In vivo-restricted and reversible malignancy induced by human herpesvirus-8 KSHV: a cell and animal model of virally induced Kaposi's sarcoma.
Transfection of a Kaposi's sarcoma (KS) herpesvirus (KSHV) Bacterial Artificial Chromosome (KSHVBac36) into mouse bone marrow endothelial-lineage cells generates a cell (mECK36) that forms KS-like tumors in mice. mECK36 expressed most KSHV genes and were angiogenic, but they didn't form colonies in soft agar. In nude mice, mECK36 formed KSHV-harboring vascularized spindle cell sarcomas that were LANA+/podoplanin+, overexpressed VEGF and Angiopoietin ligands and receptors, and displayed KSHV and host transcriptomes reminiscent of KS. mECK36 that lost the KSHV episome reverted to nontumorigenicity. siRNA suppression of KSHV vGPCR, an angiogenic gene upregulated in mECK36 tumors, inhibited angiogenicity and tumorigenicity. These results show that KSHV malignancy is in vivo growth restricted and reversible, defining mECK36 as a biologically sensitive animal model of KSHV-dependent KS.
Mutlu
Agata D'Agostino
AD
Laboratory of Viral Oncogenesis, Division of Hematology-Oncology, Department of Medicine, Weill Medical College of Cornell University, New York, NY 10021, USA.
Cavallin
Lucas E
LE
Vincent
Loïc
L
Chiozzini
Chiara
C
Eroles
Pilar
P
Duran
Elda M
EM
Asgari
Zahra
Z
Hooper
Andrea T
AT
La Perle
Krista M D
KM
Hilsher
Chelsey
C
Gao
Shou-Jiang
SJ
Dittmer
Dirk P
DP
Rafii
Shahin
S
Mesri
Enrique A
EA
D042682:Angiopoietins / Q000378:metabolism; D000818:Animals; D000956:Antigens, Viral / Q000378:metabolism; D001854:Bone Marrow Cells / Q000473:pathology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D002472:Cell Transformation, Viral; D002478:Cells, Cultured; D022202:Chromosomes, Artificial, Bacterial; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000473:pathology; D019288:Herpesvirus 8, Human; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic; D009687:Nuclear Proteins / Q000378:metabolism; D012514:Sarcoma, Kaposi / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000098853:Podoplanin
D042682:Angiopoietins; D000956:Antigens, Viral; D008562:Membrane Glycoproteins; D009687:Nuclear Proteins; D042461:Vascular Endothelial Growth Factor A; C490441:Pdpn protein, mouse; D000098853:Podoplanin; C109540:latency-associated nuclear antigen; C467480:vascular endothelial growth factor A, mouse