Adenomatosis Pulmonar Review 2007

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Vet. Res. 38 (2007) 211228 211c INRA, EDP Sciences, 2007DOI: 10.1051/vetres:2006060

Review article

Jaagsiekte Sheep Retrovirus (JSRV):

from virus to lung cancer in sheep

Caroline La*, Nicolas Ga, Vincent Ca,b, TimothyGa, Jean-Franois Ma,b, Fabienne Aa

a Universit de Lyon 1, INRA, UMR754, cole Nationale Vtrinaire de Lyon, IFR 128,F-69007, Lyon, France

b Centre de rfrence des maladies orphelines pulmonaires, Hpital Louis Pradel,

Hospices Civils de Lyon, Lyon, France

(Received 11 September 2006; accepted 23 November 2006)

Abstract Jaagsiekte Sheep Retrovirus (JSRV) is a betaretrovirus infecting sheep. This virus is re-sponsible for a pulmonary adenocarcinoma, by transformation of epithelial cells from the bronchioliand alveoli. This animal cancer is similar to human bronchioloalveolar cancer (BAC), a specificform of human lung cancer for which a viral aetiology has not yet been identified. JSRV interactswith target cells through the membrane receptor Hyal2. The JSRV genome is simple and containsno recognised oncogene. It is now well established that the viral envelope protein is oncogenicby itself, via the cytoplasmic domain of the transmembrane glycoprotein and some domains of thesurface glycoprotein. Activation of the PI3K/Akt and MAPK pathways participates in the envelope-induced transformation. Tumour development is associated with telomerase activation. This reviewwill focus on the induction of cancer by JSRV.

JSRV /ovine pulmonary adenocarcinoma /bronchioloalveolar cancer /type II pneumocytes /lung

Table of contents

1. Introduction .............. ................ .............. ................ .............. ................ ............ 2122. OPA: a virus-induced cancer ........... ............... .............. ................ .............. ........... 212

2.1. Natural history .......................... ................ .............. ................ .............. ..... 2122.2. JSRV: a member of the Betaretrovirus genus.....................................................2122.3. Virus and genomic organisation ..... ..... .... ..... .... ..... ..... .... .... ..... ..... ..... ..... .... .... 2132.4. JSRV tropism ............ ................ ................ .............. ................ .............. ..... 215

3. The JSRV induced disease... ................ ................ .............. ................ .............. ..... 2163.1. Clinical presentation and histopathology ..... ..... ..... .... .... ..... ..... ..... .... ..... ..... ..... . 2163.2. Mechanisms of oncogenesis ... ................ .............. ................ .............. ........... 217

4. JSRV and human lung cancer ......... ................ .............. ................ .............. ........... 2225. Conclusion.............. .............. ................ .............. ................ .............. ................ 224

* Corresponding author: [email protected]

A r t i c l e a v a i l a b l e a t h t t p : / / w w w . e d p s c i e n c e s . o r g / v e t r e s o r h t t p : / / d x . d o i . o r g / 1 0 . 1 0 5 1 / v e t r e s : 2 0 0 6 0 6 0
http://dx.doi.org/10.1051/vetres:2006060http://www.edpsciences.org/vetres


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212 C. Leroux et al.

1. INTRODUCTION

Ovine pulmonary adenocarcinoma(OPA) is a contagious tumour originat-ing in the distal lung after infection byJaagsiekte Sheep Retrovirus (JSRV). Thedisease was initially described in 1915 inSouth Africa and is present worldwide.JSRV belongs to the Retroviridae familyand the Betaretrovirus genus. OPA issimilar to a peculiar form of humancancer, bronchioloalveolar cancer (BAC),with which it shares clinical, radiologi-cal and histopathological features [51].

Although the molecular mechanisms ofJSRV induced- tumorigenesis are still onlypartially understood, the significant recentefforts in the field of OPA research rein-force the relevance of this model for thestudy of both the virological and cancerousaspects of lung adenocarcinoma.

2. OPA: A VIRUS-INDUCED

CANCER

2.1. Natural history

Transmission of OPA among sheep hasbeen suspected for almost two centuries.The first report dates back to 1825, with aletter written by a farmer who complainedabout the loss of many of his sheep. Thedisease was called Jaagsiekte, after the

Afrikaans words for chase (Jaag) andsickness (sieckte), to describe the respi-ratory distress observed in an animal outof breath from being chased [91]. The firstevidence of a viral cause came from theobservation of retrovirus particles in thelungs from sheep presenting clinical signsof cancer [66], and was further clearly con-firmed by experimental induction of thedisease by intratracheal inoculation of viral

particles with a reverse transcriptase activ-ity [47], cytoplasmic fractions of tumoralcells [8284] or pulmonary secretions [76].

The disease can also be efficiently trans-mitted to goats by experimental inocula-tion [77, 81]. JSRV has been definitivelydemonstrated as the aetiological agent of

OPA by experimental inoculation of par-ticles produced from a JSRV-molecularclone [57].

OPA is present on all continents. Itsincidence is difficult to evaluate in the ab-sence of an appropriate screening tool. Thevirus is transmitted between animals byclose contact, mainly through aerosolizedparticles. The breeding conditions are ofmajor importance for the dissemination of

the virus. The incubation period in nat-urally infected animals ranges between 2and 4 years [78], but the cancer may bediagnosed as early as a few months af-ter birth. The incubation period may varyaccording to the type of infection (experi-mental versus spontaneous infection), andthe age of the animals [78]. Interestingly,injection of tumoural tissues into newbornlambs rapidly induces the disease in 36weeks [57]. In natural conditions, the rapiddevelopment of tumoral lesions in younganimals suggests a greater susceptibility ofthe developing lung to JSRV [8]. In uterotransmission to the fetus has been sug-gested [8].

2.2. JSRV: a member of the

Betaretrovirus genus

JSRV is the virus responsible for theinduction of OPA. JSRV belongs to thefamily Retroviridae, to the subfamily Or-thoretrovirinae and the genus Betaretro-virus. The Betaretrovirus genus also com-prises Mouse Mammary Tumour Virus(MMTV) responsible for a mammary ade-nocarcinoma in the mouse, Mason-PfizerMonkey Virus (MPMV) isolated froma Rhesus monkey, and Squirrel Monkey

RetroVirus (SMRV). In 2003, Dolly thesheep, the first mammal cloned from anadult cell, died after being diagnosed with


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JSRV and lung cancer in sheep 213

Figure 1. Organisation (A) and transcription pattern (B) of JSRV provirus (from [30]). The gag,pro, pol and env genes respectively encode the core proteins, the protease, the enzymatic activitiesand the envelope glycoproteins. x is an additional open reading frame encoding a putative proteinof unknown function. LTR: Long Terminal Repeat. SA: splice acceptor; SD: splice donor (adapted

from [80]).

an incurable pulmonary adenocarcinomainduced by JSRV.

The first attempts to characterise thevirus were made in the early 1980s bypurification of the virus from lung lavage[91]. In 1991, a cDNA library was obtainedfrom purified 1.186 g/mL density fractions[89], thus allowing the first sequencing of

the entire JSRV genome of a South Africanisolate [90].

2.3. Virus and genomic organisation

Retroviruses are RNA viruses infect-ing vertebrate species and many non-vertebrates. Virions (80100 nm in diam-eter) are spherical and surrounded by an

envelope, with spikes composed of virus-encoded glycoproteins. The envelope iscomposed of viral proteins and elements of

the host-cell membrane (lipid bilayer andproteins). The virions carry two copies ofthe genome, composed of linear, positive,single-stranded RNA. The 7.58 kb genomeof the infectious virus comprises four maingenes, organised as 5- gag- pro- pol- env -3 (Fig. 1), which encode the virus proteins(reviewed in [64, 90]). Interestingly, while

the nucleotide sequences of gag, pro andpol are homologous to their counterpartsin MPMV, the env gene of JSRV is morerelated to that of MMTV and Human En-dogenous Retrovirus -K (HERV-K). JSRVis organised as a simple retrovirus, withan additional open reading frame, namedORF-x, that overlaps the 3 end of the polgene. ORF-x is unique among retrovirusesand may encode a putative accessory pro-

tein of 166 amino acids. Although theexistence of the protein is debated, ORF-xis strongly conserved in various isolates,


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and sequence analyses suggest a selectivepressure for its conservation [6, 63, 72, 91](and our unpublished data). Interestingly,two sub-genomic mRNA with splice ac-

ceptor sites within or in the vicinity ofORF-x have been identified, suggestingthat this putative gene may actually be tran-scribed [63]. We have also identified thesetwo mRNA in tumoral lungs (unpublisheddata).

The JRSV genome contains non-codingregions at the ends of the genome, that areessential for the virus replication: R re-peated at both ends; U5 unique to the 5

end and U3 unique to the 3 end. The inte-grated genome is flanked by the long termi-nal repeat (LTR) composed of the 3 regionsU3-R-U5. The LTR serve as the sites oftranscriptional initiation. The U3 regioncontains several elements important for vi-ral transcription and tropism. The gag gene(group-specific- antigen) encodes a singlepolyprotein that is cleaved into at leastthree proteins: the matrix (MA), the major

capsid protein (CA) and the nucleocap-sid (NC). The pro gene encodes a proteincompatible with already-described dUT-Pase in its 5 part and a protease (PRO)in its 3 end. Whereas the protease cleavesthe precursor polyproteins, the dUTPase(reviewed in [11]) prevents the incorpora-tion of deoxyuridine triphosphate (dUTP)by the reverse transcriptase [91]. The polgene is predicted to encode the enzymaticactivities: Reverse Transcriptase (RT) and

integrase (IN), respectively implicated inthe replication of the viral RNA and inthe integration of the retrotranscribed DNAprovirus into the host genome. The RT is aRNA-dependent DNA polymerase, essen-tial for the conversion of viral RNA intoDNA. The env gene encodes the surface(SU) and transmembrane (TM) glycopro-teins. The SU glycoprotein interacts withthe cellular receptor of JSRV in sheep,

Hyal-2, a glycosylphosphatidylinositol an-chored hyaluronidase-2 [70]. The TM gly-coproteins presumably anchor SU into the

lipid bilayer and are composed of a hy-drophobic stretch of amino acids followedby a short cytoplasmic tail. The JSRV en-velope is a major determinant for the cel-

lular transformation as discussed in detailbelow.

JSRV is phylogenetically related to theEnzootic Nasal Tumour Virus (ENTV),the agent responsible for nasal adenocarci-noma, a contagious tumour of the mucosalnasal glands affecting sheep and goats. Ininfected animals, epithelial cell prolifer-ation is responsible for continuous nasaldischarge, respiratory distress, exophthal-

mos and important skull deformations (forreview see [19]). Co-infection of ENTVand JSRV has been reported [54].

A family of endogenous retroviruses,enJSRV (endogenous JSRV) closely re-lated to JSRV, is present in domestic andwild sheep and goats [34]. JSRV and en-JSRV genomes are highly related with9098% homology in deduced amino-acidsequences [59]. Endogenous retroviruses(ERV) are vertically transmitted as sta-ble Mendelian genes in the germline ofmost eukaryotes. They derive from the in-tegration of exogenous viruses in the hostgenomes, followed by genetic stabilisationthrough accumulation of mutations. Sev-eral families of HERV such as HERV-F,HERV-FRD, HERV-K, HERV-R, HERV-Tand HERV-W (defined by the tRNA com-plementary to their putative primer bindingsite using the one letter code for the tRNAs

corresponding amino acid) have been de-scribed in the human genome. Eight totwelve copies of enJSRV have been lo-cated on metaphase chromosome spreadsof sheep and goats using fluorescent in situhybridisation [10] (Fig. 2).

The biological significance of ERV isstill largely debated. Expression of ERVhas been described in the placenta and gen-ital tract of mammals including humans

with HERV-W. In the female genital tract,enJSRV expression is limited to the ep-ithelia and is particularly abundant in the


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Figure 2. Chromosomal localisation of the en-JSRV copies. Integration sites were determinedby in situ hybridisation with a full-length JSRVprobe on ovine metaphase spreads. Chromo-somes were identified by R-banding, and in-tegration sites are indicated by arrows. Chr.:Chromosome. (A color version of this figure isavailable at www.edpsciences.org/vetres.)

endometrium[22,25,26,62].Envelope pro-teins and env mRNA are present in themononuclear trophoblasts and particularlyabundant in the binucleate cells and thesyncytiotrophoblast plaques of the ovineplacenta [24,25,62]. Only low levels of ex-pression have been described in the lungepithelium [62].

2.4. JSRV tropism

JSRV is unique among the retrovirusesin that it induces transformation of dif-ferentiated lung epithelial cells, i.e. typeII pneumocytes (also called alveolar typeII cells) in the alveoli, and Clara cells inthe bronchioli. Tumours exclusively occurin the sheep lung, as a result of selec-tive replication of JSRV in these two celltypes demonstrated by the detection of theviral protein only in the tumoural cells

and their neighbouring epithelial cells [55,68, 75]. However JSRV may infect dif-ferent cell types in vitro, with a larger

cellular tropism. Hence, ovine cell linesissued from various tissues may be in-fected in vitro by JSRV, however viralproduction stays weak [58]. Presence of vi-

ral DNA can be demonstrated in naturallyinfected animals in lymphoid tissues, alve-olar macrophages and in peripheral bloodmononuclear cells such as monocytes or Band T lymphocytes [29,33,37,56,75].

Viral envelope and LTR regions are es-sential determinants for the tropism andthe expression of retroviruses. Locatedat the surface of the viral particle, sur-face (SU) glycoproteins specifically inter-

act with cellular receptors, allowing entryof the virus into the cell. It is now well es-tablished that Hyal2 (hyaluronidase 2) isthe cellular receptor for JSRV (Fig. 3) insheep [23, 70]. Hyal2 is a member of thehyaluronglucosaminidase family, enzymesthat degrade hyaluronic acids of the ver-tebrates extracellular matrix. Hyal2 onlyshows a weak hyaluronidase activity incomparison to other proteins of the same

family. Hyal2 a glycosylphosphatidylinos-itol (GPI)-anchored cell-surface receptor,is ubiquitously expressed in human andmouse tissues [14]. Hyal2 also acts asa cellular receptor for ENTV [23], therelated Betaretrovirus that induces nasaltumours. Ubiquitous expression of Hyal2is expected in sheep, in accordance withthe capacity of JSRV to infect differentcell types. JSRV may thus be able to en-ter different cells via its ubiquitous re-

ceptor [56, 58], however its active repli-cation is restricted to bronchioloalveolarepithelial cells (tropism restriction). In-deed, the productive infection is strictlycontrolled at the cellular and molecularlevel. Retroviral LTR contain the viral pro-moter and enhancer elements that inter-act with cellular transcription factors; theyare specifically activated in cells express-ing transcription factors that bind to the

enhancer regions. Restriction of JSRV ex-pression to lung epithelial cells is largelydue to its LTR transcriptional specificity


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Figure 3. Pathways involved in JSRV-induced transformation and in the maintenance of the tu-mour (adapted from [80]). Two main pathways have been shown to be activated following in vitro

expression of the JSRV envelope in different cell lines: the MAPKinase and PI3K/Akt pathways.

[60]. Promoters of specific genes fromtype II pneumocytes or Clara cells, suchas surfactant proteins SP-A, SP-B, SP-C,SP-D and CCSP (Clara Cell Secretory Pro-tein or CC10) share different regulatoryelements. JSRV LTR have several bind-ing sites for transcription factors. Amongthose, HNF-3 (Hepatocyte Nuclear Factor

3) a factor involved in regulating the ex-pression of surfactant protein genes, andC/EBP (CCAAT/Enhancer Binding Pro-tein), are essential for the transcriptionalactivity of JSRV LTR. Directed mutagene-sis experiments have established that alter-ations of NF-I, HNF3 and C/EBP bindingsites reduce LTR activity of JSRV by 40to 70% in MLE-15, a murine type II pneu-mocyte cell line [48,60]. C/EBP is also an

important activator of transcriptional activ-ity of the LTR in MtCC1-2, a murine Claracell line, while HNF-3 is not essential [48].

The endogenous virus enJSRV uses thesame Hyal2-cellular receptor as JSRV. Thiscould lead to a phenomenonof interferenceat the time of cell infection by the exoge-nous form of the virus [79]. ExogenousJSRV and enJSRV are differentially regu-lated, since LTR of enJSRV may respondto progesterone but not to the transcription

factors that regulate expression of exoge-nous virus LTR [59].

3. THE JSRV INDUCED DISEASE

3.1. Clinical presentation andhistopathology

OPA shows different symptoms suchas progressive dyspnea, abundant bron-

chorrhea, cough, anorexia and cachexia.Death usually results from end-stage respi-ratory failure. A typical sign (known as the


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Figure 4. Subtypes of lesions observed in OPA: bronchioloalveolar (A), acinar (B) and papillary(C). (A color version of this figure is available at www.edpsciences.org/vetres.)

wheelbarrow test) is the flow of abun-dant mucoid fluid (up to 500 mL per day inadvanced disease) from nostrils when therear legs of the animal are raised. Extra-thoracic metastases are rare. Macroscopicexamination shows enlarged lungs infil-trated with tumoural areas, varying fromsmall nodules (130 mm) to lobar consol-idation [18, 51]. The disease is multifocal,

disseminated in both lungs, pneumonic inappearance, with the airways filled withfluid produced by the tumoural cells.

According to the latest WHO classifi-cation for human lung cancers [7], OPAshould be referred to as a mixed adeno-carcinoma with associated bronchioloalve-olar, papillary and/or acinar subtypes. Thesubtypes are defined by their cell growthand differentiation patterns [51] (Fig. 4).

The bronchioloalveolar differentiation ischaracterised by the expansion of cells fol-lowing the alveolar septa, also referredto as the lepidic spread, without destruc-tion of the alveolar architecture. The pap-illary subtype is defined by the pres-ence of papilla-like structures protrudingabove the epithelial layer and replacingthe underlying alveolar architecture. Fi-nally, the acinar subtype is composed of

duct-like structures or acini and tubulescomposed of cells resembling bronchialglands. In JSRV-induced adenocarcinoma,

these three histopathological subtypes maybe present within the same tumoural tissue.

The OPA tumoural cells derive fromepithelial cells of the distal lung, namelyalveolar type II cells (for 80% of thecells) and Clara cells (for 15% of thecells) [68] (Fig. 5). Type II pneumocytesproduce different components of surfac-tant, a tensio-active agent that allows the

maintenance of alveolar integrity.Interestingly, tumoural cells over-express CD208/DC-LAMP (DendriticCell Lyzosomal Associated MembraneProtein) [74], a protein belonging to theLAMP family of proteins (Lysosomal-Associated Membrane Protein), andinitially described in activated dendriticcells. CD208/DC-LAMP is also con-stitutively expressed in human, murineand ovine type II pneumocytes, and is

over-expressed in human bronchioloalve-olar carcinoma and OPA [74]. In type IIpneumocytes, CD208 is expressed in theconstitutive membranes of the lamellarbodies, specific vesicles specialised insurfactant production. The role of CD208over-expression in tumoural developmentis still unknown.

3.2. Mechanisms of oncogenesis

Oncogenic retroviruses have beenhistorically divided into two groups


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Figure 5. Microscopic pattern of lesions from OPA. Typical aspect of a non-tumoural (A) andtumoural ovine lung (B) labelled with an anti SP-A (Surfactant Protein A) antibody. Arrows showtumoural cells, i.e. type II pneumocytes labelled with and anti SP-A antibody. (A color version ofthis figure is available at www.edpsciences.org/vetres.)

depending on the speed of disease induc-tion. Acute and non acute retrovirusescause tumours with a short or longlatency period respectively. Acute retro-viruses have been described in mice,birds, primates and are oncogene-bearingretroviruses. Viral oncogenes are derivedfrom normal cellular genes or proto-oncogenes, involved in regulation of cell

proliferation. Once captured by the virus,proto-oncogenes undergo mutations thatlead to uncontrolled cell proliferation.Rous Sarcoma Virus (RSV) is an exampleof avian retrovirus bearing an oncogene,v-src, deriving from a mammalian cellularkinase.

Typical lesions of OPA may be observedin just a few weeks following experimentalinoculation of concentrated JSRV particles

[64, 83, 84]. This timeframe of disease in-duction and the multifocal pattern of OPAare compatible with the presence of anoncogene in the JSRV genome [18]. JSRVDNA transfection in murine NIH 3T3 fi-broblasts induces foci of transformed cells,clearly indicating that the JSRV genomecontains an oncogenic element [44, 70].However, to date no sequence homolo-gous to any cellular oncogene has been

detected in the JSRV genome [72]. Theopen reading frame (orf-x) of JSRV mightbe a potential oncogene, although it does

not present any sequence homology withknown oncogenes [6, 72], and its deletiondoes not prevent transformation in vitro.

It is now clearly established that JSRVinduces tumours via the oncogenic prop-erties of its envelope, which is both nec-essary and sufficient to induce transfor-mation. The transforming property of the

JSRV envelope has been demonstrated invitro in various cell lines including murineNIH 3T3 fibroblasts [44], rat 208F fibrob-lasts [70], avian DF-1 fibroblasts [4, 93],bronchial human BEAS-2B epithelial cells[16], canine kidney MDCK epithelial cells[43], and rat kidney RK3E cells [46].The oncogenic property of the JSRV en-velope has also been shown in vivo in animmuno-deficient mouse model [87] andrecently in sheep [9]. Expression of the

JSRV envelope in mice using a replication-incompetent adeno-associated virus vector,AAV6, results in lung tumours similar tothose observed in sheep [87]. The bron-chioloalveolar localisation of the tumoursand the expression of the surfactant proteinSP-C show that the transformed cells arederived from type II pneumocytes [87]. Us-ing a replication-defective virus carryingthe env gene under the control of the JSRV

LTR, it has been shown that the JSRVenvelope is sufficient to induce lung tu-mours in sheep. The envelope of the related


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ENTV virus displays the same oncogenicproperty both in vitro [2, 23] and in vivo[88].

Deletion experiments show that the TM(transmembrane) region of the envelopeis the main determinant for cell trans-formation [12, 36, 38]. In addition to theTM region, deletions of the SU (sur-face) glycoprotein (going from the signalpeptide to the junction between the SUand TM subunits) also abolish transfor-mation induced by the envelope, suggest-ing that multiple domains of SU may beinvolved in cellular transformation. The

cytoplasmic tail of TM, composed of 43amino acids, is essential for the trans-formation process in MDCK and NIH-3T3 cells [43, 61]. This region containsa peptidic YXXM motif (Fig. 3), cor-responding to a potential consensus site(phosphorylated on tyrosine Y) linked tothe SH2 domain of the p85 subunit ofPI3K (Phosphatidyl-Inositol-3 Kinase), akinase that activates Akt. The PI3K-Aktsignalling pathway is determinant in cel-lular proliferation and survival (for review[15]) (Fig. 3). Following a membrane stim-ulus such as a growth factor binding to itsreceptor, PI3K is recruited to the cell mem-brane. Phosphorylated-PI3K phosphory-lates the second messenger PIP2 (phos-phatidylinositol (4,5) biphosphate) intoactive PIP3 (phosphatidylinositol (3,4,5)triphosphate). PIP3 can then recruit PDK1(phosphatidylinositol-dependent kinase 1),

which in turn phosphorylates Akt. The ki-nase Akt can phosphorylate diverse sub-strates involved in signalling cascades con-trolling cellular proliferation, survival andmetabolism. Akt phosphorylation inhibitsproteins such as GSK-3 (Glycogen Syn-thase Kinase 3), FOXO (forkhead box tran-scription factor), p24 or Kip1, and activatesmTOR (mammalian target of rapamycin),an important regulator of cell growth.

Mutations of the YXXM motif of theJSRV-env gene abolish cell transformationof NIH-3T3 [43, 61] and rat 208F and

RK3E cells [38]. Akt activation was ob-served in different cell lines transformedby JSRV (Fig. 3), while it was absent fromparental cells. OPA-derived type II pneu-

mocytes do not respond to EGF (EpidermalGrowth Factor) stimulation, an activatorof the PI3K-Akt pathway [80], suggest-ing dysregulation of the Akt pathway byJSRV infection. We recently showed thatAkt activation was observed in 37% ofOPA tumours sampled at a late stage ofdisease [80]. These results support the in-volvement of the Akt signalling pathway inthe development and/or the maintenance of

OPA, and also suggest the involvement ofan Akt-independent pathway [80].The mechanisms leading to JSRV-

induced cell transformation are in factmuch more complex than previously con-sidered. Several experiments rule out adirect role for the YXXM motif in Akt ac-tivation. In JSRV-transformed cells, phos-phorylation of the Y590 residue of theintra-cytoplasmic TM tail, or interaction

between the p85 subunit of PI3K and theenvelope (a prerequisite for Akt activa-tion), have never been shown [42, 43].Mutations of the YXXM motif do not abol-ish Akt phosphorylation, so that the exactrole of this motif remains to be deter-mined [42, 43, 93]. Moreover, implicationof the YXXM motif may differ betweencell types in in vitro experiments [4, 36,41, 42, 61, 93]; while it is essential fortransformation of NIH 3T3 fibroblasts, it

is not required for transformation of avianDF-1 fibroblasts. Nevertheless, the pres-ence of the YXXM motif seems to affectthe efficiency of envelope-mediated trans-formation [43]. Since the YXXM motifdoes not explain the oncogenic propertiesof JSRV, the mechanism of Akt activationin transformed cells still need to be de-termined. Interestingly, treatment of cellswith LY294002, a PI3K-specific inhibitor,

drastically reduces Akt phosphorylation inNIH 3T3 cells [42-45, 93], suggesting thatPI3K-dependent Akt activation may occur.


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Figure 6. Activation of PI3K/Akt and MAPK pathways. Binding of growth factor, such as epi-

dermal growth factor (EGF) to its tyrosine kinase receptor (such as EGF receptor) may induceactivation of different pathways involved in the control of cell proliferation, apoptosis and differen-tiation (adapted from [80]).

In addition, PI3K inactivation does notprevent cell transformation [46], and Aktactivation may be observed in NIH 3T3cells deficient for the p85 subunit of PI3K[45], suggesting that PI3K may not be nec-essary for Akt activation [28,73].

JSRV-mediated cell transformation isassociated with the activation of the Ras-MEK-MAPK pathway. Mitogen-activatedProtein Kinase (MAPK) are a groupof kinases important in signal transduc-tion, that may be activated by the smallRas protein (Fig. 6). The MAPK path-way includes 4 protein families: ERK1/2(extracellular signal-regulated kinase 1and 2) also named p44/42; SAPK/JNK

(stress-activated protein kinase/c-Jun NH2-terminal kinase); MAPK p38 and BMK(big mitogen-activated protein kinase 1).

MAPK are regulated and phosphorylatedby the MAPK kinase (MAPKK) suchas MEK1/2, themselves activated by theMAPKK kinase (MAPKKK) such as Raf(Fig. 6). Activation of this signalling cas-cade leads to translocation of MAPK into

the nucleus, where they activate differ-ent transcription factors. The Ras-MEK-MAPK pathway is activated in JSRV-transformed NIH 3T3 and RK3E cells[38, 46] (Fig. 3). As we have reviewedabove for Akt, the significance of thissignalling pathway in cell transformationseems to vary according to the cell typesused in the in vitro studies [46]. Inhibitorsof MEK1 (MAPKK), can totally abolishtransformation in fibroblasts and epithe-lial cells. On the contrary, although aninhibitor of MAPKKK totally abolishes the


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Figure 7. Tumoural type II pneumocytes in OPA-derived primary cultures. Cytoplasm is rich inlamellar bodies (LB) (A) as shown in an enlarged view (B). In vitro-derived cells express cytokeratin(C), the surfactant protein C (SP-C) (D) and co-express both cytokeratin and SP-C (E). (A colorversion of this figure is available at www.edpsciences.org/vetres.)

transformation of fibroblast NIH 3T3, itseffect on epithelial RK3E cells is only par-

tial. A recent study on JSRV and ENTVtumoural tissues gives more clues to un-derstand the JSRV complex signalling cas-cades. In naturally and experimentally in-duced OPA, MAPK Erk1/2 seems to be thepredominant activated pathway [20].

Since the first description of the onco-genic properties of the JSRV envelope,many studies performed in various celltypes (fibroblasts, epithelial cells) and

species (human, sheep, mouse, rat) haveled to a better understanding of the mech-anisms leading to cell transformation.Although a number of points remain unan-swered, the transformation steps are be-lieved to be dependent on the nature andorigin of the cells. Hence, understandingthe key events in the transformation ofovine type II pneumocytes (i.e. cells thatrepresent the cells at the origin of the tu-

mours) is now the challenge of ongoingwork. Our group has developed primarycell cultures isolated from tumoural ovine

lungs [5, 80]; those tumour-derived cellsare clearly type II pneumocytes as revealed

by the presence of lamellar bodies in thecytoplasm, and the expression of surfac-tant protein C (SP-C) (Fig. 7). Analysisof transformation mechanisms in the ovinetype II pneumocytes is in progress.

The activation of telomerase was re-cently evidenced in OPA-derived type IIpneumocytes and in tumoural lung tissues,suggesting that replicative senescence maybe negatively regulated in this tumour [80]

(Fig. 3). Replicative senescence, leading tothe natural death of the cells after severaldivisions, is essential for the maintenanceof homeostasis and strict regulation of thecell life span. Replicative senescence ismainly regulated by the telomerase, a ri-bonucleoprotein enzyme complex able tomaintain telomere length during cell divi-sion, by de novo synthesis of telomeres andelongation of existing telomeres. Telom-

erase activation has been implicated asa crucial factor in oncogenesis throughinhibition of replicative senescence and


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down-regulation of cell death. Telomeraseactivity is itself regulated by a variety offactors, including the Akt kinase pathway.We reported telomerase activation and Akt

activation in OPA tumours [80], suggest-ing that Akt activation may contributeto telomerase activation and inhibition ofsenescence and cell death in JSRV infectedcells, thereby contributing to the accumu-lation of tumoural cells in the ovine lung.

In most of the cell lines studied, JSRVenvelope-induced transformation is inde-pendent of its interaction with the cellularreceptor Hyal2. Hyal2 is weakly active as a

JSRV receptor in mice and the deletion ofthe receptor binding domain (RBD), pre-dicted by sequence homology with otherretroviruses, from the JSRV envelope doesnot abolish the transformation [41, 49, 50,70].

Although incompletely understood, theoriginal mechanism of JSRV-cell transfor-mation may not be unique among retro-viruses. Envelope-mediated activation of

cellular proliferation has also been shownfor MMTV [39], Spleen Focus FormingVirus (SFFV) [1, 86] and Avian Heman-gioma Virus (AHV) [3]. Expression ofthe MMTV envelope in the human andmurine mammary epithelial cell line in-duces morphological changes compatiblewith cell transformation [39]; cell trans-formation is dependent on an Immunore-ceptor Tyrosine-based Activation Motif(ITAM motif), a potential anchor site for

signalling proteins carrying a SH2 motif,and encoded by the MMTV env gene [39].ITAM (Yxx(L/I)x68Yxx(L/I)) motifs areassociated with cell survival, activationand differentiation; tyrosine (Y) residuesare necessary and sufficient for signallingfunction. The envelope-mediated transfor-mation has been well established in thecase of SFFV, a murine retrovirus caus-ing erythroleukemia. The SFFV genome

encodes a truncated envelope protein thatinteracts with and activates the erythropoi-etin receptor, and a truncated form of the

receptor tyrosine kinase Stk/Ron [40, 53]that induces the proliferation of the tar-get cell. Despite the direct effect of theenvelope on cell signalling, other molecu-

lar events are necessary for cell transfor-mation, such as integration of the virusgenome in the vicinity of protooncogenes[71].

Tumorigenesis is a multistep processand the JSRV envelope might not be suf-ficient to induce transformation of cellsin vivo. Insertional mutagenesis cannot beruled out. Except in neonates, OPA is char-acterised by a slow progression from in-

fection to disease, suggesting a non-acutemechanism of transformation [78]. A multistep gene walking technique was recentlyused to clone and sequence JSRV inte-gration sites from sheep with OPA [13]and identified multiple integration sites inmost tumours, suggesting a random distri-bution. Interestingly, a common integrationsite has been described in sheep chromo-some 16 [13] and in or near the receptorprotein tyrosine phosphatase (RPT Pase) gene [67]. In this context, insertionalmutagenesis may participate to the devel-opment of the tumour in sheep.

4. JSRV AND HUMAN LUNG

CANCER

Fifteen to 20% of all human cancersare thought to be associated with infec-

tious agents (reviewed in [31]). OPA hasbeen considered as a model for human ade-nocarcinomas, and especially pneumonic-type bronchioloalveolar carcinoma (BAC),since the two tumours share common clini-cal, radiological and histopathological fea-tures [51]. Similarly to OPA, BAC is aslow-growing tumour with rare metastaticspread. It is clinically associated withhighly productive cough and progressive

restrictive respiratory failure [51, 85]. Theepidemiology of BAC differs from that ofother non-small cell lung cancers, with a


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Table I. JSRV and human lung cancer.

For AgainstAnalogy to the ovine pulmonary adenocarci-

nomaSpecific epidemiology of the bronchioloalveo-lar cancer

No epidemiologic evidence of JSRV transmissionfrom sheep to humans

Presence of JSRV-receptor Hyal2 in humancells

Lack of JSRV DNA or RNA in human adenocarci-noma

Possible neoplastic transformation of humancells with JSRV envelope proteinEvidence for a protein related immunologicallyto JSRV in some human lung tumoursDetection of JSRV-related DNA sequences inAfricans

less important epidemiologic link to to-bacco smoking, an increased frequency inwomen and younger patients, and a bet-ter outcome than other non-small cell lungcancers (with a 5-year survival of about60%). Given the similarities of OPA andhuman BAC, a viral cause to human BAChas long been hypothesised; several recentclinical and molecular observations have

been reported studying the link betweenJSRV and human lung carcinoma (Tab. I).

Clinically, an interesting argument infavour of an underlying infectious condi-tion in human lung cancer came from thepattern of recurrence of BAC after lungtransplantation. Although usually con-traindicated in cancer, lung transplantationhas been reported as a feasible treatmentof unresectable BAC because of the lack

of metastatis in this tumour type. Sinceour first report of lung transplantation in apatient with BAC [27], about thirty caseshave been described, showing recurrencerates of about 50%, within a median timeof 45 months [21]. Microsatellite analy-sis of the lung specimens of the donorand the recipient have showed that recur-rent tumours originated from the transplantrecipient [30, 65]. Since BAC is consid-

ered as a localised disease (and excludingpossible tumoural contamination duringthe transplantation procedure), these ob-

servations suggest the existence of eitherextra-pulmonary tumoural stem cells thatwould remain dormant for several years[32], or of infectious agents with an extra-pulmonary preclinical reservoir.

Hyal2, the cellular receptor of JSRV, hasbeen shown to be present at the surfaceof a wide range of human cells, includ-

ing alveolar cells, and moreover to bindthe JSRV envelope protein [70]. Further-more, the gene coding for Hyal2 is locatedin the chromosomal region 3p21 which isfrequently deleted in human lung cancer,making this gene a potential tumour sup-pressor in lung carcinogenesis [69,70].

Interestingly, de las Heras et al. [17]showed the presence of an antigen cross-reacting with JSRV-Gag antiserum in about

30% of human BAC, and 26% of lung ade-nocarcinomas. However, these results havenot been confirmed by further molecularstudies and 2 PCR-based analyses failedto detect any exogenous or endogenousJSRV-related genome in human BAC andadenocarcinoma [35,92].

More recently, Morozov et al. [52] re-ported the presence of JSRV-related se-quences in healthy and HIV positive

Africans, but not in the few lung cancer pa-tients tested. Their significance remains tobe evaluated.


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Up to date, no conclusive molecular ev-idence of a link between JSRV and humanBAC has been provided (Tab. I). As analternative approach, a case control epi-

demiologic study is currently underway inFrance, conducted by our group. The ob-jective is to determine if ovine or caprineexposure is a risk factor for BAC in hu-mans.

5. CONCLUSION

Over the last few years, research onJSRV and the resulting OPA has focussed

on the molecular mechanisms of cell trans-formation. Interesting results came fromthe discovery that the virus envelope actsas a potent oncogene. Several cellularpathways seem to occur in the cell trans-formation.

To conclude, research into the biologyof JSRV and mechanisms leading to the de-velopment of OPA is of great interest bothfor the naturally induced cancer in sheep

and for BAC, the related human cancer.Even though a viral agent remains uncer-tain in BAC patients, understanding thesteps leading to the transformation of lungepithelia may be of interest in the contextof therapeutic approaches in human lungcancers in general and BAC in particular.

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Adenomatosis Pulmonar Review 2007

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