Monocyte chemoattractant protein-1 gene delivery enhances antitumor effects of herpes simplex virus thymidine kinase/ganciclovir system in a model of colon cancer

Abstract

Suicide gene therapy using the herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV) system is a well-characterized tool for cancer gene therapy; however, it does not yet exhibit sufficient efficacy to cure patients of malignancies. We have reported that adenovirally delivered monocyte chemoattractant protein (MCP)-1 augmented the antitumor effects of the HSV-tk/GCV system in an athymic nude mouse model. The current study, which uses an immunocompetent mouse model of colon cancer, was designed to evaluate the antitumor effects of MCP-1 gene delivery in conjunction with this suicide gene therapy system. Subcutaneous tumor foci were directly transduced with both recombinant adenoviruses (rAds) expressing an HSV-tk gene and either of the MCP-1, CD80 and LacZ genes, followed by GCV administration. The growth of tumors was markedly suppressed by codelivery of HSV-tk and MCP-1 genes, which was exclusively associated with the recruitment of monocytes/macrophages, T helper 1 (Th1) cytokine gene expression and cytotoxic activity of the splenocytes. Furthermore, the antitumor effects were more efficient than that obtained by the combination of HSV-tk and CD80 genes. These results suggest an immunomodulatory effect of MCP-1 in the context of suicide gene therapy of colon cancer via orchestration of innate and acquired immune responses.

Tumor Cell-Microenvironment Interaction Models Coupled with Clinical Validation Reveal CCL2 and SNCG as Two Predictors of Colorectal Cancer Hepatic Metastasis

“…In one hand, CCL2 can potentiate both the innate and acquired immune responses that inhibit tumor growth through recruiting immune cells to enter the tumors and enhance contact-dependent cytolysis of tumor cells (33)(34)(35). On other hand, CCL2 induces macrophage accumulation and cyclooxygenase-2 expression promoting inflammation in colorectal adenoma epithelium, which has been reported to promote tumor progression in autocrine and paracrine fashions (36)(37)(38)(39).…”

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

“…6 We further demonstrated that the antitumor effects depended on the activation of macrophages. 4,5 The adenovirus-specific spatial and temporal expression pattern may result in the production of the transgene for a limited time.…”

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“…5fluorocytosinewas administered into the peritoneal cavity. All mice in the control groups had tumour progression, but tumour growth was significantly inhibited in the treated mice 73 . Chemo-gene and radiation-gene therapies are the combinations of gene therapy with chemotherapy or radiation therapy respectively.…”