Distant Bystander Effect of REIC/DKK3 Gene Therapy Through Immune System Stimulation in Thoracic Malignancies

Anticancer Res. 2017 Jan;37(1):301-307. doi: 10.21873/anticanres.11321.

Abstract

Background: Reduced expression in immortalized cell (REIC)/Dickkoph-3 (DKK3) is a tumor-suppressor gene, and its overexpression by adenovirus vector (Ad-REIC) exhibits a remarkable therapeutic effect on various human cancer types through a mechanism triggered by endoplasmic reticulum stress.

Materials and methods: We examined the direct anti-tumor effect of Ad-REIC gene therapy on lung cancer and malignant mesothelioma cell lines in vitro, and the distant bystander effect using immunocompetent mouse allograft models with bilateral flank tumors.

Results: Ad-REIC treatment showed antitumor effect in many lung cancer and malignant mesothelioma cell lines in vitro. In an in vivo model, Ad-REIC treatment inhibited the growth not only of directly treated tumors but also of distant untreated tumors. By immunohistochemical analysis, infiltration of T-cells and natural killer (NK) cells and expression of the major histocompatibility complex (MHC) class I molecules were observed in bilateral tumors.

Conclusion: Ad-REIC treatment not only had a direct antitumor effect but also an indirect bystander effect through stimulation of the immune system.

Keywords: REIC/DKK3; bystander effect; gene therapy; lung cancer; mesothelioma.

MeSH terms

  • Adenoviridae / genetics
  • Animals
  • Bystander Effect*
  • Carcinoma, Non-Small-Cell Lung / immunology
  • Carcinoma, Non-Small-Cell Lung / therapy
  • Cell Line, Tumor
  • Chemokines
  • Female
  • Genetic Therapy*
  • Genetic Vectors
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Killer Cells, Natural / immunology
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / therapy*
  • Mesothelioma / immunology
  • Mesothelioma / therapy
  • Mice, Inbred BALB C
  • T-Lymphocytes / immunology

Substances

  • Chemokines
  • DKK3 protein, human
  • Intercellular Signaling Peptides and Proteins

Supplementary concepts

  • Mesothelioma, Malignant