title: Oncolytic herpes simplex virus kills stem-like tumor-initiating colon cancer cells.
abstract: Stem-like tumor-initiating cells (TICs) are implicated in cancer progression and recurrence, and can be identified by sphere-formation and tumorigenicity assays. Oncolytic viruses infect, replicate in, and kill a variety of cancer cells. In this study, we seek proof of principle that TICs are susceptible to viral infection. HCT8 human colon cancer cells were subjected to serum-free culture to generate TIC tumorspheres. Parent cells and TICs were infected with HSV-1 subtype NV1066. Cytotoxicity, viral replication, and Akt1 expression were assessed. TIC tumorigenicity was confirmed and NV1066 efficacy was assessed in vivo. NV1066 infection was highly cytotoxic to both parent HCT8 cells and TICs. In both populations, cell-kill of >80% was achieved within 3 days of infection at a multiplicity of infection (MOI) of 1.0. However, the parent cells required 2-log greater viral replication to achieve the same cytotoxicity. TICs overexpressed Akt1 in vitro and formed flank tumors from as little as 100 cells, growing earlier, faster, larger, and with greater histologic atypia than tumors from parent cells. Treatment of TIC-induced tumors with NV1066 yielded tumor regression and slowed tumor growth. We conclude that colon TICs are selected for by serum-free culture, overexpress Akt1, and are susceptible to oncolytic viral infection.
authors.affiliation: Department of Surgery, City of Hope , Duarte, California, USA.
authors.forename: Susanne G
authors.initials: SG
authors.lastname: Warner
authors.affiliation: Department of Radiology, Memorial Sloan-Kettering Cancer Center , New York, New York, USA.
authors.forename: Dana
authors.initials: D
authors.lastname: Haddad
authors.affiliation: Department of Surgery Fox Chase Cancer Center , Philadelphia, Pennsylvania, USA.
authors.forename: Joyce
authors.initials: J
authors.lastname: Au
authors.affiliation: Department of Surgery University of Texas Medical Branch , Galveston, Texas, USA.
authors.forename: Joshua S
authors.initials: JS
authors.lastname: Carson
authors.affiliation: Department of Surgery, City of Hope , Duarte, California, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: O'Leary
authors.affiliation: Thomas Jefferson College of Medicine , Philadelphia, Pennsylvania, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Lewis
authors.affiliation: Laboratory of Comparative Pathology and the Genetically Engineered Mouse Phenotyping Service, Memorial Sloan-Kettering Cancer Center , New York, New York, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Monette
authors.affiliation: Department of Surgery, City of Hope , Duarte, California, USA.
authors.forename: Yuman
authors.initials: Y
authors.lastname: Fong