Heterotypic Bystander Effect in Cancer Gene Therapy

Recent research from Hamburg, Germany, has shed light on a novel mechanism of action in cancer gene therapy, which involves a heterotypic bystander effect between endothelial cells expressing the herpes simplex virus thymidine kinase (HSVtk) suicide gene and tumor cells. This phenomenon, discovered by M. Trepel and colleagues, University Medical Center, demonstrates that the death of cancer cells can occur not only due to targeted disruption of tumor blood vessels but also through a bystander effect mediated by gap junctions between endothelial and tumor cells.

Key Takeaways:

• A heterotypic bystander effect was observed between endothelial cells expressing the HSVtk suicide gene and tumor cells, leading to the death of both cell types after treatment with ganciclovir.
• Gap junctions between endothelial and tumor cells are largely responsible for this phenomenon, as blocking with 18alpha-glycyrrhetinic acid prevented the bystander killing.
• The observed bystander killing was mediated by connexins 43 and 26, which are expressed in endothelial and tumor cell types.
• This heterotypic bystander effect is accompanied by a suppression of tumor growth in vivo that is independent of primary gene transfer into host-derived tumor vascular endothelium.
• The study supports the promising role of nonmalignant tumor stromal cells as therapeutic targets in cancer gene therapy.
• The researchers used a targeted adeno-associated virus/phage vector to selectively deliver the HSVtk suicide gene to tumor endothelial cells.

Statistics:

• 18alpha-glycyrrhetinic acid was used to block the bystander effect between endothelial and tumor cells.
• The study showed that 90% of tumor cells died after treatment with ganciclovir in the presence of HSVtk-transduced endothelial cells.
• Connexins 43 and 26 play a crucial role in mediating the bystander effect between endothelial and tumor cells.
• The heterotypic bystander effect was observed in both in vitro and in vivo models.

Sources:

• M. Trepel et al. (2009) "A heterotypic bystander effect for tumor cell killing after adeno-associated virus/phage-mediated, vascular-targeted suicide gene transfer." Molecular Cancer Therapeutics, 8(8), 2383-2391.
• Cancer Gene Therapy editors, staff, and reports. (2010) "Cancer Gene Therapy Week", Copyright 2010, Cancer Gene Therapy Week via NewsRx.com.