*3.1. Tumor Targeting*

Although OVs have tumor tropism based on some overexpressed receptors and adhesion molecules on the tumor cells, the tumor tropism of wild OVs is not enough. GMOVs can express receptors with a high affinity for TAAs. For instance, insertion of singlechain antibodies (scAb) against human epidermal growth factor receptor (HER)-2, epithelial cell adhesion molecule (EpCAM), and carcinoembryonic antigen (CEA) increases the specificity of OVs to tumors [128–130]. Insertion of sequences such as the arginine-glycineaspartate (RGD) motif or specific domain from AdV3 and AdV35 to AdV5, makes AdV5 specific for integrins, desmoglein-2, and CD46, which are overexpressed in tumors [131,132]. VSV expressing HIV-derived glycoprotein (gp)-160 is a specific VSV against leukemia and T lymphomas [133].

Defects in the IFN-I antiviral response, lack of tumor suppressor genes such as the retinoblastoma (Rb), and increased Ras signaling in tumor cells lead to the specific proliferation of OVs in tumor cells [134]. Insertion of tumor-specific promoters such as prostatespecific antigen (PSA) and human telomerase reverse transcriptase (hTERT) promoters, which are highly expressed in tumor cells, causes specific expression of viral genes in tumor cells [135,136]. Some micro-RNAs (miRNAs) are overexpressed in healthy cells while they are at negligible levels in tumor cells. Hence, targeting these miRNAs by miRNA-targeting sequences (miRNA-TS) destroys viral RNA in normal cells. Low expression of miRNA-TS targets in tumor cells causes viral RNAs to remain and replicate in tumor cells [137].
