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tissue sarcomas, osteosarcomas, ependymomas and is mediated by the expression of the viral oncoproteins
choroid plexus papillomas, and neoplasms of the identified as E6 and E7. The role of HPV E6 and E7
hematopoietic system, such as lymphocytic leukemia, oncoproteins in HPV-associated cervical carcinogenesis
histiocytic lymphomas and rarely, and B-cell lymphomas, is mainly due to their interaction with the cellular tumor
respectively. [87,110-112] Direct inoculation of SV40 into the suppressor p53 and members of the pRB family,
pleural space induces malignant mesothelioma in 100% respectively. [136-138] The mechanisms of action of HPV
of the injected hamsters. [111] The oncogenic potential of cause genetic instability and cell transformation resulting
SV40 is confirmed by the generation of transgenic mice in in cell cycle regulated escape and inhibition of apoptosis-
which polyomavirus large Tag expression is regulated by hallmarks of cancer initiation and progression. [139] Studies
the native viral early promoter enhancer. [113] Furthermore, on the association between HPV and cervical neoplasia
SV40-transgenic mice develop ependymomas and choroid have indicated a strong link between these oncogenic
plexus papillomas, as well as other neoplasms. [87,114-116] virus types. [140]
Many reports were published on SV40 sequences
detected, at high prevalence in human cancers of the Research demonstrates that only a fraction of HPV-positive
same histotypes induced by this small DNA tumor virus women develops genital tumors. [141] Indeed, the majority of
in experimental animals, that is, lymphoproliferative patients who are infected with HPV can clear these viral
disorders, mesothelioma, and bone and brain tumors. [72,117,118] agents naturally within 1 year. [142] Persistent infection
SV40 sequences were also detected at low prevalence in with HR HPV at a high viral load in cervical mucosa is
healthy subjects. [119-121] considered the main cause of the initiation and progression
of genital tumors [143] as it is a well-established cause of
Most of these studies were obtained by polymerase chain cervical cancer. In addition to E6 and E7 transformations,
reaction techniques. More recently, investigations reported HR HPV oncogenic types 16, 18, 31, 33, 35, 45, 52, 58,
the detection at high prevalence of specific antibodies and 66 are associated closely with > 95% of cases of
in serum samples from patients affected by malignant squamous cell carcinoma of the cervix. [144] Moreover,
pleural mesothelioma, [122] glioblastoma multiforme, [123] only genotype HPV 16 accounts for > 55% of diagnosed
osteosarcoma, [124] ocular melanoma, [125] and non-Hodgkin tumors. [145] Although infection with HR HPV is the major
lymphoma, [126] suggesting an association of SV40 with risk factor associated with cervical cancer, some studies
these human cancers. Indeed, in serum samples from have reported a possible tumor-initiating and promoting
normal individuals [127-129] or patients affected by tumors, role in cervical cancer for other DNA tumor viruses. Taken
and [130,131] /other pathologies [132,133] unrelated to SV40, the together, this interaction may synergize with HPV in a
prevalence of antibodies against SV40 is lower than that normal cell to initiate and progress a tumorigenic cell. [146]
detected in human cancers found to be associated with
SV40. It is worth noting that taken at all, the prevalence of ONCOGENIC DNA VIRUSES AND
SV40 sequences and the prevalence of specific antibodies MODULATION OF THE NOTCH PATHWAY
against SV40 in these human tumors/normal tissues and
sera, respectively, are very similar. This result indicates As previously discussed, the Notch signaling pathway
that SV40 is also a human virus, which infection occurs influences cell fate decisions, proliferation versus
at low prevalence in normal individuals. Altogether, differentiation, and cell survival. Similarly, viruses in
these data suggest that this small DNA tumor virus of infected cells promote cell survival, promote or block cell
monkey origin seems to be associated at high prevalence cycling and employ a variety of mechanisms to evade
with specific human cancers. It is also possible that the innate cellular anti-viral responses to ensure their own
immunologic data are due to the cross-reactivity with a survival and multiplication. In light of these similarities,
new, still undetected, human polyomavirus closely related it is not surprising that several viruses highjack the
to SV40. Notch pathway to ensure the completion of their own life
cycles. [147]
HPV
HPV infection is considered to be the main oncogenic The first report of an interaction between a virus and
agent for the onset of female genital tumors. [134] HPVs the Notch pathway came from studies showing that
are non-enveloped small DNA tumor viruses, with a binding of Epstein-Barr virus (EBV) nuclear antigen 2
double-stranded genome of approximately 8.2 kb. HPVs (the transcriptional activator essential for EBV-driven
are sub-divided into 2 classes such as low-risk, which B-cell immortalization) to responsive promoters requires
are detected in mainly genital warts, and high-risk (HR), the interaction with the nuclear effector of Notch signaling
which are associated with invasive cervical cancer. HR CSL. [148] More recently, also, the Kaposi’s sarcoma (KS)-
HPV includes 15 types (16, 18, 31, 33, 35, 39, 45, 51, associated herpes virus replication and transcription
52, 56, 58, 59, 68, 73 and 82), whereas low-risk HPV activator protein (involved in controlling the switch from
includes 12 types (6, 11, 40, 42, 43, 44, 54, 61, 70, 72, 81 latency to lytic replication) has been found to activate lysis-
and 108). [135] However, the oncogenic potential of HPV related gene by binding to CSL. [149] Studies using γ-secretase

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