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Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cell & Developmental Biology

journal homepage: www.elsevier.com/locate/semcdb

Review

SV40 TAg mouse models of cancer

Emily K. Colvin, Chris Weir, Rowan J. Ikin, Amanda L. Hudson ∗
Bill Walsh Translational Cancer Research Laboratory, Kolling Institute of Medical Research, University of Sydney, Royal North Shore Hospital, St. Leonards,
New South Wales 2065, Australia

a r t i c l e i n f o a b s t r a c t

Article history: The discovery of a number of viruses with the ability to induce tumours in animals and transform human
Available online xxx cells has vastly impacted cancer research. Much of what is known about tumorigenesis today regarding
tumour drivers and tumour suppressors has been discovered through experiments using viruses. The
Keywords: SV40 virus has proven extremely successful in generating transgenic models of many human cancer types
SV40 and this review provides an overview of these models and seeks to give evidence as to their relevance in
Cancer
this modern era of personalised medicine and technological advancements.
Mouse model
© 2014 Elsevier Ltd. All rights reserved.
Transgenic

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Origins of SV40 research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2.1. SV40 Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Is SV40 an aetiological agent in human malignancies? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Transgenic mouse models of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.1. Brain cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.2. Pancreatic cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.3. Bone cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.4. Blood cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.5. Prostate cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.6. Breast cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.7. Lung cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.8. Mesothelioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4.9. Ovarian cancer models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

1. Introduction individual genetic susceptibility and predisposition, disease initia-

tion and progression, the role of the immune system or the cell of
The origins of the transgenic mouse model stem from the neces- origin.
sity to develop model systems which better recapitulate human The first transgenic mouse model was produced in 1974 by
disease. Before the invention of transgenic models, investigating Jaenisch and Mintz [1]. These researchers recognised that Simian
cancer was predominantly restricted to the use of cell lines in vitro. Virus 40 (SV40) DNA could be injected into embryos and detected
However, these did not capture the intricacies of human can- in the DNA of tissues from the adult mice later in life. While this
cer and did not allow for studies into the histological subtype, approach did not result in tumour formation or genetic transfer of
SV40 DNA to progeny, it did pave the road for future experiments
in transgenics. At the same time the era of genetic engineering was
∗ Corresponding author. Tel.: +61 2 9926 4722.
born. Advancements in these fields led to the first published report
E-mail addresses: [email protected] (E.K. Colvin),
of tumour prone transgenic mice [2] and the evolution of SV40
[email protected] (C. Weir), [email protected] (R.J. Ikin), transgenic mouse models of cancer began. A historical timeline of
[email protected], [email protected] (A.L. Hudson). key dates is shown in Fig. 1.

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Table 1
SV40 mouse models of cancer.

Tumour type Transgenic mouse model Cell type SV40 targeted to and region of Features of the model References
(promoter used) SV40 used

Brain cancer SV-MK (metallothionein Choroid plexus epithelium (CPE); both CPE tumours develop along with thymic hypertrophy and kidney [2]
promoter/regulator fused to the large T and small t pathology
thymidine kinase structural gene
of herpes simplex virus, type 1)
SV11 (native SV40 enhancer CPE; both large T and small t Anaplastic foci of CPE by 36–41 days with consistent progression [34]
promoter region) to CPE tumours

Pancreatic tumours RIP-Tag2 (rat insulin promoter) Pancreatic ␤ cells; both large T and small t Multistage tumour progression of ␤-cell tumours (insulinomas) [35]
AVP-SV40 (vasopressin promoter) Pancreatic ␤ cells and anterior pituitary; Mice develop insulinomas and tumours of the anterior pituitary [151]
both large T and small t

E.K. Colvin et al. / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
Glucagon-SV40 (several variations Pancreatic ␣ cells; both large T and small t Mice develop glucagonomas, some models also develop tumours [62–65]
of the glucagon promoter) in the large intestine
Elastase-SV40 (elastase promoter) Pancreatic acinar cells; both large T and Mice develop acinar cell carcinomas with rare metastasis [152,153]

ARTICLE IN PRESS
small t
Amy-Tag (amylase-2.2 promoter) Pancreatic acinar cells; both large T and Mice develop acinar cell and stomach carcinomas with a high [154]
small t incidence of metastasis

Bone tumours mP1-SV40 (mouse protamine Round spermatids; both large T and small t Bone and heart tumours develop [66]
gene)
Amy-1a 501 (␣-amylase late gene) Osteoblasts; both large T and small t A high proportion of mice (65%) develop osteosarcoma with liver [67]
metastatic disease in 30%
MOTO (osteocalcin promoter) Mature osteoblasts; both large T and small Mice develop multi-osteotic bone tumours with 100% penetrance. [71]
t Histopathology, disease progression and genomic aberrations very
similar to human osteosarcoma.

Blood tumours Ig-SV40 (immunoglobulin (Ig) gene Lymphoid cells; large T only Mice developed B cell lymphoma, histiocytic lymphoma and [73,74]
enhancer linked to the SV40 native non-specific thymomas (in the 1987 model) and pre-leukaemias or
promoter) myelodysplastic syndrome (in the 1994 model)
IgH.T or IgH.TE␮ (Ig heavy chain D Lymphoid cells; large T only Mice consistently develop chronic B cell lymphocytic leukaemia [75]
and JH gene segments) (B-CLL) which resembles human B-CLL

Prostate cancer TRAMP (−426/+28 probasin Prostate epithelial cells; both large T and Mice develop prostatic intraepithelial neoplasia (PIN) which [81]
promoter) small t progresses to carcinomas by 24 weeks. Metastases occur in 100%
of mice. Tumours resemble human prostate neuroendocrine
carcinoma.
LADY (large probasin promoter) Prostate epithelial cells; large T only Mice develop PIN which progresses to carcinoma. Metastases are [93]
rare. Tumours resemble human prostate neuroendocrine
carcinoma.
G/T-15 (G␥-globin promoter) Prostate epithelial cells; large T only Mice develop prostate tumours with mixed epithelial and [98]
neuroendocrine features. Metastases occur in distant organs in a
proportion of mice.
PSP94-TGMAP (prostate secretory Prostate epithelial cells; both large T and Mice develop PIN that progresses to poorly differentiated prostate [96]
protein of 94 amino acids) small t tumours and metastases to lymph nodes and kidney
CR2-T-Ag (cryptdin-2 promoter) Neuroendocrine cells of the prostate; large Mice develop PIN that progresses to metastatic disease by 6 [97]
T only months
TgAPT121 (modified probasin Prostate epithelial cells; truncated form of This model only inactivates Rb family proteins (RB/p107/p130) [99]
promoter) large T (T121 ) capable of binding Rb family causing PIN and progression to adenocarcinoma with no
proteins but not p53 neuroendocrine features
C3(1)/Tag (rat prostatic steroid Prostate epithelial cells; both large T and Mice develop PIN that progresses to adenocarcinoma after 8 [79]
binding protein promoter) small t months of age that resembles poorly differentiated human
prostate cancer. Tumours develop in other organs including
thyroid and salivary gland.
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Breast cancer WAP-T (whey acidic protein Mammary epithelial after first pregnancy; Hormone dependent. 100% penetrance in females and 50% get lung [102]
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promoter) both large T and small t metastases, some metastatic disease also found in liver and lymph nodes.
Histology and gene expression similar to basal-like triple negative (TN)
and luminal B human breast cancers. No metastatic disease found in brain
or bone which is a major difference between this model and human breast
cancer.
C3(1)/Tag (prostate steroid binding Mammary epithelial cells in virgin Non-hormonal regulated. Originally developed as a model for prostate [79]
protein promoter) mammary glands; both large T and small t cancer. 100% penetrance in females and 15% get lung metastases with a
predictable time course for disease progression. Histology and gene
expression similar to basal-like TN human breast cancers. No metastatic
disease found in brain, bone or lymph which is a major difference between
this model and human breast cancer.
tTA/TAg/ER␣ (mouse mammary Mammary epithelium; large T only Expression of large T antigen and oestrogen receptor alpha (ER␣) are [155]
tumour virus long terminal repeat regulated by the tetracycline-responsive transactivator (tTA) which is
[MMTV LTR]) targeted to mammary epithelium through the MMTV LTR.
Undifferentiated mammary adenocarcinomas develop in 37% animals by
11 months which are oestrogen responsive. Salivary adenocarcinomas and

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lymphomas also develop. Transgenic tumours resemble human
adenocarcinomas which are responsive to oestrogen stimulation.

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Lung cancer UG-TAg (uterglobin gene Lung; both large T and small t Bronchioalveolar neoplasms develop along with urogenital tract [119]
promoter) neoplasms
CC10/Tag (Clara cell 10 kDa protein Clara non-ciliated bronchiolar secretory Multistage progression. Mixed solid and papillary adenocarcinomas [121]
promoter) cells of the pulmonary epithelium; both develop by 5 months with no metastatic disease. Similar to aggressive
large T and small t non-small cell adenocarcinomas with mixed, solid and papillary
phenotypes.
CC10/Tag:CC10/hASH1 (Clara cell Clara non-ciliated bronchiolar secretory Bitransgenic model; CC10/Tag transgenic mouse (above) crossed with a [128]
10 kDa protein promoter) cells of the pulmonary epithelium; both mouse expressing the human acetate homologue 1 (hASH1)
large T and small t transcriptional factor. Similar to human adenocarcinoma with some
neuroendocrine differentiation.
SP-C/Tag (surfactant protein C) Type II alveolar cells of the pulmonary Predictable time course; adenocarcinomas develop in 4–5 months with no [126]
epithelium; both large T and small t metastatic disease
CaBP9K/Tag (calbindin-D9 K Lung epithelial cells; both large T and small Predictable time course for disease development. Mice develop multifocal [156]
promoter) t pulmonary tumours by 1 year; however tumours develop in other tissues.

Mesothelioma MexTAg (mesothelin promoter) Mesothelial cells; large T only Malignant formation requires co-administration of asbestos. 100% [130]
penetrance with disease developing 5–10 months after asbestos exposure.
Transgenic tumours resemble human sarcomatoid mesotheliomas.
Response to treatment, tumour location, carcinogen used and latency
period (in terms of lifespan of animal) very similar to human
mesothelioma.

Ovarian tumours TgMISIIR-Tag Ovary and epithelium of the female 50% of mice develop bilateral poorly differentiated ovarian tumours that [140]
reproductive tract; both large T and small t disseminate intraperitoneal and form ascites. Tumours resemble human
poorly differentiated ovarian carcinoma and display a similar pattern of
dissemination.
tgCAG-LS-Tag + adenoviral cre Ovarian surface epithelium; both large T Mice develop poorly differentiated ovarian carcinomas that were [145]
recombinase and small t metastatic. Tumours resemble poorly differentiated ovarian carcinoma
with features of sex-cord stromal tumours.
AMH-SV40 Ovary (granulosa cells and follicles); large Mice develop granulosa cell tumours [139]
T only

Bladder cancer UPII-SV40T (uroplakin II promoter) Suprabasal and basal cells of the Invasive urothelial tumours develop in a multistage progression. Bladder [157]
urothelium; both large T and small t carcinoma in situ (CIS), invasive and metastatic bladder transitional cell
carcinoma (TCC) develop at 3–5 months (depending on the number of
transgene copies). Histology, progression and gene expression very similar
to human invasive urothelial tumours.
CK19-Tag (cytokeratin 19 gene) Urothelial cells; both large T and small t Multistage disease progression beginning with bladder CIS and
progressing to stromal and tissue invasion resulting in highly invasive
bladder neoplasms. 20% of mice also develop lung metastatic disease.
Histology, progression and gene expression very similar to human invasive
urothelial tumours.

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Table 1 (Continued)

Tumour type Transgenic mouse model Cell type SV40 targeted to and region of Features of the model References
(promoter used) SV40 used

[158]

Liver cancer ASV (human antithrombin III gene) Hepatocytes; both large T and small t 100% penetrance and 10% get lung metastasis. Multistage disease [159]
progression with tumours developing rapidly. Histology and multistage
progression similar to human hepatocellular carcinomas (HCC). Human
HCC develop slowly which is the major difference with this model.
AT3-Stop-Tag (see ASV above) Hepatocytes; both large T and small t HCC tumours develop in 5 months after administration of adenoviral [160]
Cre-recombinase or tamoxifen-inducible Cre. Histology and multistage
progression similar to human HCC.

E.K. Colvin et al. / Seminars in Cell & Developmental Biology xxx (2014) xxx–xxx
AAT/Tag (␣-1-antitrypsin gene) Hepatocytes; large T only HCC tumours develop in 2–6 months. Kidney hyperplasia and carcinomas [161]
of the stomach and pancreas also identified. A liver only stable 1812
transgenic line also identified.

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ST (serum amyloid P component Hepatocytes; large T only HCC tumours develop in 2–3 months [162]
promoter)
Alb/Tag (albumin enhancer Hepatocytes; both large T and small t HCC tumours develop in 3–5 months. Activating point mutation of c-H-ras [163–166]
promoter) oncogene identified in 40% of mice. A conditional model with the same
name using the same promoter also exists.
MUP/Tag (major urinary protein Hepatocytes; both large T and small t HCC tumours develop in 2–8 months. Androgen regulated and highly [167,168]
promoter) active in males. A conditional model with the same name using the same
promoter also exists.

Melanoma Tyr-SV40E/TySV40 (tyrosinase Pigment cells; both large T and small t Ocular and cutaneous melanomas characterised by hypo-rather than [169,170]
promoter) hyper-pigmentation. Ocular tumours originated in the retinal pigment
epithelium (RPE) and were aggressive, highly invasive and metastatic with
the liver being the primary site. Histology similar to pigmented intraocular
and cutaneous human melanomas.
Tyr-Tag (tyrosinase promoter) RPE; both large T and small t Multistage progression beginning in the RPE with subsequent retinal and [171]
choroidal invasion, extraocular extension and metastasis. No cutaneous
disease identified. Histology, growth and response to treatment closely
resembles human uveal (choroid) melanoma. Human uveal melanoma
begins in the melanocytes whereas in this model disease originates in the
RPE.
TRP-1/Tag (tyrosinase-related RPE; both large T and small t Pigmented epithelial tumours develop. By 3 months metastatic disease [172]
protein 1 promoter) was identified in the lymph nodes and spleen. Histology, growth and
response to treatment closely resembles human uveal melanoma. Human
uveal melanoma begins in the melanocytes whereas in this model disease
originates in the RPE.

Retinoblastoma LH␤-Tag (luteinizing hormone Gonadotrope cells of the anterior pituitary; Originally developed as a model for pituitary adenomas. However, one [173,174]
␤-subunit gene) both large T and small t transgenic mouse developed ocular neoplasms with 100% penetrance in
their offspring. Ocular neoplasms develop by 5–6 months with multistage
progression starting in the inner retinal layer, progressing to choroid and
then invading the optic nerve with extension into the brain. Ocular
neoplasm very similar to human retinoblastoma in terms of histology,
ultrastructure, morphology, tumour progression and invasion.
Pax6-TAg (Pax6 promoter) Embryonic retina; both large T and small t Transgene expressed in the undifferentiated still proliferating embryonic [175]
retina. Retinal and lens tumours identified by embryonic day 12.5 with
100% penetrance. Retinal-derived tumours invade choroid and metastasise
to the brain. Histology very similar to human retinoblastoma.
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Fig. 1. Historical timeline of key dates in SV40 Tag research. Red hatched lines indicate the development of major SV40-based cancer models. Black solid lines indicate key
SV40 research findings.

While not all of the SV40 transgenic cancer models are still used protein. Importantly, these studies also identified a protein of host
today, mainly due to uncovering the real ‘genetic players’ in the dis- origin that was found to bind to the large T viral protein [11,12].
ease, for some cancer types such models are still highly relevant due The identification of this 53 kDa protein, now known as p53, has
to similar genotypes and phenotypes being present. This review been fundamental to cancer research.
provides an overview of SV40 mouse models of several human can- In 1978, complete sequencing of SV40 revealed two major
cer types and discusses their strengths and weaknesses. Additional genome regions for SV40: one encoding the early proteins (large
models are summarised in Table 1 and due to space constraints T, small t and a third protein known as 17 KT antigen) which were
apologies are given for any research we were unable to include. It expressed from the early promoter after differential splicing, and
also seeks to provide a brief history on the origins of SV40 and how the other encoding the late structural proteins which make up the
this virus has become of monumental importance in the cancer capsid [13]. The proteins encoded by the early region of the genome
research world. were originally identified to be responsible for cell transforma-
tion. Later studies revealed that only large T antigen was required
[14] with small t being incapable by itself; however, when used in
2. Origins of SV40 research conjunction with large T, could enhance the effects.

SV40 was one of the first DNA tumour viruses to be discovered,

a small circular virus of the Polyomaviridae family. SV40 is a non-
enveloped virus with an icosahedral capsid and a double stranded 2.1. SV40 Mechanisms
supercoiled DNA genome of 5.2 kb. First discovered in 1953 as an
unknown agent that could promote salivary gland carcinoma when SV40 is able to take control of the host’s cellular machinery
inoculated into newborn mice [3], SV40 was soon identified as a for its own replication, as well as being able to integrate into the
new virus [4] with tumorigenic properties [5] and cell transforming cell genome to cause malignant transformation. The main cellular
abilities [6]. mechanisms used by SV40 to achieve malignant transformation are
While SV40 does not naturally infect humans, due to its ability inactivating the tumour suppressors p53 and retinoblastoma (Rb),
to cause cancer in animals it became a major cause of concern when which forces host cells back into S-phase of the cell cycle, allowing
it was discovered as a contaminant in poliovirus vaccines admin- them to escape normal apoptosis. By binding to p53, large T anti-
istered to an estimated 127 million people worldwide between gen stabilises the protein, increasing its half-life and preventing it
1955 and 1963 [7,8]. Research therefore focused on detecting SV40 from being degraded, consequently inactivating its normal apop-
in human sera samples and discovering how it functioned due to totic gatekeeper function. Additionally, binding to Rb and to a lesser
the potential pandemic that could arise. Early experiments using extent the other Rb protein family members p107 and p130, results
sera from SV40-infected animals identified two major viral pro- in a loss of suppression of the E2F transcription factors that induce
teins [9,10]; large T antigen (TAg), a 90–100 kDa protein located expression of cell cycle-promoting genes (reviewed in Ihler et al.
in the nucleus, and small t antigen (tag), a smaller 17–22 kDa [15]). Together these two events result in inactivation of cell cycle

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checkpoints which results in highly proliferative and uncontrolled generated, all of which formed tumours, however the RIP1-Tag2
cell growth (reviewed in Atkin et al. [16]). line is the most commonly used and well-characterised. RIP1-Tag2
While inactivation of both p53 and Rb by SV40 is essential for mice are born with normal pancreatic islet morphology, which pro-
cellular transformation, studies have also shown that large T anti- gresses to form multiple ␤-cell tumours (insulinomas). Multistage
gen interacts with a number of other host proteins including hsc70, tumour progression begins with hyperplasia in up to 75% of islets
CBP/p300, Cul7 IRS1, Fbxw7 and Bub1 (reviewed by Cheng et al. at 3–4 weeks of age [36], followed by induction of angiogenesis
[17]). Additionally, small t antigen has been found to interact with in approximately 10% of islets by 10 weeks [37] and finally the
the tumour suppressor serine-threonine protein phosphatase 2A development of solid, encapsulated tumours by 14 weeks. Despite
(PP2A) leading to a number of signalling pathways that enhance all of the islets expressing SV40 Tag in this model, only 1.5–2%
the transformation and tumorigenic potential of large T antigen; progress to form tumours, indicating additional genetic events
reviewed by Cheng et al. [17]. All these functions of SV40 make it are required for oncogenesis. Consequently, several genes have
a powerful tool for generating mouse cancer models as only a sin- since been identified that influence tumorigenesis in this model,
gle transgene is required for tumorigenesis. This is in contrast to including IGF-II [38] and Bcl-xL [39]. Further genetic characterisa-
many other mouse models where targeting of at least two endoge- tion of RIP1-Tag2 tumours demonstrated several chromosomal and
nous genes is required, making SV40 models much faster and cost DNA copy number changes [40–43] that could potentially influence
effective to produce. tumour progression. Additionally, microRNA profiling of RIP1-Tag2
tumours and metastases revealed that each stage of tumorigene-
3. Is SV40 an aetiological agent in human malignancies? sis has a unique microRNA profile. Importantly, these microRNAs
were similarly altered in several human cancers, including a partial
While SV40 has potent tumorigenic potential and cell trans- overlap with human pancreatic neuroendocrine tumours [44].
forming abilities in certain species, its ability to cause cancer in Of significance, this model was one of the first in vivo mod-
humans remains controversial. Published data argues both for and els to successfully demonstrate the requirement of angiogenesis
against the role of SV40 as a human carcinogen with brain [18–20], in tumour formation [37]. Since then, the RIP1-Tag2 model has
malignant mesothelioma [21–25], blood [26,27] and bone [28,29] been used extensively to investigate mechanisms of angiogenesis
malignancies being more significantly associated with the virus. [45–50].
SV40 biological markers have been found in these tumours and The clinical relevance of the RIP1-Tag2 as a model of pancre-
although a number of studies have identified potentially flawed atic neuroendocrine tumour, specifically insulinoma, is debatable.
laboratory techniques as the reason for this (reviewed in [30]), it The role of the SV40 target p53 has been widely investigated in
remains unclear as to whether the remaining data suggests causal- pancreatic neuroendocrine tumours, with the majority of studies
ity [31,32]. finding that mutation of TP53 is not a common feature of these
tumours [51–53]. However, a recent study has identified that neg-
ative regulators of p53 activity, specifically MDM2, MDM4 and WIP1,
4. Transgenic mouse models of cancer are aberrantly activated alone or in combination in approximately
70% of human pancreatic neuroendocrine tumours [54]. Similarly,
4.1. Brain cancer models allelic loss of RB1 is not a feature of pancreatic neuroendocrine
tumours in humans [55], however Rb pathway components Cdk4
The first milestone in the development of SV40-induced mouse and Cyclin D1 are overexpressed in a significant proportion [56].
models of cancer occurred in 1984 when Brinster and colleagues This indicates that the use of SV40 to inhibit p53 and Rb activity
first demonstrated that SV40 caused tumours in mice [2]. This in pancreatic ␤ cells in order to induce tumours has some rele-
model introduced the early coding region of SV40, both the large vance. In addition, both TP53 and RB1 have recently been found to
T and small t, into a metallothionein promoter/regulator fused be mutated in the majority of poorly differentiated neuroendocrine
to the thymidine kinase structural gene of herpes simplex virus, carcinomas of the pancreas [57]. Interestingly, closer analysis of the
type 1, to generate SV-MK transgenic mice. SV-MK mice developed RIP1-Tag2 model has revealed that 70% of mice develop at least one
thymic hypertrophy and kidney pathology as well as choroid plexus poorly differentiated invasive carcinoma in addition to insulinomas
epithelial (CPE) tumours. These mice revealed a number of impor- [58]. Finally, the RIP1-Tag2 model has proven utility in predicting
tant findings in relation to the oncogenic potential of SV40: firstly the efficacy of several therapeutics in treating human pancreatic
small t was not essential for tumorigenesis as it was noted that neuroendocrine tumours [59–61].
choroid plexus tumours still developed when a construct with only Other SV40 models of pancreatic neuroendocrine tumours
large T antigen was used; secondly, the MK fusion gene and the site include the Vasopressin-SV40 mouse, which develop insulinomas
of integration were not important for causing CPE-specific tumours and tumours of the anterior pituitary. Also, several models of
[33]. These experiments led to the generation of SV11 transgenic glucagonoma have been developed. Variations of the glucagon gene
mice which carried the SV40 native enhancer promoter region and promoter have successfully been used to target SV40 expression to
only large T antigen, with no tissue-specific promoter. SV11 mice the pancreatic ␣-cells and mice develop glucagonomas [62–65].
developed anaplastic foci of CPE cells by 36–41 days, which consis- In addition to pancreatic neuroendocrine tumours, SV40 mouse
tently progressed to CPE tumours. These tumours showed a clear models of pancreatic acinar cell carcinoma have been developed
progression of cancer development, transforming from papillary to using elastase or amylase 2.2 promoters to drive SV40 expression
non-papillary cells and becoming invasive in later stages [34]. The (Table 1).
successful generation of tumours in these early models led to the
generation of SV40 mouse models of many other tumour types. 4.3. Bone cancer models

4.2. Pancreatic cancer models One of the first mouse models that developed bone cancer used
the mouse protamine gene (mP1) fused to the early coding region
One of the most widely used SV40 transgenic models was first of SV40 (mP1-SV40) to induce expression in round spermatids [66].
published by Hanahan in 1985, which targeted the early region Interestingly, while this study attempted to determine the sus-
of SV40 to pancreatic ␤-cells using the rat insulin promoter (RIP) ceptibility of haploid spermatids to neoplastic transformation by
[35]. Several founder mice and subsequent transgenic lines were large T antigen, these transgenic mice also developed both heart

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and bone tumours. A more refined model was developed in 1990 4.5. Prostate cancer models
which used the mouse alpha-amylase (Amy-1a ) late gene promoter
fused to the early coding region of SV40 to generate Amy-1a 501 lin- The first transgenic model of prostate cancer was developed
eage transgenic mice [67]. A high proportion of these mice (67%) by using the rat prostatic steroid binding protein [C3(1)] gene to
develop osteosarcomas by 15–20 months with 30% also developing drive SV40 early region expression in the mouse prostatic epithe-
liver metastases, thus resembling osteosarcoma development and lium [79]. Male mice developed prostate hyperplasia from 3 months
metastases in humans. A number of other promoters have also been that progressed to prostatic intraepithelial neoplasia (PIN) and then
used in an attempt to develop bone tumour models [68–70]. Inter- adenocarcinomas after 8 months of age. However, a limitation of
estingly, regardless of the promoter used the most frequent site this model is the lack of specificity of the C3(1) promoter, with
of osteosarcoma development in these models was in the cranial tumours developing in other organs [80]. Conversely, it was this
bones. lack of specificity which led to the identification of the C3(1)/TAg
A more recent and relevant development in osteosarcoma mod- breast cancer model that developed in female transgenic mice (dis-
els was made in 2010 with the generation of Murine Osteocalcin cussed in Section 4.6).
Tag Osteosarcoma (MOTO) transgenic mice [71]. These mice were To better restrict transgene expression, the rat minimal probasin
developed by directing expression of large and small T antigens (PB) promoter was used, to direct expression of the SV40 early
to the mature osteoblasts using the osteocalcin promoter. These region to the prostate epithelium [81]. The resulting transgenic ade-
mice developed normally and formed multi-osteotic bone tumours nocarcinoma mouse prostate (TRAMP) model has become the most
with 100% penetrance and morbidity by 21 weeks of age. MOTO widely used and well-characterised model of prostate cancer and
mice developed skeletal tumours with varying degrees of calcifi- has been extensively used to test various therapies and chemo-
cation at all sites known to be affected in human osteosarcoma, prevention strategies. Mice develop PIN as early as 6 weeks, which
particularly in the long bones. However, similar to other SV40 progresses to high-grade PIN (HGPIN) by 12 weeks and poorly dif-
induced models, development of craniofacial tumours was fre- ferentiated adenocarcinomas by 24 weeks of age [82,83]. One of
quent. Metastatic disease of the lungs occurred in 90% of transgenic the main advantages of the TRAMP model is that all mice demon-
animals, and less frequently in the liver, kidney and spleen, again strate metastases to distant sites such as lymph nodes and lung,
consistent with human osteosarcoma [71]. Interestingly, genome an occurrence that has been difficult to replicate in other prostate
deletion of Prkar1a was identified in these mice, which was found cancer mouse models (reviewed in [84,85]). Mice do not commonly
to correspond with a subset of human osteosarcoma patients. By develop bone metastases, a major site of metastasis in human
all definitions including histopathology, disease development and prostate cancer; however, crossing TRAMP mice on a C57BL/6 back-
progression as well as genomic aberrations, the MOTO mouse rep- ground to FVB mice increases the incidence of bone metastases
resents a viable model for studying osteosarcomas. In addition, the [83].
established role of both p53 and Rb in the development of human Similar to many other SV40 cancer models, the TRAMP model
osteosarcoma further strengthens the validity of using SV40-based has been crossed with several other transgenic mice to investi-
models (reviewed by Ng et al. [72]). gate genes and pathways that influence prostate cancer progression
including caveolin-1 [86], EGR1 [87] and IGF-1 [88–90].
The major criticisms of the TRAMP model are based on the use
4.4. Blood cancer models of the androgen-dependent PB promoter, confounding the study
of castration-resistant prostate cancer, and the fact that tumours
The ability of SV40 to induce blood cancers was first reported in primarily resemble neuroendocrine carcinomas [91]. While neu-
1987. Suda et al. [73] directed the expression of SV40 large T anti- roendocrine prostate tumours are rare in humans, neuroendocrine
gen to lymphoid cells using the immunoglobulin (Ig) gene enhancer differentiation occurs in greater than 30% of prostate adenocarci-
linked to the SV40 promoter as the regulatory unit. Transgenic mice nomas and is associated with a poor prognosis [92]. Despite the
developed a number of non-specific tumours including choroid limitations of the TRAMP model, it still remains one of the most
plexus tumours, B cell lymphomas, histiocytic lymphomas and thy- widely used models to investigate prostate cancer progression and
momas. In 1994 large T antigen and the Ig enhancer were again metastasis.
used to generate a mouse transgenic mouse which developed fea- Another model similar to TRAMP was developed using the large
tures resembling pre-leukemias or myelodysplastic syndrome in probasin (LPB) promoter to drive expression of large T antigen to
humans [74]. It was not until over a decade later when the first SV40 the mouse prostate. LPB-Tag (also known as LADY) mice develop
mouse model that consistently developed chronic B cell lympho- PIN by 10 weeks of age that progresses to carcinoma and rare
cytic leukaemia (B-CLL) was developed [75]. This model introduced metastasis [93]. Characterisation of one of the transgenic lines
SV40 large T antigen without its promoter, and in antisense ori- revealed that, like the TRAMP model, neuroendocrine differenti-
entation, in between IgH chain D and JH gene segments of the ation was present in tumours [94]. Metastases in this model could
mouse. In pro-B cells, antisense transcription occurs, meaning this be increased by crossing with mice transgenic for Hepsin [95].
backward T antigen sequence is transcribed in early pro-B cells. Significantly, double transgenic mice developed skeletal metas-
When IgH gene arrangement occurs in the process of B cell matu- tases.
ration, the large T antigen is excised; rarely, some B cells maintain Additional SV40-induced prostate cancer models have been pro-
their germline arrangement and therefore still contain the intact duced that use different promoters to target SV40 to the mouse
large T antigen, generating IgH.T and IgH.TE␮ transgenic mice. prostate. These include the PSP94-SV40 [96], CR2-T-Ag [97], G␥/T-
IgH.T and IgH.TE␮ mice are born normal and develop leukaemia 15 [98] and TgAPT121 [99] and are summarised in Table 1.
in the blood, bone marrow and spleen by 10 months of age. Dis- Inactivation of p53 and Rb using SV40 can be considered a
ease development in these mice reflects the development of human relevant approach to developing models of prostate cancer; Rb
B-CLL [75,76] where both p53 and Rb are implicated. TP53 muta- signalling is altered in 34% of human primary prostate tumours
tions occur in 8–10% of human B-CLL, however mutation rates are and 74% of metastases, while heterozygous or homozygous copy
significantly higher in refractory B-CLL (reviewed in [77]). Also, number loss of TP53 occurs in approximately 24% of tumours [100].
type II deletions of 13q14, which span the RB1 gene are present in Importantly, conditional inactivation of both p53 and Rb in the
20% of B-CLL patients and are associated with a decreased survival mouse prostate yields a similar phenotype to the TRAMP model
[78]. [101].

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4.6. Breast cancer models bronchiolar cells (Clara), Type II alveolar cells and mucin-producing
cells [118]. The first SV40 lung cancer model attempted to target
There are two major SV40 breast cancer mouse models: the expression of the early region of SV40 to Clara cells using the rabbit
WAP-T and the C3(1)/TAg model. The WAP-T model was first cre- uteroglobin gene promoter, homologous to the human Clara cell
ated in 1993 [102] and is still used today. This model targets the 10 kDa (CC10) protein promoter [119]. As well as developing mul-
expression of the early coding region of SV40 specifically to the tifocal bronchioloalveolar adenocarcinomas, mice also developed
mammary gland epithelial cells through transcriptional control tumours in other secretory epithelial cells [120]. Later experiments
of the whey acidic protein (WAP) promoter. During late preg- refined the model by using the mouse CC10 promoter to initiate
nancy, the transgene is expressed in the epithelial cells of the tumorigenesis in the Clara cells, resulting in little or no off-target
terminal ductal lobular units (TDLUs) of the differentiating and effects [121]. At 2 months of age mice developed areas of bron-
lactating glands resulting in premature mammary gland involu- chiolar epithelial hyperplasia which progressed into mixed solid
tion [103,104]. TLDUs represent the cell of origin for 80% of human and papillary adenocarcinomas with no metastatic disease by 5
breast cancer [105]. After the first lactation period transgenic ani- months [121–123]. These tumours resembled human non-small
mals begin to develop breast tumours. By 4–6 months of age 100% cell lung cancers (NSCLC) [124] in which RB1 and TP53 are mutated
of females develop mammary adenocarcinomas providing they in 15–30% and 47% of tumours respectively [125].
have undergone at least one pregnancy [106–108]. These tumours The second commonly used model targets expression of the
metastasise to the lungs in 55% of WAP-T animals, as well as rare early region of SV40 to the type II alveolar cells using the surfac-
liver and lymph node metastases [109]. This is unlike human breast tant protein C (SP-C) transcriptional element [126]. SP-C/TAg mice
cancer where metastatic disease is common, occurring in multi- developed pulmonary tumours along a predictable time course.
ple sites including the liver, bone, lung and brain. However, there Within 4–5 months adenocarcinomas with no metastatic disease
appears to be no efficient breast cancer mouse model available developed that were indistinguishable from human solid, papillary
which can recapitulate this [110]. and bronchioloalveolar adenocarcinoma subtypes. These were sim-
Based on histology, genetic profiling and expression of differ- ilar to those that developed in the CC10-TAg transgenic model even
ential markers, WAP-T tumours exhibit similarities to two distinct though SV40 expression was targeted to different cells.
histological subtypes: both basal-like triple negative (TN) and non- It is the much smaller group of lung cancers, the small cell lung
basal-like [108,111]. In basal-like TN and non-basal like tumours cancers (SCLC), where SV40 lung cancer models should be more
TP53 is mutated in 80% and 29% respectively [79,112,113] and Rb relevant as RB1 and TP53 are functionally inactivated in 90% and
is functionally lost in 72% and 62% respectively [114]. Interestingly, 75–100% of human SCLC respectively [127]. However, the CC10/TAg
gene expression patterns have been used to cluster together human model displayed no neuroendocrine features and therefore no sim-
breast cancer subtypes with mouse models. These results demon- ilarities with human SCLC. In an attempt to produce a mouse
strated that the WAP-T transgenic model is still relevant 20 years lung cancer model that more accurately reflected the neuroen-
after its development, particularly for studying the basal-like TN docrine phenotype of human SCLC, new models based on CC10-TAg
and luminal B subtypes [108,111]. However, caution must be taken were developed. The human acetate-scute homologue 1 (hASH1)
as this model is considered somewhat artificial due to its hormonal transcriptional factor was identified as being highly expressed
dependence. in pulmonary neuroendocrine cells as well as playing a critical
The C3(1)/TAg model was originally developed as a transgenic role in regulating the neuroendocrine phenotype [128]. Driving
model for prostate cancer, however it was soon identified that expression of hASH1 using the same CC10 promoter meant that
female mice also developed mammary gland cancer [79,115]. Sim- a bi-transgenic model could be created (CC10-TAg/CC10-hASH1).
ilar to the WAP-T model, this model targets the expression of the Even though this model did not recapitulate human SCLC, it did
early coding region of SV40 to the ductal epithelial cells, terminal closely resemble human NSCLC with neuroendocrine differentia-
buds and the TLDUs in virgin mammary glands [116]. However, tion.
unlike the WAP-T model, this model is hormone independent and Due to the failure to produce the neuroendocrine phenotype
tumours develop over a predictable time course [116]. By 8 weeks of of SCLC in transgenic animals, new models were again developed.
age 100% of transgenic animals develop mammary epithelial atypia These transgenic models used a truncated form of TAg, T121 , to only
that progresses to mammary intraepithelial neoplasia by 12 weeks inactivate the Rb family. Transgenic expression was directed to the
[79], similar to human ductal carcinoma in situ (DCIS), a well-known lung epithelial cells by either the CC10 or the SP-C promoter and
precursor to invasive breast cancer. Gene expression and histolog- resulted in neonatal lethality. However, post-mortem inspection of
ical analysis show these tumours resemble human basal-like TN the neonatal lungs revealed a neuroendocrine phenotype similar to
aggressive cancers with poor response. Invasive carcinoma gen- human SCLC [129]. Although lethal, these results indicated that the
erally develops after 16 weeks and approximately 15% of animals Rb family of proteins were essential in lung epithelium for neonatal
develop lung metastases. C3(1)/TAg tumours also exhibit loss of survival [129] and demonstrated a reason why SV40-driven SCLC
oestrogen receptor (ER) and are unresponsive to hormones, similar mouse models could not be created.
to human breast cancers that progress from ER positive to ER neg-
ative [116]. While lung is the predominant site of metastasis, other 4.8. Mesothelioma
sites such as liver, adrenal and heart have been found. No brain,
bone or lymph node metastases have been reported, limiting the Currently only one SV40 transgenic mesothelioma model has
use of this model [115]. been generated, the MexTAg. This model was first developed
in 2006 [130] and is considered a robust pre-clinical model for
4.7. Lung cancer models mesothelioma studies today [131,132]. While a lack of evidence
exists to conclude that SV40 can cause human mesothelioma, there
While SV40 lung cancer mouse models are still used today, still remains the probability that SV40 acts as a co-carcinogen in
primarily for immunological studies [117], each model has its lim- conjunction with asbestos. Previous evidence supports this theory
itations. as SV40 has been shown to increase the risk of mesothelioma devel-
The cell or cells of origin for lung carcinomas are not fully opment in asbestos-exposed individuals [133]. Recently it was also
understood. Much research has focused on the cell of origin being demonstrated that SV40 and asbestos acted synergistically to cause
derived from the pulmonary epithelial cells, including non-ciliated malignant transformation of human mesothelial cells [23]. Such

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studies support the validity of the MexTAg model. This model tar- A limitation of using the MISIIR promoter is SV40 gene
gets the expression of large T antigen to mesothelial cells using expression is present in the developing reproductive tract, how-
the mesothelin promoter and requires the addition of asbestos ever ovarian tumour development occurs from stochastic genetic
for disease development; therefore tumours can be targeted to changes in mature cells. To overcome this, a model was created
only mesothelial cells in tissues of interest. This requirement using a Cre-lox conditional SV40 mouse where SV40 was activated
for asbestos exposure correlates well with human mesothelioma in the ovarian surface epithelium (OSE) by injection of adenoviral
where exposure to asbestos fibres accounts for 80% of mesothe- cre recombinase under the ovarian bursa in mature 6–8 week old
liomas [134,135]. By 5–10 months after asbestos exposure 100% of mice [145]. Mice developed large vascular tumours with a median
MexTAg mice develop mesothelioma. This latency period is com- survival of 113 days. Intra-abdominal spread of tumours and the
parable with human mesothelioma development in terms of the development of ascites were common features of this model. His-
lifespan of the mice [131]. MexTAg tumours were histologically tologically, these tumours were classified as poorly differentiated
classified as sarcomatoid in nature, which represents the minor- carcinoma displaying features of sex-cord stromal tumours. Treat-
ity subtype in humans but also the most aggressive, with poor ment of these mice with oestrogen resulted in decreased survival
response to treatment [136]. Similarly, a previous study performed and the development of papillary histology [145]. Importantly, this
in human mesotheliomas found that SV40 expression was signif- model represents one of the few cancer mouse models that targets
icantly associated with sarcomatoid histology and represented an adult rather than developing cells, and represents an innovative
important prognostic cofactor [137], although contaminated lab- approach that could be applied to other cancer types.
oratory reagents may have contributed to this result. Response Using SV40 to generate mouse models of EOC can definitely be
to chemotherapy and the increased disease progression associ- considered a reasonable approach since both the p53 and Rb path-
ated with older MexTAg mice is consistent with findings in human ways are heavily implicated. TP53 mutations are present in 96% and
mesothelioma patients [131]. Another important attribute of this members of the Rb pathway are altered in 67% of human high-grade
MexTag model that mimics human mesothelioma tumours is the serous EOC, the most common and aggressive subtype of ovarian
genetic abnormalities identified. While RB1 and TP53 are genet- cancer [146]. However, other attempts to model serous EOC in mice
ically stable in the majority of human mesotheliomas, they are by using conditional inactivation of Trp53 and/or Rb1 directly have
functionally inactivated by upstream pathways. The most com- met with conflicting results. One study demonstrated loss of Trp53
mon aberration in human mesothelioma is homozygous deletion and Rb1 in the OSE led to the development of high-grade serous EOC
of p16INK4A /p14ARF which occurs in 90–100% of the sarcoma- [147], while in another model the same genetic changes resulted
toid subtype [22,138]. Thus the MexTAg model resembles human in the development of leiomyosarcomas, possibly due to transgene
mesothelioma in many ways and is a valid and clinically relevant activation in the ovarian bursa [148]. A recent study addressed
model to study. these issues by using T121 , expressed from the cytokeratin 18 pro-
moter, to selectively inactivate Rb and related proteins p107 and
p130 in the OSE and not the ovarian bursa [149]. Mice developed
4.9. Ovarian cancer models early changes in the OSE that led to the development of ovarian
tumours resembling stage I serous EOC in 18% of mice after 24
The development of SV40-driven ovarian tumour models has months. Tumour incidence and stage was increased by crossing
occurred relatively recently compared to the development of other with conditional Trp53 null or Trp53 mutant mice. Importantly,
cancer models. This has been due largely to the still unresolved gene expression profiling of tumours revealed similar changes to
cell of origin for ovarian cancer and the limited number of suitable human serous EOC.
tissue-specific promoters to drive oncogene expression.
One of the first successful attempts in generating ovarian cancer
in mice used an anti-Müllerian hormone (AMH) gene promoter to 5. Conclusions and perspectives
drive expression of SV40 large T antigen in the granulosa cells of the
ovary [139]. Granulosa cell tumours represent only a small propor- The discovery that the SV40 virus could induce tumorigenesis in
tion of ovarian malignancies and subsequent attempts to develop mice has led to the development of many mouse models of human
mouse models of ovarian cancer have focused on epithelial ovarian cancer, some of which are described in this review. Furthermore,
cancer (EOC). investigation into how SV40 transforms cells led to the discovery of
In 2003 Connolly et al. developed a model of EOC by using one of the most well-known and well-studied tumour suppressor
the Müllerian inhibiting substance type 2 receptor (MISIIR, also genes, TP53, as well as provided useful information into the function
known as Amhr2) to target SV40 large and small T antigen to of another well-known tumour suppressor, RB1. Given that pertur-
the developing reproductive tract [140]. 50% of females developed bation of both these tumour suppressor genes are implicated in
bilateral ovarian tumours between 6 and 13 weeks of age that were the vast majority of human cancers, SV40 models represent a legit-
characterised as poorly differentiated ovarian carcinoma. Tumours imate approach to study many human tumour types. Indeed, these
displayed dissemination to other abdominal organs and a propor- models have been used in several important discoveries relevant to
tion developed ascites, reminiscent of human disease. Due to the human cancer, such as the requirement of angiogenesis in tumour
rapid onset of tumours, females were infertile preventing the devel- formation and the discovery of genes relevant to human osteosar-
opment of stable transgenic lines. Several of the male founders coma. Despite the original SV40 tumour model being developed
developed testicular tumours, but were able to be bred and a male three decades ago and the emergence of more sophisticated mouse
founder was used to establish the TgMISIIR-Tag-DR26 line [141]. modelling techniques, SV40 models still represent the primary
From this line, 100% of females developed bilateral ovarian tumours mouse model for several cancer types. As with any mouse model
with a median survival of 152 days and histology similar to the orig- of human cancer, SV40 models do have several limitations. For
inal female founders. Further studies using these mice confirmed most human cancer types, SV40 is not considered an aetiological
the overexpression of several markers also increased in human factor and the validity of using SV40 models can be disputed for
EOC [142]. This model has since been used in developing imaging this reason. However, due to SV40’s ability to inactivate p53 and
modalities to visualise tumours in vivo [141,143] as well as inves- Rb, SV40 models have still proven useful in investigating human
tigating the role of immune complement in tumour progression cancers where p53 and Rb are implicated. Approximately 75% of
[144]. TP53 mutations in human cancers are missense mutations known

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Please cite this article in press as: Colvin EK, et al. SV40 TAg mouse models of cancer. Semin Cell Dev Biol (2014),
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