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Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV) closely resembles lung cancer in sheep infected with JSRV.

Wootton SK, Metzger MJ, Hudkins KL, Alpers CE, York D, DeMartini JC, Miller AD - Retrovirology (2006)

Bottom Line: Jaagsiekte sheep retrovirus (JSRV) causes a lethal lung cancer in sheep and goats.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. swootton@fhcrc.org

ABSTRACT

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.

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Mab staining of mouse and sheep lung tumors. Left panels are from a mouse exposed 2 months previously to an AAV6 vector encoding JSRV Env (ARJenv) [10], and right panels are from sheep 85RS14 (Table 1) that was experimentally infected with JSRV. Sections were stained with the Env Mab C9 and were counterstained with methyl green. Arrow in lower right panel indicates inflammatory  cells that do not stain for Env expression.
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Figure 1: Mab staining of mouse and sheep lung tumors. Left panels are from a mouse exposed 2 months previously to an AAV6 vector encoding JSRV Env (ARJenv) [10], and right panels are from sheep 85RS14 (Table 1) that was experimentally infected with JSRV. Sections were stained with the Env Mab C9 and were counterstained with methyl green. Arrow in lower right panel indicates inflammatory cells that do not stain for Env expression.

Mentions: All eight of the selected Mab brightly stained tumors in histologic sections of lungs from immunodeficient mice exposed to an AAV6 vector that expresses JSRV Env, ARJenv [10], with little to no staining of histologically-normal lung tissue (Fig. 1, left panels; data not shown). Notably, Env expression appears to be required for tumorigenesis in this system, because we never observed masses of epithelial cells (tumors) that did not stain with the Env Mab in sections of lungs from different animals that in total contained over 500 Env+ tumors. Mab clones B3 and C9 were chosen for subsequent studies. These two Mab appear to recognize different epitopes since optimal antigen recognition in histological sections requires an antigen retrieval step for the C9 Mab but not for the B3 Mab. However, both Mab recognize the same cells in serial sections of JSRV Env-induced lung tumors in mice (not shown). Neither Mab recognized histologically-similar lung tumors induced in mice by urethane [18] (samples kindly provided by Alvin M. Malkinson; data not shown). In addition to their histological similarity, both Env- and urethane-induced tumors are primarily composed of cells that express the alveolar type II cell marker surfactant protein C and do not expresses the non-ciliated bronchiolar Clara cell marker CC-10 [10,18]. These data indicate that the Mab are specific for JSRV Env and do not recognize mouse tumor antigens expressed by this type of tumor.


Lung cancer induced in mice by the envelope protein of jaagsiekte sheep retrovirus (JSRV) closely resembles lung cancer in sheep infected with JSRV.

Wootton SK, Metzger MJ, Hudkins KL, Alpers CE, York D, DeMartini JC, Miller AD - Retrovirology (2006)

Mab staining of mouse and sheep lung tumors. Left panels are from a mouse exposed 2 months previously to an AAV6 vector encoding JSRV Env (ARJenv) [10], and right panels are from sheep 85RS14 (Table 1) that was experimentally infected with JSRV. Sections were stained with the Env Mab C9 and were counterstained with methyl green. Arrow in lower right panel indicates inflammatory  cells that do not stain for Env expression.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1764900&req=5

Figure 1: Mab staining of mouse and sheep lung tumors. Left panels are from a mouse exposed 2 months previously to an AAV6 vector encoding JSRV Env (ARJenv) [10], and right panels are from sheep 85RS14 (Table 1) that was experimentally infected with JSRV. Sections were stained with the Env Mab C9 and were counterstained with methyl green. Arrow in lower right panel indicates inflammatory cells that do not stain for Env expression.
Mentions: All eight of the selected Mab brightly stained tumors in histologic sections of lungs from immunodeficient mice exposed to an AAV6 vector that expresses JSRV Env, ARJenv [10], with little to no staining of histologically-normal lung tissue (Fig. 1, left panels; data not shown). Notably, Env expression appears to be required for tumorigenesis in this system, because we never observed masses of epithelial cells (tumors) that did not stain with the Env Mab in sections of lungs from different animals that in total contained over 500 Env+ tumors. Mab clones B3 and C9 were chosen for subsequent studies. These two Mab appear to recognize different epitopes since optimal antigen recognition in histological sections requires an antigen retrieval step for the C9 Mab but not for the B3 Mab. However, both Mab recognize the same cells in serial sections of JSRV Env-induced lung tumors in mice (not shown). Neither Mab recognized histologically-similar lung tumors induced in mice by urethane [18] (samples kindly provided by Alvin M. Malkinson; data not shown). In addition to their histological similarity, both Env- and urethane-induced tumors are primarily composed of cells that express the alveolar type II cell marker surfactant protein C and do not expresses the non-ciliated bronchiolar Clara cell marker CC-10 [10,18]. These data indicate that the Mab are specific for JSRV Env and do not recognize mouse tumor antigens expressed by this type of tumor.

Bottom Line: Jaagsiekte sheep retrovirus (JSRV) causes a lethal lung cancer in sheep and goats.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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. swootton@fhcrc.org

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus