cell growth and differentiation by modulating mitogenic path- ways. Known classes of oncogenes include growth factors, tyro- sine/serine/threonine kinases, GTPases, and transcription fac- tors.(3) Due to a variety of mutational events such as single nu- cleotide polymorphisms or indels within the coding sequence, insertional misregulation in coding or promoter sequences, genomic aberrations such as translocations, copy number variations, and gene fusions, as well as modifications of regulatory transcription factors and miRNAs,(4)these genes can be activated and become tumor inducing agents. In contrast to the strict definition of cellu- lar oncogenes as positive regulators of the mitogenic pathway that may induce cancer if mutated or misexpressed, the concept of vi- rally derived oncogenes is used in a considerably broader sense and
78 from basic research to clinical applications
(5)Stehelin et al.(1976)
(6)Knudson(1971)
(7)Bishop(1991),Weinberg(1989) (8)Butel(2000),Temin and Rubin(1958) (9)Duesberg and Vogt(1970),Martin
(2004)
(10)Der et al.(1982),Parada et al.(1982) (11)Butel(2000)
(12)Baltimore(1970),Temin and Mizutani
(1970)
Virus Viral oncogene Cellular factor
HBV HBx p53, CBP/p300,
PI3K
HCV Core, NS3,
NS5A p53, pRb, TNFR,TBP, PI3K
EBV LMP-1 TRAFs, TRADD,
RIP, vimentin, JAK3 HPV E5-E7 p53, TNFR, pRb, p21, CycA, CycE HTLV-1 Tax pRb, CBP/p300, p21, CycA, CycE
HIV Tat CycT1, TFIIH,
P-TEFb, PKR, pCAF, CBP/p300, TAFII250
KSVH vIRF, vGCR,
Kaposin CBP/p300
Table 10.2:Frequent cellular targets of
viral oncogenes. Investigation of frequent targets of viral oncogenes lead to the identification of cellular proto-oncogenes. Only selected cellular factors are shown. From Boccardo and Villa(2007).
(13)Javier and Butel(2008),McLaughlin-
Drubin and Munger(2008),Teodoro and Branton(1997)
(14)McLaughlin-Drubin and Munger
(2008)
(15)Smith(1994)
includes all genes that code for protein factors that modulate mi- togenic, apoptotic or or immune pathways in ways that predispose the cell to malignant transformation.
Proto-oncogenes are positive regulators of the cell cycle and their activation usually has a dominant oncogenic effect (that is, in vitro transformation or in vivo oncogenesis occurs if at least one allele of the proto-oncogene is activated).(5) In contrast, tumor suppres- sors such as p53 or rb that are engaged DNA repair, repression of cell devision, and triggering of apoptosis are negative regulators of the cell cycle and their deactivation by means similar to oncogene activation has a recessive effect, requiring at least two transfor- mative mutations or "hits" in order to trigger oncogenesis.(6) The realization that multiple genetic events are necessary for cancerous transformation gave rise the theory of multi-step oncogenesis and it is now accepted that discrete genetic events cooperatively and suc- cessively confer survival advantages and thus clinical malignancy to the cancerous cell.(7)
As mentioned in previous sections, advances in the technol- ogy of culturing cells that can be infected with viruses lead to the possibility of employing viruses as biological model systems for oncology.(8) Based on the identification of the first cellularly derived oncogene in retroviruses(9)and followed by the realization that mu- tations in cellular proto-oncogenes are causative for most somatic cancers,(10)experimental investigations resulted in the discovery of more then 70 cellular proto-oncogenes(11)(see Table10.2for a list of selected examples). In addition, these studies revealed one of the major innovations of the viral world: the reverse transcriptase.(12)
Many viral factors modulate core cellular regulatory and defense mechanisms in order to increase the viral replicative time window, for example by inhibiting or modulating tumor suppressor proteins such as p53 and Rb to fixate the cell cycle and prevent apoptosis, or by inhibiting antiviral defense mechanisms such as cellular endonu- cleases.(13) While all these events predispose the cell to oncogenesis by enhancing proliferation of aberrant cells, these events are not sufficient for oncogenesis and further conditions such as somatic mutations, environmental risk factors, and immunosuppression are generally considered to be necessary for cancer formation.(14)
Viral genomes frequently contain cellularly or virally derived genes that facilitate persistence of the virus by decreasing recog- nition of viral factors by components of the adaptive and innate immune system, such as chemokines, cellular proliferation factors, and inhibitors of apoptosis (cf. ChapterIIIfor a discussion of viral strategies of immune evasion in a context of viral host factors).(15) Especially larger DNA viruses, as for example KSHV and Poxvirus, employ several passive and active strategies to evade the host im- mune system (see Table10.3). These strategies induce prolonged immunosuppression of infected cells and result in cellular stress as well as in unhindered modulation of mitogenic and apoptotic pathways, thereby creating an ideal background from which cancer
molecular mechanisms of tumor virus transformation 79
(17)Sun et al.(2005),Trivedi et al.(2004) (18)Engels et al.(2006),Miller et al.(1996)
1. Restriction of viral transcription by proviral, episomal, or epigenetic la- tency mechanisms
2. Infection of cellular compartments that are under lessened immune surveil- lance such as brain or kidney 3. Variation of the viral genome by error-
prone viral polymerases to decrease antibody and T-cell recognition of viral antigens
4. restriction of host major histocompat- ibility complex expression by viral inhibitors
5. Inhibition of antigen processing and presentation
6. Infections of immune cells
Table 10.3:Viral modulation of the host
immune system. Viral strategies to modulate the host immune system in order to support viral persistence. Derived fromButel(2000).
(19)Virimia: Medical condition where viral
particles have access to the bloodstream.
(20)Centurion-Lara et al.(2004) (21)Johnson and Desrosiers(2013) (22)An episome is a viral genome or parts
thereof persisting as linear or lariat (lasso-shaped) structures in the cellular cytoplasm or nucleus independently and physically separated from the host genetic material.
(23)Retroviruses insert their genome into
the host genome as an obligatory part of their life cycle. After viral entry, the viral RNA genome is reverse-transcribed into a double-stranded DNA molecule by a viral enzyme, reverse transcriptase. The double-stranded viral DNA is integrated into the host genome by the viral integrase enzyme. The integrated copy of the viral genome is termed a provirus and would resemble cellular genes if it were not under transcriptional control of a specific viral promoter element, the long terminal repeat (LTR). The integration site of the integrated genome, the provirus, is essentially random, although preferences for specific sequence motifs or chromatin states have been reported (Deichmann et al.,2011).
can arise.(16)
Similarly, the replication of some oncogenic viruses is controlled in healthy patients but increases to pathogenic levels in contexts of immunosuppression as, for example, induced by HIV infections or medication after organ transplants. While an intact immune system can remove rare neoplastic cells, immunosuppressed and persis- tently infected patients may harbor a critical mass of cells with virus-induced decreased immune surveillance, thus making suc- cessful proliferation and immune escape of cancerous cells possible. In addition, primary infections that favor survival of altered cells and promote opportunistic infections may act cooperatively with a subsequent infection of an oncogenic driver virus, as for example shown for HIV/KSHV and EBV/KSHV:(17)KSHV probably infects the whole genus homo; however, the cases of Kaposi’s sarcoma his- torically had only low incidence rates until the onset of the AIDS epidemic, after which the number of KSHV-associated cancer cases in immunosuppressed patients rose by several thousand percent(18)