactivating AKT pathway [144][145][146][147] …”

Gene Directed Enzyme-Prodrug Therapy

“…In vivo antitumor activity of the HSV-TK/GCV system has been demonstrated in several animal tumor models, including glioma (12,13), leukemia (14), bladder cancer (15), liver cancer (16), colon adenocarcinoma (17,18), and oral cancer (19). The encouraging results obtained in the preclinical studies led to its application in a number of clinical trials against different types of cancers (20)(21)(22)(23)(24)(25).…”