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cardiotoxicity linked to the use of Notch inhibitors. [63] in the late pre-mRNA has also been detected. [79,80] SV40
is phylogenetically, closely related to HPyV. There is
The mutations causing the activation of Notch signaling evidence of similarity with respect to size (about 5.2 Kb),
have been identified for T-ALLs; however, little is genome organization, and DNA sequence. The tags of
[38]
known about the molecular mechanism involved in SV40, BKPyV, and JCPyV strongly cross-react with the
dysregulating Notch in other malignancies. Few activating same antisera [81,82] while a less, strong cross-reactivity is
mutations of the Notch pathway have been found in solid observed in most structural antigenic determinants of
tumor patients, with most being observed in non-small the viral proteins, named VP1, 2 and 3. A genus-specific
cells lung and head and neck cancers. In breast and capsid antigen, located on viral peptide VP1, has been
[64]
[65]
lung cancers, inactivation of Numb, a protein involved identified. The DNA sequences of SV40 share 70%
[83]
in Notch1 downregulation, has also been identified. [64,66] homology with BKPyV, and 69% with JCPyV. The
[85]
[84]
Rearrangements of the Notch gene families have been greatest homology is found in the early region coding for
found in breast cancer. [67] the Tags and tags, whereas a lower homology is detected
in the regulatory region.
THE ROLE OF SMALL DNA TUMOR VIRUSES
IN THE PATHOGENESIS OF CANCER Transformation of rodent and human cells by SV40
is induced by the 2 oncoproteins, Tag and tag, which
SV40 display multiple functions. The main activity of Tag
[69]
SV40 is a monkey virus, which was accidentally for cell transformation and tumorigenesis is to target
[68]
administered to humans, in the years 1955-1963, through key cellular proteins, [86-88] such as the tumor suppressor
contaminated poliovirus vaccines. [69,70] However, a more p53 [89-91] and retinoblastoma protein (pRB) family
recent study indicates that some oral poliovirus vaccines proteins, inactivating their functions. [92-94] SV40 Tag may
were contaminated with infectious SV40 in sub-sequent also lead to transformation by inducing mutations to the
[95]
years. Early experiments both in vitro and in vivo cellular genome or numerical and structural alterations
[71]
classified SV40 as a transforming and oncogenic viral agent. of chromosomes, [96,97] such as gaps, breaks, dicentric
These activities are due to SV40 large tumor antigen (Tag) and ring chromosomes, chromatid exchanges, deletions,
[98]
and small tumor antigen (tag), which act as activated viral duplications, and translocations. The principal role of
oncogenes. [69,70] These studies addressed a new wave of the tag in transformation is to bind the catalytic (36 kDa)
investigations into the potential of SV40 to induce cancer in and regulatory (63 kDa) sub-units of protein phosphatase
humans. To date, hundreds of molecular and epidemiologic 2A (PP2A), [69,86] inactivating their function. Moreover,
studies aimed at investigating whether SV40 infects tag interacts with the centrosome and blocks mitosis in
[99]
humans, its potential mode of transmission and its putative human cells, suggesting that it may disrupt cell cycle
role in human tumors have been carried out. [72-74] progression. Recently, it has been shown that in human
mammary epithelial cells tag activates PI3K [100] an enzyme
SV40 was assigned to the family of Papovaviridae, an involved in pathways crucial for cell proliferation, and
acronym proposed by Melnick obtained by fusing the transformation through phosphorylation of the hydroxyl
[75]
names of the 3 representative viruses papilloma, polyoma, moiety present on the phosphatidylinositol inositol
and vacuolating agent. However, this nomenclature at ring. Aberrant regulation of EGFR upstream from PI3K
present is considered obsolete. More recently, SV40 has through mutations in EFGR can lead to cancer promotion
been enclosed among polyomaviruses, together with in glioblastoma. [101,102] In addition, SV40 tag can enhance
the human polyomaviruses (HPyV), BK Polyomavirus transcription from E2F-activated promoters of early
(BKPyV), and JC polyomavirus (JCPyV). The virion is growth response genes. [103,104] The process of rodent cell
about 45 nm, an icosahedral particle, with a density of 1.34- transformation induced by SV40 typically depends on the
1.35 g/cm . The viral genome is a circular, double-stranded integration of the viral DNA into the host genome
3
DNA molecule. SV40 encodes for six main viral proteins: where it produces a high level of expression of the major
Two early non-structural polypeptides, Tag and tag, an viral oncogenic proteins, Tag, and tag. However, human
agnoprotein, probably involved in the assembly of viral cells experimentally transformed by SV40 harbor viral
particles and processing of late messenger RNA (mRNA) genomes in an episomal state in addition to integrated
and 3 capsid proteins, VP1, VP2 and VP3. [76-78] The early viral DNA. SV40 immortalized [105] and transformed
and late genes are transcribed on different DNA strands in human cells [106-108] can induce tumors when implanted
a way that the transcription proceeds divergently from the subcutaneously in autologous hosts. [107] An SV40 Tag
regulatory region. This region contains the origin of DNA needs cooperation of the catalytic sub-unit of telomerase
replication and binding sites for the transcription factors and the activated c-HRas oncogene, for the complete
that control viral gene expression and terminates within transformation of human cells, as shown in cotransfection
DNA sequences containing the polyadenylation signals. experiment. [109] SV40 is highly oncogenic in rodents
Recently, a predicted late polarity pre-microRNA to the and when inoculated subcutaneously, intra-cerebrally,
untranslated region 3’ of the polyadenylation cleavage site or intra-venously in newborn hamsters induces soft

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Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ Issue 1 ¦ January 15, 2016 ¦