Role of tumor invasiveness, the extracellular matrix, and chromatin sequestration in the susceptibility of uveal melanoma to herpes simplex virus type 1.
To better understand determinants of susceptibility/resistance of uveal melanomas to herpes simplex virus type 1 (HSV-1) oncolytic therapy, uveal melanoma cell lines of low (OCM1a) and of high (M619, MUM2B) invasive potential were infected with HSV-1 either in the presence or absence of a laminin-rich extracellular matrix (Matrigel). OCM1a cultures were destroyed faster by HSV-1 than M619 and MUM2B cultures. In the presence of Matrigel, all melanoma cultures demonstrated delayed destruction by HSV-1 relative to Matrigel-free cultures. As sequestration of chromatin is a characteristic feature of highly invasive uveal melanomas that is further increased by exposure to laminin, we explored whether chromatin sequestration could be reversed by HSV-1 infection. HSV-1 infection induced a global reversal of chromatin sequestration in highly invasive uveal melanoma cells. However, this viral effect was first observed only 2h following virus infection and required novel protein synthesis from input viral DNA. These findings suggest that tumor invasiveness, the spatial relationship of tumor cells to laminin and chromatin sequestration are determinants of susceptibility/resistance of melanomas to HSV-1 oncolytic therapy. Furthermore, these findings indicate for the first time that HSV-1 infection is associated with global exposure of normally highly sequestered cellular DNA in malignant cells.
Valyi-Nagy
Klara
K
Department of Pathology, University of Illinois at Chicago, College of Medicine, 840 South Wood Street, Room 110, M/C 847, Chicago, IL 60612, USA.
Folberg
Robert
R
Valyi-Nagy
Tibor
T
Maniotis
Andrew J
AJ
D016923:Cell Death; D002843:Chromatin / Q000378:metabolism*; D003094:Collagen; D004198:Disease Susceptibility; D004338:Drug Combinations; D005109:Extracellular Matrix / Q000502:physiology; D006561:Herpes Simplex / Q000150:complications*; D018259:Herpesvirus 1, Human / Q000472:pathogenicity*; D006801:Humans; D007797:Laminin; D008545:Melanoma / Q000235:genetics / Q000473:pathology / Q000821:virology*; D009361:Neoplasm Invasiveness; D050130:Oncolytic Virotherapy; D011509:Proteoglycans; D014407:Tumor Cells, Cultured; D014604:Uveal Neoplasms / Q000235:genetics / Q000473:pathology / Q000821:virology*; D014774:Virulence
D002843:Chromatin; D004338:Drug Combinations; D007797:Laminin; D011509:Proteoglycans; C059485:matrigel; D003094:Collagen