title: Doxorubicin-enriched, ALDH(br) mouse breast cancer stem cells are treatable to oncolytic herpes simplex virus type 1.
abstract: BACKGROUND
  The primary objective of this study was to test whether oncolytic herpes simplex virus type 1 (HSV1) could eradicate chemoresistant cancer stem cells (CSCs).
  
  
  METHODS
  The fluorescent aldefluor reagent-based technique was used to identify and isolate ALDH(br) cells as CSCs from the 4T1 murine breast cancer cell line. The presence of ALDH(br) 4T1 cells was also examined in 4T1 breast cancer transplanted in immune-competent syngeneic mice.
  
  
  RESULTS
  Compared with ALDH(lo) cells, ALDH(br) cells had a markedly higher ability to form tumor spheres in vitro and a higher tumorigenic potential in vivo. ALDH(br) cells also exhibited increased doxorubicin resistance in vitro, which correlated with a selective increase in the percentage of ALDH(br) cells after doxorubicin treatment and an increased expression of P-glycoprotein (P-gp), a known chemoresistance factor. In contrast, oncolytic HSV1 was able to kill ALDH(br) cells in vitro and even more markedly in vivo. Furthermore, in in vivo studies, systemic administration of doxorubicin followed by intratumoral injection of oncolytic HSV1 resulted in much more significant suppression of tumor growth with increased median survival period compared with each treatment given alone (p<0.05). Though more CD8(+) T lymphocytes were induced by oncolytic HSV1, no significant specific T cell response against CSCs was detected in vivo.
  
  
  CONCLUSIONS
  These results suggested that the use of oncolytic HSV1 following doxorubicin treatment may help eradicate residual chemoresistant CSCs in vivo.
authors.affiliation: Department of Immunology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100021, China.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Zhuang
authors.forename: Wen
authors.initials: W
authors.lastname: Zhang
authors.forename: Yatong
authors.initials: Y
authors.lastname: Chen
authors.forename: Xiangping
authors.initials: X
authors.lastname: Han
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Yu
authors.initials: Y
authors.lastname: Zhang
authors.forename: Youhui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuren
authors.initials: S
authors.lastname: Zhang
authors.forename: Binlei
authors.initials: B
authors.lastname: Liu
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000096:biosynthesis; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology / Q000628:therapy*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D005434:Flow Cytometry; D018259:Herpesvirus 1, Human; D051379:Mice; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000201:enzymology; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses
chemical_list: D000970:Antineoplastic Agents; D004317:Doxorubicin; D000444:Aldehyde Dehydrogenase