Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV) closely resembles lung cancer in sheep infected with JSRV
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Date
2006Author
Wooton, Sarah K.
Metzger, Michael J.
Hudkins, Kelly
Alpers, Charles E.
York, Denis
DeMartini, James C.
Miller, A. Dusty
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Background: Jaagsiekte sheep retrovirus (JSRV) causes a lethal lung cancer in sheep and goats. Expression
of the JSRV envelope (Env) protein in mouse lung, by using a replication-defective adeno-associated virus
type 6 (AAV6) vector, induces tumors resembling those seen in sheep. However, the mouse and sheep
tumors have not been carefully compared to determine if Env expression alone in mice can account for
the disease features observed in sheep, or whether additional aspects of virus replication in sheep are
important, such as oncogene activation following retrovirus integration into the host cell genome.
Results: We have generated mouse monoclonal antibodies (Mab) against JSRV Env and have used these
to study mouse and sheep lung tumor histology. These Mab detect Env expression in tumors in sheep
infected with JSRV from around the world with high sensitivity and specificity. Mouse and sheep tumors
consisted mainly of well-differentiated adenomatous foci with little histological evidence of anaplasia, but
at long times after vector exposure some mouse tumors did have a more malignant appearance typical of
adenocarcinoma. In addition to epithelial cell tumors, lungs of three of 29 sheep examined contained
fibroblastic cell masses that expressed Env and appeared to be separate neoplasms. The Mab also stained
nasal adenocarcinoma tissue from one United States sheep, which we show was due to expression of Env
from ovine enzootic nasal tumor virus (ENTV), a virus closely related to JSRV. Systemic administration of
the AAV6 vector encoding JSRV Env to mice produced numerous hepatocellular tumors, and some
hemangiomas and hemangiosarcomas, showing that the Env protein can induce tumors in multiple cell
types.
Conclusion: Lung cancers induced by JSRV infection in sheep and by JSRV Env expression in mice have
similar histologic features and are primarily characterized by adenomatous proliferation of peripheral lung
epithelial cells. Thus it is unnecessary to invoke a role for insertional mutagenesis, gene activation, viral
replication, or expression of other viral gene products in sheep lung tumorigenesis, although these
processes may play a role in other clinically less important sequelae of JSRV infection such as metastasis
observed with variable frequency in sheep.