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View and review on viral oncology research

View and review on viral oncology research To date, almost one and a half million cases of cancer are diagnosed every year in the US and nearly 560,000 Americans are expected to die of cancer in the current year, more than 1,500 people a day (data from the American Cancer Society at http://www.cancer.org/). According to the World Health Organization ( WHO), roughly 20% of all cancers worldwide results from chronic infections; in particular, up to 15% of human cancers is characterized by a viral aetiology with higher incidence in Developing Countries. The link between viruses and cancer was one of the pivotal discoveries in cancer research during the past Century. Indeed, the infectious nature of specific tumors has important implications in st terms of their prevention, diagnosis, and therapy. In the 21 Century, the research on viral oncology field continues to be vigorous, with new significant and original studies on viral oncogenesis and translational research from basic virology to treatment of cancer. This review will cover different viral oncology aspects, starting from the history of viral oncology and moving to the peculiar features of oncogenic RNA and DNA viruses, with a special focus on human pathogens. A brief history of viral oncology rus) [9]. As far as primates is concerned, in 1962, Eddy, The first evidence of tumor viral aetiology dates back to Hilleman, and co-workers showed the tumorigenic 1907 when Ciuffo and co-workers showed that human potential of simian virus 40 (SV40) [10,11] while, interest- warts could be transmitted by cell-free filtrates derived ingly, Trentin and colleagues reported, for the first time, from lesions [1]. Seventy years later, papillomaviruses that viruses could be linked to cancer development also were linked to human cancer. In 1908, Ellermann and in humans, at least under experimental conditions. Bang, reported that also leukemia could be transferred to Indeed, these authors showed that specific human adeno- healthy chicken by a cell-free filtrate of cells obtained viruses are tumorigenic in experimentally infected ani- form affected birds [2]. Moreover, in 1911, Rous and col- mals [12]. Starting from then, studies were focused on leagues showed that the spindle cell sarcoma could be connection among viruses and human cancer. In 1965, transmitted to healthy chickens using filtered cell-free Epstein, Barr, and colleagues were able to visualize by tumor extracts [3]. This study led to the identification of electron microscopy herpesvirus-like particles in a cell the first oncogenic virus: the Rous sarcoma virus (RSV). line, established from Burkitt's lymphoma (BL) [13]. This Over the next four decades after the discovery of RSV virus resulted to be biologically and antigenically distinct new tumor viruses were identified. In particular, in 1935, from other known human herpesviruses [14] and was Rous and Beard demonstrated that the cottontail rabbit named Epstein-Barr Virus (EBV). In addition to a causal papillomavirus (CRPV), discovered few years earlier [2], role in BL, EBV infection has been subsequently associ- was able to induce skin carcinomas in domestic cottontail ated with nasopharyngeal carcinoma, post-transplant rabbit [4]. Moreover, in 1951, studies by Gross and co- lymphomas, and some Hodgkin's lymphomas (HL), thus workers led to the identification of the first mouse leuke- representing the first known human tumor virus. In the mia virus (murine leukemia virus) [5], later confirmed by same year, Blumberg, during a study aimed to correlate Moloney and others [6-8], and in 1953 of a mouse virus inherited polymorphic traits in different geographic areas that induced a variety of solid tumors (mouse polyomavi- of the world with particular disease patterns, found that one blood sample from an Australian aborigine contained * Correspondence: giorgio.palu@unipd.it an antigen that reacted specifically with the serum from Department of Histology, Microbiology and Medical Biotechnologies, an American haemophilia patient. This antigen was Division of Microbiology and Virology, University of Padova, Via A Gabelli 63, named the Australia (Au) antigen and its role was Padova 35121, Italy unknown till a technician working with human sera con- Full list of author information is available at the end of the article © 2010 Bergonzini et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com- mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduc- BioMed Central tion in any medium, provided the original work is properly cited. Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 2 of 11 http://www.infectagentscancer.com/content/5/1/11 tracted hepatitis, becoming Au antigen-positive. In 1967 from patients [30]. Moreover, patients with ATL but not and 1968, Blumberg, Okochi, Murakami, and Prince, control individuals were shown to produce antibodies published seminal studies showing that blood from hepa- that specifically recognized antigens expressed in HTLV- titis patients contained the Au antigen [15-17], being the 1-infected human T-cells. Since then different molecular surface antigen of a hepadnavirus called hepatitis B virus mechanisms behind HTLV-1 oncogenic activity have (HBV), the aetiologic agent of serum hepatitis disease been undisclosed and will be analysed later on in this [18]. In 1975, Blumberg and colleagues linked chronic review. HBV infection to hepatocellular carcinoma (HCC) [19], In 1989, Houghton and colleagues, by employing an which is among the most common cancers in the world. innovative techniques based on phage display library, Importantly, in 1976 the first effective HBV vaccine was identified an antigen encoded by a previously unknown developed by large-scale purification of HBV surface RNA virus, which was named HCV [31]. Moreover, using antigen from the serum of chronic HBV carriers [20] fol- the first serologic test for HCV, Houghton was also capa- lowed by a second-generation recombinant HBV surface ble to confirm that HCV was indeed the aetiologic agent antigen subunit vaccine produced in 1980 which is still in for post-transfusion hepatitis related neither with HBV use. The HBV vaccine protects not only from acute and nor with hepatitis A virus, an other hepatitis virus trans- chronic hepatitis but also from the development of HCC mitted by the fecal-oral route, via contaminated food or [21,22], thus representing a key achievement in cancer drinking water [32,33]. In addition, he reported an associ- research. The success of the HBV vaccine in decreasing ation between chronic HCV infection with HCC, similar the incidence of liver cancer prompted similar efforts to to the one well established for HBV [34,35]. develop safe vaccines capable of preventing other types of Kaposi's sarcoma (KS) is an endemic tumor of the Med- cancers. In particular, the attention was focused on cervi- iterranean basin and Africa [36] rarely life-threatening, cal carcinoma. Indeed, in 1974, for the first time, Harald usually affecting elderly males, with skin localization. In zur Hausen had proposed that the human papillomavirus, acquired immune deficiency syndrome (AIDS) patients, HPV, may represent the aetiologic agent for cervical can- however, KS displays frequent involvement of extra-cuta- cer [23,24]. In particular, zur Hausen had demonstrated neous sites, typically lungs and gastrointestinal tract, with the presence of novel types of HPV DNA, namely HPV16 severe complications. Moreover, since AIDS patients and HPV18, in cervical cancers [25,26]. Evidence now exhibited a 20,000-fold higher risk for developing KS, an clearly indicates that different types of HPV are human infectious aetiology for the tumor was suggested. Having tumor viruses responsible for causing virtually all cases of epidemiologic and experimental evidence ruled out a role cervical cancer [27], the third leading cause of cancer- for the human immunodeficiency virus 1 (HIV-1) in this related deaths in women worldwide. Furthermore, HPVs context, the studies were focused on the research of new have also being linked to other anogenital cancers, as well sexually transmitted infectious agents. As with the search as to a subset of head and neck cancers. In fact, HPVs are for HCV, a modern molecular biological approach played associated with more human cancers than any other a central role in the identification of KSHV. Indeed, in virus, causing up to 500,000 cases of cancer per year 1994, Chang, Moore, and colleagues reported the use of worldwide [28]. Consequently, HPV has emerged as one representational difference analysis to identify in 90% of of the most important risk factors for human cancer. In KS tissues from AIDS patients DNA fragments distantly 2005 and 2006, large-scale clinical trials with a VLP- homologous to the herpesvirus EBV [37]. This new virus based HPV vaccines have been undertaken [28] and cur- was called KSHV or human herpesvirus type 8 (HHV-8). rent estimates suggest that these HPV vaccines could pre- Studies carried on in the past 15 years strongly indicate a vent more than 300,000 cervical cancer cases per year on causal role for KSHV in the development of KS [36], even a global scale. though the viral infection is clearly not sufficient to pro- The most recent milestones in tumor virology have duce the disease and other cofactors have been hypothe- come from the identification of additional human tumor sized. viruses: human T-cell leukemia virus type 1 (HTLV-1), Finally, a new polyomavirus, MCPyV, has been recently hepatitis C virus (HCV), Merkel cell polyomavirus detected in samples derived from patient affected by an (MCPyV), and Kaposi's sarcoma virus (KSHV). aggressive human skin cancer, the Merkel cell carcinoma In 1980, Gallo and colleagues detected in cultured [38,39]. human T-cell lymphoma cells retroviral reverse tran- A summary of the human viruses clearly linked to can- scriptase activity and visualized retroviral particles, cer development is reported in Table 1. immunologically distinct from other known viruses [29]. The new retrovirus was named HTLV-1. In 1981, a causal The viral oncogenetic mechanisms: an introduction role for HTLV-1 in adult T-cell leukemia (ATL) was given Tumor viruses are classified in two general groups based by the discovery of retroviral particles in cell lines derived on whether an RNA or DNA genome is packaged into the Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 3 of 11 http://www.infectagentscancer.com/content/5/1/11 Table 1: Human viruses associated with cancer development. Virus family Virus Human tumors Vaccine Papillomaviridae HPV16/18 Cervical, Anogenital and √ Oesophageus tumors Polyomaviridae JCV Brain and Colon tumors SV40 Mesothelioma and Colon tumors MCPyV Merkel cell carcinoma Hepadnaviridae HBV Hepatocellular carcinoma √ Flaviviridae HCV Hepatocellular carcinoma Herpesviridae EBV Nasopharingeal carcinoma, Burkitt's lymphoma, Hodgkin's lymphoma, B-cell lymphoproliferative diseases HHV-8 Kaposis's sarcoma, Primary effusion lymphoma Retroviridae HTLV-1 Adult T-cell leukemia infectious viral particle. Besides the difference in replica- tive RSV variant. This cancer-causing gene (oncogene) tion and life cycle, RNA and DNA viruses differ also in was named src according to the type of tumor caused by their general mechanisms of inducing cellular transfor- RSV in chickens, the sarcoma. The established dispens- mation/immortalization, the first step to tumor develop- ability of the src gene for RSV replication lead to the ment. RNA tumor viruses, in particular animal hypothesis that oncogenes have a cellular origin and that retroviruses, are usually characterized by the ability to carcinogenic events activate cellular genes to promote carry and/or alter important cellular growth-regulatory cancer. Thus, the reverse transcriptase-dependent life genes, namely the oncogenes. The proteins encoded by cycle typical of most RNA oncogenic viruses, like RSV, these cellular genes are not essential for viral replication would allow the viral genome to capture a cellular onco- and are usually key player in cell cycle control. On the gene. In 1976, Bishop and Varmus proved that this other hand, DNA tumor viruses (like SV40, mouse polyo- hypothesis was correct [42]. Indeed, they were able to mavirus, adenovirus, and papillomavirus) cause cell obtain src specific probes, starting from transforming transformation by encoding proteins of exclusively viral RSV genome, and demonstrated its hybridization with origin and essential for viral replication. the DNA of normal chicken cells and with the DNA of other avian species, even though with lower stringency. Oncogenic RNA viruses: the oncogene discovery This evolutionary conservation of src sequences provided The RNA viruses associated with human cancer are strong evidence that src was indeed a cellular gene mainly included in Retroviridae and Flaviviridae families acquired by RSV from the chicken genome, rather than (Figure 1). being a viral gene. Moreover, this finding suggested that Animal retroviruses have been characterized earlier, the cellular gene, designated a proto-oncogene, must sus- starting from the RSV studies. Indeed, one of the major tain a mutation to cause cancer thus associating tumors breakthrough in understanding the molecular mecha- with mutagenic events. Supporting this view, it was then nisms behind the ability of RNA viruses to cause cancer demonstrated that ras oncogenes present in human blad- came from the RSV field. In particular, the observation der carcinoma cell lines, and rat mammary carcinomas that cellular transformation and viral replication by RSV contained a mutation crucial for inducing cellular trans- were dissociable properties [40] suggested that the virus formation absent in ras proto-oncogene present in nor- was encoding a cancer-causing gene, dispensable for viral mal cells [43,44]. Viral oncogenes carry as well mutations replication. In 1970, Duesberg and Vogt by comparing the or are constitutively expressed with negative effects on genomes of two closely related replication-competent cell proliferation control. Indeed, to date, more than 70 RSV variants, one of which could transform cells and the cellular proto-oncogenes have been identified through other which could not [41] demonstrated that the trans- studies of oncogenic retroviruses, and nearly all of these formation-competent RSV variant exhibited at the level genes code for key cell signaling proteins involved in the of the 3'-end additional sequences accounting for a control of cellular proliferation and apoptosis [45]. The genome 20% larger than the one of transformation-defec- ability to encode viral oncogenes is not the only mecha- Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 4 of 11 http://www.infectagentscancer.com/content/5/1/11 A) Virus Viral oncoprotein Cellular targets Tax NFκB, Akt, PDZ protein p300/CBPp53 HTLV-1 HBZ CREB-2 p12 MHC-I, STAT-5 HIV Tat pRb2/p130 HCV Core and non structural hTERT, p53, Rb proteins B) Figure 1 (A) Representative* list of cellular/viral protein interactions involved in RNA virus-related oncogenic transformation; (B) Schemat- ic representation of Tax and HBZ roles in HTLV-1 mediated oncogenesis. Tax modulates the expression of many viral and cellular genes and it also promotes malignant transformation through disruption of different host-cell growth control pathways, resulting in aberrant cell division. More- over, Tax adversely influences cellular homeostasis through a number of mechanisms, including the physical interaction with cell-cycle regulators and transcriptional activation of cell-cycle control genes, leading to uncontrolled cell division and proliferation. The basic leucine zipper protein (HBZ) is encoded by the complementary strand of the HTLV-1 genome, and it is expressed in all ATL cells, where it is capable of promoting cell proliferation and suppressing Tax-mediated transactivation. LTR: Long Terminal Repeat; NFκB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; MHC- I: Major Histocompatibility Complex Class-I; STAT-5: Signal Transducer and Activator of Transcription-5; hTERT: human Telomerase Reverse Tran- scriptase. *Additional cellular/viral interactions involved in cell transformation and oncogenetic mechanisms have been described. This list is repre- sentative, not exhaustive. nism by which RNA viruses can cause cancer. It has been matches that of HTLV-1 infections [47]; ii) when checked, demonstrated that retroviruses not carrying oncogenes in ATL patients always underwent HTLV-1 infection; iii) their genome may influence expression/function of cellu- leukemic cells cultured derived from ATL patients are lar oncogenes by insertional mutagenesis [45]. positive for HTLV-1; iv) HTLV-1 infection of normal Among human retroviruses, the earliest oncogenic human T cells induced cellular transformation and virus identified was HTLV-1, associated with the ATL, an immortalization. aggressive clonal malignancy of mature CD4+ T lympho- Interestingly, by contrast to mechanisms typical of ani- cytes that presents after a 20-40 years period of clinical mal retroviruses, HTLV-1 does not cause cancer by inser- latency [46]. Interestingly, HTLV-1 still represents the tional mutagenesis or by capturing and activating cellular only known human retrovirus directly linked to a specific proto-oncogenes. Rather, the major oncogenic determi- human malignancy. Indeed, several epidemiological and nant of HTLV-1 is the viral Tax gene that encodes a pro- molecular evidence implicates HTLV-1 as the aetiologic tein essential for viral replication [48]. In particular, it has agent of ATL: i) the geographic distribution of ATL in dif- been demonstrated that Tax associates with centrosomes, ferent world areas, from Japan to Central African, the causing their fragmentation [49], and it is crucial for Caribbean basin, Taiwan, and Papua New Guinea transactivation/repression of viral and cellular gene Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 5 of 11 http://www.infectagentscancer.com/content/5/1/11 expression. Oncogenic transformation of infected and been suggested that Tat, by physically interacting with transfected cells would hence be due to the interaction pRb2/p130, might alter pRb2/p130 cell growth-suppres- with various transcription factors [50]. Furthermore, Tax sive properties, leading to the loss of cell cycle control induces genome instability by deregulation of cell cycle [62]. checkpoints. According to the chromosomal alterations Besides, considering clinical data about HIV-1-associ- observed in ATL patients, it has been described that Tax ated primary cerebral lymphoma, several important dif- is able of inducing a delay in the cellular recognition and ferences of AIDS to non-AIDS related primary cerebral response to DNA damage, and of suppressing the DNA lymphomas have been described [59,63,64]. Among them repair machinery activation [51]. Thus, Tax drives are the higher aggressiveness, the presence of multi-focal genome instability and cellular transformation by inter- lesions, the reduced percentage of therapy responders, fering with cell cycle checkpoint pathways and DNA and an elevated mortality [63,64]. repair mechanisms. Hence, Tax can be considered a viral In addition to the retroviruses, HCV, a member of the oncoprotein, since Tax alone transforms rat fibroblasts Flaviviridae family, is associated with human cancer. and primary human T lymphocytes, while transgenic HCV infection affects more than 170 million individuals mice expressing Tax develop tumors [52]. Moreover, worldwide and represents one of the main causes of recent evidence supports a role for the HTLV-1 basic leu- chronic liver disease (CLD) that can evolve in HCC [65]. cine-zipper factor (HBZ) as an additional viral player in Among patients infected with HCV, it is almost exclu- cancer development [53,54]. Interestingly, HBZ expres- sively those with cirrhosis (roughly 20%) who develop sion in transgenic mice confers a phenotype similar to the HCC, revealing a major risk factor for malignant progres- one observed in ATL patients, and in particular the infil- sion. For these patients, the annual risk for developing tration of lymphocytes into skin and lung [53,54]. A sche- HCC is 1% to 4%, with patients from Japan having an matic representation of HBZ role in HTLV-1 mediated even higher risk. Chronic inflammation and cirrhosis are oncogenesis is reported in Figure 1. Finally, it has been believed to play key roles in promoting HCV-associated shown that HTLV-1 is able of altering the major histo- HCC, although the underlying mechanisms of this pro- compatibility complex class-I (MHC-I) and the T cell cess are not yet understood. In addition to HCC, HCV is receptor (TCR) cascade activation through the accessory also involved in polyclonal B lymphocyte activation [66] protein p12. p12 targets the free MHC-I chain and and epidemiological studies show that HCV seropositive increases Signal Transducer and Activator of Transcrip- individuals have a 5.5 times higher risk developing NHL tion-5 (STAT-5) protein activation and calcium release compared to HCV-seronegative individuals [67]. Clonal B [55]. Furthermore, p12 decreases viral expression in cells may evolve to overt HCV-related NHL as result of TCR-stimulated T cells and is recruited to the immuno- an antigen-driven process triggered by the E2 protein logical synapse [56]. Besides, HTLV-1 accessory proteins [66,67]. Noteworthy, the characterization of clonal B cells p13II is able to target the mitochondria and to induce activation mechanisms may represent a suitable target to changes in its morphology. In particular, the effects on develop a therapy for HCV-associated NHL [66,67]. mitochondria result mainly at the membrane permeabil- ity level, altering the inner membrane potential, and the Oncogenic DNA viruses: the discovery of tumor oxygen consumption (respiration), thus affecting cellular suppressors proliferation, apoptosis, and reactive oxygen species By contrast to RNA viruses, usually oncogenes of DNA (ROS) production [57,58]. tumor viruses lack any recognizable sequence similarities The hypothesis of an HIV-1 involvement in tumor to cellular genes and how the products of these viral pathogenesis is based on the evidence that AIDS-related genes were able to transform cells was not elucidated till tumors have been described, such as KS, non-Hodgkin's late 1970s [68,69]. It has been demonstrated few years lymphomas (NHLs), and invasive cervical carcinoma earlier that SV40 was capable to induce tumor formation (ICC) [59]. HIV-1 infection can play a direct and/or indi- in experimentally infected hamsters, by the expression of rect role in HIV-1-related tumorigenesis. Among the the viral large tumor (T) antigen, the major oncogenic HIV-1 proteins of particular importance with regard to a determinant of SV40 [70-72]. By employing co-immuno- possible role in the carcinogenesis is the accessory pro- precipitation techniques, it was shown that the SV40 tein Tat [60]. In this context, it has been proposed that large T antigen was interacting with a cellular protein the Tat-induced DNA repair deficiencies may play a sig- having an approximate molecular weight of 53 kDa. nificant role in the development of AIDS-associated can- Based on its size, this cellular protein was named p53. cers [60]. In particular, in the case of ICC, HIV-1 Tat, This finding represented the first evidence that products besides enhancing the activity of HPV oncogenes, by of DNA tumor virus oncogenes could function through upregulating HPV E6 and E7 gene expression [61], could physical/direct interactions with cellular proteins. By also promote cell cycle progression [61]. Moreover, it has cloning p53 genes from neoplastic rodent and human Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 6 of 11 http://www.infectagentscancer.com/content/5/1/11 cells it was possible to demonstrate that in all cases the tumor viruses emerged since it has been demonstrated coding sequences differed from those present in normal that oncoproteins encoded by SV40, adenovirus, and cells, by carrying important gain-of-function mutations. HPV share similar capacities for inactivating both the Rb Indeed, p53 is mutated or lost in almost 50% of all human and p53 tumor suppressors [45]. A schematic representa- cancer cases worldwide, representing the most com- tion of DNA viruses and related cellular/viral genes monly mutated gene in human tumors. This finding sug- involved in oncogenesis is reported in Figure 2. gests that p53 acts as a tumor suppressor gene, which in To date, the DNA viruses consistently associated with contrast to proto-oncogenes function to prevent rather human tumors, are the HBV, HPV, EBV, and HHV-8 than to promote cancer [73]. Several studies have con- [80,81]. In addition, several evidence suggest a causative tributed to demonstrate that a wide variety of cellular role in some human cancers also for SV40, BK Virus stress stimuli, such as DNA damage but also viral infec- (BKV) and JC Virus (JCV) [80-83]. tion, induce the activation of p53, which binds to and reg- HPV represents a typical example of human oncogenic ulates the activity of several important cellular factors DNA virus. Specific genotypes have been clearly linked to [73]. In this way, p53 controls cell cycle progression, different forms of tumors, mainly cervical cancer, but also senescence, apoptosis, and DNA repair thus preventing some penile and upper aerodigestive tract carcinomas tumor formation by reducing the accumulation of genetic [45,84]. Being the viral aetiology of the above tumors so lesions. In the case of viral infection p53 activation repre- well established, as for HBV, it is expected that the sents the attempt of the host cell to block viral replica- recently tested HPV vaccines [45,84] will have a profound tion, by inducing, for instance, apoptosis. Thus, several impact on their prevention [45,84-90]. The HPV E6 and DNA viruses have evolved proteins, such as the SV40 E7 oncoproteins play an important role in cervical large T antigen, to bind and inactivate p53, in order to tumors development, and are continuously expressed in escape the cellular antiviral response [45], with cell trans- the lesions, while tumor arises only several years after the formation as a consequence. initial cellular immortalising events. In fact, the continu- Inactivation of p53 is not the only mechanisms evolved ous expression of E6 and E7 is required for maintenance by DNA oncogenic viruses which induces tumors. A sec- of the transformed phenotype, and prevention of cell ond tumor suppressor genes, was discovered by studying growth arrest and/or apoptosis [91,92]. The best-charac- the childhood tumor retinoblastoma (Rb) [74]. Rb sus- terised HPV16 E6 activity is its ability to induce degrada- ceptibility was linked to a single recessive trait and the tion of the tumour suppressor protein p53 via the gene encoding the specific tumor suppressor gene was ubiquitin pathway [93]. Moreover, among additional identified and cloned [75,76] and the protein named Rb. functions, E6 protein can also interfere with cellular dif- In 1988, Harlow, Livingston and co-workers, demon- ferentiation and cell cycle progression [94]. E7 is an acidic strated that the Rb protein immunoprecipitates with ade- phosphoprotein of 98 amino acids, which is structurally novirus E1A and with SV40 large T antigen from and functionally related to a gene product of other DNA transformed cells [77,78]. tumour viruses, the adenovirus E1A protein and SV40 Studying the interactions among human adenovirus large T antigen. As mentioned above, all three proteins E1A and SV40 large T antigen with Rb was essential for are capable of binding to the tumour suppressor protein understanding the cellular tumor suppressor function retinoblastoma (pRb1) and its related proteins p107 and [79] with the demonstration that a hypophosphorylated p130, involved in cell cycle regulation. By doing so, and form of Rb negatively regulates G1 to S phase progression thanks to other functions, E7 controls cell cycle progres- through the cell cycle by binding to and blocking the sion [94]. In addition to E6 and E7, HPV E5 protein, a activity of E2F, a transcriptional factor activating several small hydrophobic protein, localized in the endomem- genes involved in cellular DNA replication. Cell progres- brane compartments of the Golgi apparatus and endo- sion through G1 to S phase depends on the G1 cyclin- plasmic reticulum could play a role in HPV dependent kinases activity, which directly hyperphospho- carcinogenesis. Indeed it has been demonstrated that rylate and inactivate Rb leading to the release of active E2. HPV E5 down-regulates surface MHC-I, thus preventing Viral oncoproteins specifically bind to and inactivate the its transport to the cell surface; hence, E5 can potentially hypophosphorylated form of Rb. Thus free active E2F allow infected cells to escape adaptive immune response accumulates, with consequent uncontrolled cellular pro- of cytotoxic T lymphocytes (CTL), thus favouring viral liferation. persistence [95,96]. In summary, studies of DNA tumor viruses provided As for HCV, HBV chronic infection represents an seminal contributions to our understanding of both Rb important risk factor for the development of HCC, a and p53, two of the most important cellular tumor sup- malignant tumor frequently observed in some countries pressor proteins. Moreover, a common theme for DNA of Asia and Africa [97,98]. It is important to underline Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 7 of 11 http://www.infectagentscancer.com/content/5/1/11 A) Virus Viral oncoprotein Cellular targets HPV E6 p53 E7 Rb E1A Rb Adenovirus E1B p53 Large T antigen SV40 p53, Rb Small t antigen PP2A EBV LMP1 TRAFs, NF-κB HBV X protein p53 B) Figure 2 (A) Representative* list of cellular/viral protein interactions involved in DNA virus-related oncogenic transformation; (B) p53 and Rb are central targets of viral oncoproteins. The viral proteins Large T antigen of SV40, E1A/E1B of Adenovirus, and E6/E7 of HPV, are capable of interfering with either Rb and/or p53, altering their activities and thus essential cell cycle check-points. PP2A: Protein Phosphatase 2A; TRAFs:Tumor necrosis Factor Associated. * Additional cellular/viral interactions involved in cell transformation and oncogenetic mechanisms have been described. how major achievements in the prevention of virus- ability of HB×Ag to modulate specific cell pathways has induced cancers may be attributable to strategies to con- been linked to the upregulated gene clone 11 (URG11) trol infection in human populations. In fact, HBV vacci- cellular protein, which appears to be a direct effector of nation has dramatically decreased the number of HCC the viral protein. Indeed, URG11 is upregulated in [45,99-101]. However, the molecular mechanisms of HBV HB×Ag-positive liver cells and seems to be involved in carcinogenesis are still not fully clarified. Different stud- cancer evolution, by controlling cell cycle progression ies suggest a role for the hepatitis B virus × antigen [103]. (HB×Ag) in this context. Indeed, in addition to a physical There is emerging interest in the polyomaviruses as binding and functional inactivation of p53, HB×Ag pro- possible human carcinogens [80,83,104-107]. SV40, motes fibrogenesis by stimulating fibronectin expression, which naturally infects the rhesus monkey, was inadver- inhibits apoptosis mediated by Fas and tumor necrosis tently introduced into the human population as a con- factor-alpha (TNF-α) and its expression correlates with taminant of early poliovirus vaccines, whereas the BK and the development and progression of CLD [102,103]. In JC polyomaviruses are natural human pathogens associ- particular, HB×Ag expressed by HBV genome integrated ated with disease processes in the urinary tract or brain, into chromosomal DNA is often functional in trans-acti- respectively. Genomic sequences of these three polyoma- vation assays [102]. Moreover, it can alter patterns of host viruses, which are tumorigenic under experimental con- gene expression, contributing to carcinogenesis, by acti- ditions, have been detected in human mesothelioma, vating signal transduction pathways in host-infected cells osteosarcoma, NHL, brain tumors, and prostate cancer. [102,103]. HB×Ag transforms cell lines in vitro, giving In addition, an integrated form of a new polyomavirus, rise to liver cancer in transgenic mice [103]. A role in the MCPyV, was recently observed in Merkel cell carcinoma, Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 8 of 11 http://www.infectagentscancer.com/content/5/1/11 a rare but aggressive human skin cancer of neuroendo- γ-herpesvirus infection, few viral genes are expressed. crine origin [39,84]. Whereas EBV latent proteins contribute to cell immortal- EBV and HHV-8 are two members of the Herpesviridae ization, HHV-8 lytic genes play an important role in can- family that are classified as cancerogenic agents. These cer development and progression. An Italian study viruses can establish long-term viral infections in their investigated the latent and lytic antibodies seropreva- target cells, promoting cellular immortalisation and lence in elderly subjects, and the possible correlation with transformation [80,81]. EBV is the most important aetio- clinical stage and disease progression in classical KS logical factor in classic BL [108], and it is also detectable [118,119]. While the antibody levels against HHV-8 latent in undifferentiated nasopharyngeal carcinomas, in a sub- antigens were observed in all KS cases, antibody levels set of HL, and in some cases of NHL, notably in immuno- against HHV-8 lytic antigens increase with the progres- suppressed patients [79,80,108]. sion of KS, and higher HHV-8 antibody levels were The alteration of cell signaling represents the molecular observed in the fast progressive form of the disease [119]. basis for cellular proliferation occurring in association According to the literature, these results support the with several viral infections. In particular, both EBV and hypothesis that active viral replication probably contrib- HHV-8 target important cell signaling pathways involved utes to progression of KS. In addition, HHV-8 DNA was in oncogenesis, such as the β-catenin pathway that plays a constantly detected in saliva and PBMC samples of classi- key role in the control of cell adhesion and tissue mor- cal KS but without any correlation with the clinical stage phogenesis [109,110]. The level of β-catenin protein is of the disease, suggesting that oral shedding is likely to subject to tight regulation, particularly through ubiq- occur in these patients and contributes to viral transmis- uitin-mediated proteasomal degradation. Latent mem- sion [119]. brane protein-1 (LMP-1) and latent membrane protein- 2A (LMP-2A) of EBV affect the β-catenin stabilization Conclusive remarks and activation avoiding the ubiquitination [110], as many By the first decade of the 21st Century, much evidence other oncoproteins of tumorigenic viruses, such as T had accumulated pointing out at least six human viruses, antigen in JCV [105]. It is beginning to emerge that tumor namely HPV, HBV, EBV, HHV-8, HCV, and HTLV-1, as viruses modulate the ubiquitination of specific cell fac- aetiologic agents of human cancers. As mentioned above tors for their needs [111,112] by employing different these viruses are responsible of roughly 20% of all human strategies. Among them, viruses encode their own ubiq- tumors worldwide [45]. Moreover, oncogenic viruses uitin ligases and deubiquitinating enzymes (DUBs), as have also proved to be powerful tools for dissecting fun- recently demonstrated in the case of herpesviruses damental pathways and proteins involved in cell cycle [112,113]. Indeed, since the discovery that the largest teg- progression and regulation. For example, a number of ument protein of Human Herpes Virus-1 (HSV-1), UL36, oncogenes have been identified through studies focused contains a deubiquitinating activity it has been reported on RNA tumor viruses, while essential tumor suppres- that all members of the Herpesviridae family, including sors, such as p53 and Rb, were discovered and character- EBV and HHV-8, encode UL36 homologues, suggesting ized through DNA tumor viruses. In the future, it is an important role of this protein in the viral life cycle expected that the characterization of new tumor viruses [111,114]. On the other hand, the presence of the viral will contribute in clarifying relevant aspects of cell biol- latency-associated nuclear antigen (LANA) in all HHV-8- ogy and carcinogenesis. Indeed, other candidate human associated tumors significantly correlates with β-catenin tumor viruses have been proposed [120]. Particularly over-expression. In this context it has been demonstrated intriguing in this context is the study of human endoge- that introduction of anti-LANA small interfering RNA nous retroviruses role in seminomas, breast cancer, (siRNA) into primary effusion lymphomas (PEL) cells myeloproliferative disease, ovarian cancer, melanoma, eliminated β-catenin accumulation, while LANA itself and prostate cancer [121]. Moreover, as demonstrated in upregulated expression of β-catenin in transfected cells. the case of HBV and HPV, prophylactic vaccines offer the LANA stabilizes β-catenin by binding to its negative reg- potential to prevent cancers having a viral aetiology. ulator GSK-3β, causing a cell cycle-dependent nuclear Thus, the development of new vaccines against other accumulation of GSK-3β [115]. The importance of this human tumor viruses should be a must for the future pathway to HHV-8-driven cell proliferation is highlighted research. by the observation that LANA stimulates entry into S Competing interests phase. The authors declare that they have no competing interests. In the past 10 years much effort has been devoted to the Authors' contributions study of HHV-8. HHV-8 is consistently detected in all All authors have contributed in writing the review. All the authors read and forms of KS, in PEL, and in a subset of multicentric Cas- approved the final manuscript. tleman's disease [116,117]. During the latency program of Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 9 of 11 http://www.infectagentscancer.com/content/5/1/11 Author Details 25. Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen Department of Histology, Microbiology and Medical Biotechnologies, Division H: A new type of papillomavirus DNA, its presence in genital cancer of Microbiology and Virology, University of Padova, Via A Gabelli 63, Padova biopsies and in cell lines derived from cervical cancer. EMBO J 1984, 35121, Italy and Department of Biology, University of Padova, Via Ugo Bassi 3:1151-1157. 58B, Padova 35123, Italy 26. Durst M, Gissmann L, Ikenberg H, zur Hausen H: A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples Received: 15 January 2009 Accepted: 24 May 2010 from different geographic regions. Proc Natl Acad Sci USA 1983, Published: 24 May 2010 80:3812-3815. 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Abstract

To date, almost one and a half million cases of cancer are diagnosed every year in the US and nearly 560,000 Americans are expected to die of cancer in the current year, more than 1,500 people a day (data from the American Cancer Society at http://www.cancer.org/). According to the World Health Organization ( WHO), roughly 20% of all cancers worldwide results from chronic infections; in particular, up to 15% of human cancers is characterized by a viral aetiology with higher incidence in Developing Countries. The link between viruses and cancer was one of the pivotal discoveries in cancer research during the past Century. Indeed, the infectious nature of specific tumors has important implications in st terms of their prevention, diagnosis, and therapy. In the 21 Century, the research on viral oncology field continues to be vigorous, with new significant and original studies on viral oncogenesis and translational research from basic virology to treatment of cancer. This review will cover different viral oncology aspects, starting from the history of viral oncology and moving to the peculiar features of oncogenic RNA and DNA viruses, with a special focus on human pathogens. A brief history of viral oncology rus) [9]. As far as primates is concerned, in 1962, Eddy, The first evidence of tumor viral aetiology dates back to Hilleman, and co-workers showed the tumorigenic 1907 when Ciuffo and co-workers showed that human potential of simian virus 40 (SV40) [10,11] while, interest- warts could be transmitted by cell-free filtrates derived ingly, Trentin and colleagues reported, for the first time, from lesions [1]. Seventy years later, papillomaviruses that viruses could be linked to cancer development also were linked to human cancer. In 1908, Ellermann and in humans, at least under experimental conditions. Bang, reported that also leukemia could be transferred to Indeed, these authors showed that specific human adeno- healthy chicken by a cell-free filtrate of cells obtained viruses are tumorigenic in experimentally infected ani- form affected birds [2]. Moreover, in 1911, Rous and col- mals [12]. Starting from then, studies were focused on leagues showed that the spindle cell sarcoma could be connection among viruses and human cancer. In 1965, transmitted to healthy chickens using filtered cell-free Epstein, Barr, and colleagues were able to visualize by tumor extracts [3]. This study led to the identification of electron microscopy herpesvirus-like particles in a cell the first oncogenic virus: the Rous sarcoma virus (RSV). line, established from Burkitt's lymphoma (BL) [13]. This Over the next four decades after the discovery of RSV virus resulted to be biologically and antigenically distinct new tumor viruses were identified. In particular, in 1935, from other known human herpesviruses [14] and was Rous and Beard demonstrated that the cottontail rabbit named Epstein-Barr Virus (EBV). In addition to a causal papillomavirus (CRPV), discovered few years earlier [2], role in BL, EBV infection has been subsequently associ- was able to induce skin carcinomas in domestic cottontail ated with nasopharyngeal carcinoma, post-transplant rabbit [4]. Moreover, in 1951, studies by Gross and co- lymphomas, and some Hodgkin's lymphomas (HL), thus workers led to the identification of the first mouse leuke- representing the first known human tumor virus. In the mia virus (murine leukemia virus) [5], later confirmed by same year, Blumberg, during a study aimed to correlate Moloney and others [6-8], and in 1953 of a mouse virus inherited polymorphic traits in different geographic areas that induced a variety of solid tumors (mouse polyomavi- of the world with particular disease patterns, found that one blood sample from an Australian aborigine contained * Correspondence: giorgio.palu@unipd.it an antigen that reacted specifically with the serum from Department of Histology, Microbiology and Medical Biotechnologies, an American haemophilia patient. This antigen was Division of Microbiology and Virology, University of Padova, Via A Gabelli 63, named the Australia (Au) antigen and its role was Padova 35121, Italy unknown till a technician working with human sera con- Full list of author information is available at the end of the article © 2010 Bergonzini et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Com- mons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduc- BioMed Central tion in any medium, provided the original work is properly cited. Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 2 of 11 http://www.infectagentscancer.com/content/5/1/11 tracted hepatitis, becoming Au antigen-positive. In 1967 from patients [30]. Moreover, patients with ATL but not and 1968, Blumberg, Okochi, Murakami, and Prince, control individuals were shown to produce antibodies published seminal studies showing that blood from hepa- that specifically recognized antigens expressed in HTLV- titis patients contained the Au antigen [15-17], being the 1-infected human T-cells. Since then different molecular surface antigen of a hepadnavirus called hepatitis B virus mechanisms behind HTLV-1 oncogenic activity have (HBV), the aetiologic agent of serum hepatitis disease been undisclosed and will be analysed later on in this [18]. In 1975, Blumberg and colleagues linked chronic review. HBV infection to hepatocellular carcinoma (HCC) [19], In 1989, Houghton and colleagues, by employing an which is among the most common cancers in the world. innovative techniques based on phage display library, Importantly, in 1976 the first effective HBV vaccine was identified an antigen encoded by a previously unknown developed by large-scale purification of HBV surface RNA virus, which was named HCV [31]. Moreover, using antigen from the serum of chronic HBV carriers [20] fol- the first serologic test for HCV, Houghton was also capa- lowed by a second-generation recombinant HBV surface ble to confirm that HCV was indeed the aetiologic agent antigen subunit vaccine produced in 1980 which is still in for post-transfusion hepatitis related neither with HBV use. The HBV vaccine protects not only from acute and nor with hepatitis A virus, an other hepatitis virus trans- chronic hepatitis but also from the development of HCC mitted by the fecal-oral route, via contaminated food or [21,22], thus representing a key achievement in cancer drinking water [32,33]. In addition, he reported an associ- research. The success of the HBV vaccine in decreasing ation between chronic HCV infection with HCC, similar the incidence of liver cancer prompted similar efforts to to the one well established for HBV [34,35]. develop safe vaccines capable of preventing other types of Kaposi's sarcoma (KS) is an endemic tumor of the Med- cancers. In particular, the attention was focused on cervi- iterranean basin and Africa [36] rarely life-threatening, cal carcinoma. Indeed, in 1974, for the first time, Harald usually affecting elderly males, with skin localization. In zur Hausen had proposed that the human papillomavirus, acquired immune deficiency syndrome (AIDS) patients, HPV, may represent the aetiologic agent for cervical can- however, KS displays frequent involvement of extra-cuta- cer [23,24]. In particular, zur Hausen had demonstrated neous sites, typically lungs and gastrointestinal tract, with the presence of novel types of HPV DNA, namely HPV16 severe complications. Moreover, since AIDS patients and HPV18, in cervical cancers [25,26]. Evidence now exhibited a 20,000-fold higher risk for developing KS, an clearly indicates that different types of HPV are human infectious aetiology for the tumor was suggested. Having tumor viruses responsible for causing virtually all cases of epidemiologic and experimental evidence ruled out a role cervical cancer [27], the third leading cause of cancer- for the human immunodeficiency virus 1 (HIV-1) in this related deaths in women worldwide. Furthermore, HPVs context, the studies were focused on the research of new have also being linked to other anogenital cancers, as well sexually transmitted infectious agents. As with the search as to a subset of head and neck cancers. In fact, HPVs are for HCV, a modern molecular biological approach played associated with more human cancers than any other a central role in the identification of KSHV. Indeed, in virus, causing up to 500,000 cases of cancer per year 1994, Chang, Moore, and colleagues reported the use of worldwide [28]. Consequently, HPV has emerged as one representational difference analysis to identify in 90% of of the most important risk factors for human cancer. In KS tissues from AIDS patients DNA fragments distantly 2005 and 2006, large-scale clinical trials with a VLP- homologous to the herpesvirus EBV [37]. This new virus based HPV vaccines have been undertaken [28] and cur- was called KSHV or human herpesvirus type 8 (HHV-8). rent estimates suggest that these HPV vaccines could pre- Studies carried on in the past 15 years strongly indicate a vent more than 300,000 cervical cancer cases per year on causal role for KSHV in the development of KS [36], even a global scale. though the viral infection is clearly not sufficient to pro- The most recent milestones in tumor virology have duce the disease and other cofactors have been hypothe- come from the identification of additional human tumor sized. viruses: human T-cell leukemia virus type 1 (HTLV-1), Finally, a new polyomavirus, MCPyV, has been recently hepatitis C virus (HCV), Merkel cell polyomavirus detected in samples derived from patient affected by an (MCPyV), and Kaposi's sarcoma virus (KSHV). aggressive human skin cancer, the Merkel cell carcinoma In 1980, Gallo and colleagues detected in cultured [38,39]. human T-cell lymphoma cells retroviral reverse tran- A summary of the human viruses clearly linked to can- scriptase activity and visualized retroviral particles, cer development is reported in Table 1. immunologically distinct from other known viruses [29]. The new retrovirus was named HTLV-1. In 1981, a causal The viral oncogenetic mechanisms: an introduction role for HTLV-1 in adult T-cell leukemia (ATL) was given Tumor viruses are classified in two general groups based by the discovery of retroviral particles in cell lines derived on whether an RNA or DNA genome is packaged into the Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 3 of 11 http://www.infectagentscancer.com/content/5/1/11 Table 1: Human viruses associated with cancer development. Virus family Virus Human tumors Vaccine Papillomaviridae HPV16/18 Cervical, Anogenital and √ Oesophageus tumors Polyomaviridae JCV Brain and Colon tumors SV40 Mesothelioma and Colon tumors MCPyV Merkel cell carcinoma Hepadnaviridae HBV Hepatocellular carcinoma √ Flaviviridae HCV Hepatocellular carcinoma Herpesviridae EBV Nasopharingeal carcinoma, Burkitt's lymphoma, Hodgkin's lymphoma, B-cell lymphoproliferative diseases HHV-8 Kaposis's sarcoma, Primary effusion lymphoma Retroviridae HTLV-1 Adult T-cell leukemia infectious viral particle. Besides the difference in replica- tive RSV variant. This cancer-causing gene (oncogene) tion and life cycle, RNA and DNA viruses differ also in was named src according to the type of tumor caused by their general mechanisms of inducing cellular transfor- RSV in chickens, the sarcoma. The established dispens- mation/immortalization, the first step to tumor develop- ability of the src gene for RSV replication lead to the ment. RNA tumor viruses, in particular animal hypothesis that oncogenes have a cellular origin and that retroviruses, are usually characterized by the ability to carcinogenic events activate cellular genes to promote carry and/or alter important cellular growth-regulatory cancer. Thus, the reverse transcriptase-dependent life genes, namely the oncogenes. The proteins encoded by cycle typical of most RNA oncogenic viruses, like RSV, these cellular genes are not essential for viral replication would allow the viral genome to capture a cellular onco- and are usually key player in cell cycle control. On the gene. In 1976, Bishop and Varmus proved that this other hand, DNA tumor viruses (like SV40, mouse polyo- hypothesis was correct [42]. Indeed, they were able to mavirus, adenovirus, and papillomavirus) cause cell obtain src specific probes, starting from transforming transformation by encoding proteins of exclusively viral RSV genome, and demonstrated its hybridization with origin and essential for viral replication. the DNA of normal chicken cells and with the DNA of other avian species, even though with lower stringency. Oncogenic RNA viruses: the oncogene discovery This evolutionary conservation of src sequences provided The RNA viruses associated with human cancer are strong evidence that src was indeed a cellular gene mainly included in Retroviridae and Flaviviridae families acquired by RSV from the chicken genome, rather than (Figure 1). being a viral gene. Moreover, this finding suggested that Animal retroviruses have been characterized earlier, the cellular gene, designated a proto-oncogene, must sus- starting from the RSV studies. Indeed, one of the major tain a mutation to cause cancer thus associating tumors breakthrough in understanding the molecular mecha- with mutagenic events. Supporting this view, it was then nisms behind the ability of RNA viruses to cause cancer demonstrated that ras oncogenes present in human blad- came from the RSV field. In particular, the observation der carcinoma cell lines, and rat mammary carcinomas that cellular transformation and viral replication by RSV contained a mutation crucial for inducing cellular trans- were dissociable properties [40] suggested that the virus formation absent in ras proto-oncogene present in nor- was encoding a cancer-causing gene, dispensable for viral mal cells [43,44]. Viral oncogenes carry as well mutations replication. In 1970, Duesberg and Vogt by comparing the or are constitutively expressed with negative effects on genomes of two closely related replication-competent cell proliferation control. Indeed, to date, more than 70 RSV variants, one of which could transform cells and the cellular proto-oncogenes have been identified through other which could not [41] demonstrated that the trans- studies of oncogenic retroviruses, and nearly all of these formation-competent RSV variant exhibited at the level genes code for key cell signaling proteins involved in the of the 3'-end additional sequences accounting for a control of cellular proliferation and apoptosis [45]. The genome 20% larger than the one of transformation-defec- ability to encode viral oncogenes is not the only mecha- Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 4 of 11 http://www.infectagentscancer.com/content/5/1/11 A) Virus Viral oncoprotein Cellular targets Tax NFκB, Akt, PDZ protein p300/CBPp53 HTLV-1 HBZ CREB-2 p12 MHC-I, STAT-5 HIV Tat pRb2/p130 HCV Core and non structural hTERT, p53, Rb proteins B) Figure 1 (A) Representative* list of cellular/viral protein interactions involved in RNA virus-related oncogenic transformation; (B) Schemat- ic representation of Tax and HBZ roles in HTLV-1 mediated oncogenesis. Tax modulates the expression of many viral and cellular genes and it also promotes malignant transformation through disruption of different host-cell growth control pathways, resulting in aberrant cell division. More- over, Tax adversely influences cellular homeostasis through a number of mechanisms, including the physical interaction with cell-cycle regulators and transcriptional activation of cell-cycle control genes, leading to uncontrolled cell division and proliferation. The basic leucine zipper protein (HBZ) is encoded by the complementary strand of the HTLV-1 genome, and it is expressed in all ATL cells, where it is capable of promoting cell proliferation and suppressing Tax-mediated transactivation. LTR: Long Terminal Repeat; NFκB: Nuclear Factor kappa-light-chain-enhancer of activated B cells; MHC- I: Major Histocompatibility Complex Class-I; STAT-5: Signal Transducer and Activator of Transcription-5; hTERT: human Telomerase Reverse Tran- scriptase. *Additional cellular/viral interactions involved in cell transformation and oncogenetic mechanisms have been described. This list is repre- sentative, not exhaustive. nism by which RNA viruses can cause cancer. It has been matches that of HTLV-1 infections [47]; ii) when checked, demonstrated that retroviruses not carrying oncogenes in ATL patients always underwent HTLV-1 infection; iii) their genome may influence expression/function of cellu- leukemic cells cultured derived from ATL patients are lar oncogenes by insertional mutagenesis [45]. positive for HTLV-1; iv) HTLV-1 infection of normal Among human retroviruses, the earliest oncogenic human T cells induced cellular transformation and virus identified was HTLV-1, associated with the ATL, an immortalization. aggressive clonal malignancy of mature CD4+ T lympho- Interestingly, by contrast to mechanisms typical of ani- cytes that presents after a 20-40 years period of clinical mal retroviruses, HTLV-1 does not cause cancer by inser- latency [46]. Interestingly, HTLV-1 still represents the tional mutagenesis or by capturing and activating cellular only known human retrovirus directly linked to a specific proto-oncogenes. Rather, the major oncogenic determi- human malignancy. Indeed, several epidemiological and nant of HTLV-1 is the viral Tax gene that encodes a pro- molecular evidence implicates HTLV-1 as the aetiologic tein essential for viral replication [48]. In particular, it has agent of ATL: i) the geographic distribution of ATL in dif- been demonstrated that Tax associates with centrosomes, ferent world areas, from Japan to Central African, the causing their fragmentation [49], and it is crucial for Caribbean basin, Taiwan, and Papua New Guinea transactivation/repression of viral and cellular gene Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 5 of 11 http://www.infectagentscancer.com/content/5/1/11 expression. Oncogenic transformation of infected and been suggested that Tat, by physically interacting with transfected cells would hence be due to the interaction pRb2/p130, might alter pRb2/p130 cell growth-suppres- with various transcription factors [50]. Furthermore, Tax sive properties, leading to the loss of cell cycle control induces genome instability by deregulation of cell cycle [62]. checkpoints. According to the chromosomal alterations Besides, considering clinical data about HIV-1-associ- observed in ATL patients, it has been described that Tax ated primary cerebral lymphoma, several important dif- is able of inducing a delay in the cellular recognition and ferences of AIDS to non-AIDS related primary cerebral response to DNA damage, and of suppressing the DNA lymphomas have been described [59,63,64]. Among them repair machinery activation [51]. Thus, Tax drives are the higher aggressiveness, the presence of multi-focal genome instability and cellular transformation by inter- lesions, the reduced percentage of therapy responders, fering with cell cycle checkpoint pathways and DNA and an elevated mortality [63,64]. repair mechanisms. Hence, Tax can be considered a viral In addition to the retroviruses, HCV, a member of the oncoprotein, since Tax alone transforms rat fibroblasts Flaviviridae family, is associated with human cancer. and primary human T lymphocytes, while transgenic HCV infection affects more than 170 million individuals mice expressing Tax develop tumors [52]. Moreover, worldwide and represents one of the main causes of recent evidence supports a role for the HTLV-1 basic leu- chronic liver disease (CLD) that can evolve in HCC [65]. cine-zipper factor (HBZ) as an additional viral player in Among patients infected with HCV, it is almost exclu- cancer development [53,54]. Interestingly, HBZ expres- sively those with cirrhosis (roughly 20%) who develop sion in transgenic mice confers a phenotype similar to the HCC, revealing a major risk factor for malignant progres- one observed in ATL patients, and in particular the infil- sion. For these patients, the annual risk for developing tration of lymphocytes into skin and lung [53,54]. A sche- HCC is 1% to 4%, with patients from Japan having an matic representation of HBZ role in HTLV-1 mediated even higher risk. Chronic inflammation and cirrhosis are oncogenesis is reported in Figure 1. Finally, it has been believed to play key roles in promoting HCV-associated shown that HTLV-1 is able of altering the major histo- HCC, although the underlying mechanisms of this pro- compatibility complex class-I (MHC-I) and the T cell cess are not yet understood. In addition to HCC, HCV is receptor (TCR) cascade activation through the accessory also involved in polyclonal B lymphocyte activation [66] protein p12. p12 targets the free MHC-I chain and and epidemiological studies show that HCV seropositive increases Signal Transducer and Activator of Transcrip- individuals have a 5.5 times higher risk developing NHL tion-5 (STAT-5) protein activation and calcium release compared to HCV-seronegative individuals [67]. Clonal B [55]. Furthermore, p12 decreases viral expression in cells may evolve to overt HCV-related NHL as result of TCR-stimulated T cells and is recruited to the immuno- an antigen-driven process triggered by the E2 protein logical synapse [56]. Besides, HTLV-1 accessory proteins [66,67]. Noteworthy, the characterization of clonal B cells p13II is able to target the mitochondria and to induce activation mechanisms may represent a suitable target to changes in its morphology. In particular, the effects on develop a therapy for HCV-associated NHL [66,67]. mitochondria result mainly at the membrane permeabil- ity level, altering the inner membrane potential, and the Oncogenic DNA viruses: the discovery of tumor oxygen consumption (respiration), thus affecting cellular suppressors proliferation, apoptosis, and reactive oxygen species By contrast to RNA viruses, usually oncogenes of DNA (ROS) production [57,58]. tumor viruses lack any recognizable sequence similarities The hypothesis of an HIV-1 involvement in tumor to cellular genes and how the products of these viral pathogenesis is based on the evidence that AIDS-related genes were able to transform cells was not elucidated till tumors have been described, such as KS, non-Hodgkin's late 1970s [68,69]. It has been demonstrated few years lymphomas (NHLs), and invasive cervical carcinoma earlier that SV40 was capable to induce tumor formation (ICC) [59]. HIV-1 infection can play a direct and/or indi- in experimentally infected hamsters, by the expression of rect role in HIV-1-related tumorigenesis. Among the the viral large tumor (T) antigen, the major oncogenic HIV-1 proteins of particular importance with regard to a determinant of SV40 [70-72]. By employing co-immuno- possible role in the carcinogenesis is the accessory pro- precipitation techniques, it was shown that the SV40 tein Tat [60]. In this context, it has been proposed that large T antigen was interacting with a cellular protein the Tat-induced DNA repair deficiencies may play a sig- having an approximate molecular weight of 53 kDa. nificant role in the development of AIDS-associated can- Based on its size, this cellular protein was named p53. cers [60]. In particular, in the case of ICC, HIV-1 Tat, This finding represented the first evidence that products besides enhancing the activity of HPV oncogenes, by of DNA tumor virus oncogenes could function through upregulating HPV E6 and E7 gene expression [61], could physical/direct interactions with cellular proteins. By also promote cell cycle progression [61]. Moreover, it has cloning p53 genes from neoplastic rodent and human Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 6 of 11 http://www.infectagentscancer.com/content/5/1/11 cells it was possible to demonstrate that in all cases the tumor viruses emerged since it has been demonstrated coding sequences differed from those present in normal that oncoproteins encoded by SV40, adenovirus, and cells, by carrying important gain-of-function mutations. HPV share similar capacities for inactivating both the Rb Indeed, p53 is mutated or lost in almost 50% of all human and p53 tumor suppressors [45]. A schematic representa- cancer cases worldwide, representing the most com- tion of DNA viruses and related cellular/viral genes monly mutated gene in human tumors. This finding sug- involved in oncogenesis is reported in Figure 2. gests that p53 acts as a tumor suppressor gene, which in To date, the DNA viruses consistently associated with contrast to proto-oncogenes function to prevent rather human tumors, are the HBV, HPV, EBV, and HHV-8 than to promote cancer [73]. Several studies have con- [80,81]. In addition, several evidence suggest a causative tributed to demonstrate that a wide variety of cellular role in some human cancers also for SV40, BK Virus stress stimuli, such as DNA damage but also viral infec- (BKV) and JC Virus (JCV) [80-83]. tion, induce the activation of p53, which binds to and reg- HPV represents a typical example of human oncogenic ulates the activity of several important cellular factors DNA virus. Specific genotypes have been clearly linked to [73]. In this way, p53 controls cell cycle progression, different forms of tumors, mainly cervical cancer, but also senescence, apoptosis, and DNA repair thus preventing some penile and upper aerodigestive tract carcinomas tumor formation by reducing the accumulation of genetic [45,84]. Being the viral aetiology of the above tumors so lesions. In the case of viral infection p53 activation repre- well established, as for HBV, it is expected that the sents the attempt of the host cell to block viral replica- recently tested HPV vaccines [45,84] will have a profound tion, by inducing, for instance, apoptosis. Thus, several impact on their prevention [45,84-90]. The HPV E6 and DNA viruses have evolved proteins, such as the SV40 E7 oncoproteins play an important role in cervical large T antigen, to bind and inactivate p53, in order to tumors development, and are continuously expressed in escape the cellular antiviral response [45], with cell trans- the lesions, while tumor arises only several years after the formation as a consequence. initial cellular immortalising events. In fact, the continu- Inactivation of p53 is not the only mechanisms evolved ous expression of E6 and E7 is required for maintenance by DNA oncogenic viruses which induces tumors. A sec- of the transformed phenotype, and prevention of cell ond tumor suppressor genes, was discovered by studying growth arrest and/or apoptosis [91,92]. The best-charac- the childhood tumor retinoblastoma (Rb) [74]. Rb sus- terised HPV16 E6 activity is its ability to induce degrada- ceptibility was linked to a single recessive trait and the tion of the tumour suppressor protein p53 via the gene encoding the specific tumor suppressor gene was ubiquitin pathway [93]. Moreover, among additional identified and cloned [75,76] and the protein named Rb. functions, E6 protein can also interfere with cellular dif- In 1988, Harlow, Livingston and co-workers, demon- ferentiation and cell cycle progression [94]. E7 is an acidic strated that the Rb protein immunoprecipitates with ade- phosphoprotein of 98 amino acids, which is structurally novirus E1A and with SV40 large T antigen from and functionally related to a gene product of other DNA transformed cells [77,78]. tumour viruses, the adenovirus E1A protein and SV40 Studying the interactions among human adenovirus large T antigen. As mentioned above, all three proteins E1A and SV40 large T antigen with Rb was essential for are capable of binding to the tumour suppressor protein understanding the cellular tumor suppressor function retinoblastoma (pRb1) and its related proteins p107 and [79] with the demonstration that a hypophosphorylated p130, involved in cell cycle regulation. By doing so, and form of Rb negatively regulates G1 to S phase progression thanks to other functions, E7 controls cell cycle progres- through the cell cycle by binding to and blocking the sion [94]. In addition to E6 and E7, HPV E5 protein, a activity of E2F, a transcriptional factor activating several small hydrophobic protein, localized in the endomem- genes involved in cellular DNA replication. Cell progres- brane compartments of the Golgi apparatus and endo- sion through G1 to S phase depends on the G1 cyclin- plasmic reticulum could play a role in HPV dependent kinases activity, which directly hyperphospho- carcinogenesis. Indeed it has been demonstrated that rylate and inactivate Rb leading to the release of active E2. HPV E5 down-regulates surface MHC-I, thus preventing Viral oncoproteins specifically bind to and inactivate the its transport to the cell surface; hence, E5 can potentially hypophosphorylated form of Rb. Thus free active E2F allow infected cells to escape adaptive immune response accumulates, with consequent uncontrolled cellular pro- of cytotoxic T lymphocytes (CTL), thus favouring viral liferation. persistence [95,96]. In summary, studies of DNA tumor viruses provided As for HCV, HBV chronic infection represents an seminal contributions to our understanding of both Rb important risk factor for the development of HCC, a and p53, two of the most important cellular tumor sup- malignant tumor frequently observed in some countries pressor proteins. Moreover, a common theme for DNA of Asia and Africa [97,98]. It is important to underline Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 7 of 11 http://www.infectagentscancer.com/content/5/1/11 A) Virus Viral oncoprotein Cellular targets HPV E6 p53 E7 Rb E1A Rb Adenovirus E1B p53 Large T antigen SV40 p53, Rb Small t antigen PP2A EBV LMP1 TRAFs, NF-κB HBV X protein p53 B) Figure 2 (A) Representative* list of cellular/viral protein interactions involved in DNA virus-related oncogenic transformation; (B) p53 and Rb are central targets of viral oncoproteins. The viral proteins Large T antigen of SV40, E1A/E1B of Adenovirus, and E6/E7 of HPV, are capable of interfering with either Rb and/or p53, altering their activities and thus essential cell cycle check-points. PP2A: Protein Phosphatase 2A; TRAFs:Tumor necrosis Factor Associated. * Additional cellular/viral interactions involved in cell transformation and oncogenetic mechanisms have been described. how major achievements in the prevention of virus- ability of HB×Ag to modulate specific cell pathways has induced cancers may be attributable to strategies to con- been linked to the upregulated gene clone 11 (URG11) trol infection in human populations. In fact, HBV vacci- cellular protein, which appears to be a direct effector of nation has dramatically decreased the number of HCC the viral protein. Indeed, URG11 is upregulated in [45,99-101]. However, the molecular mechanisms of HBV HB×Ag-positive liver cells and seems to be involved in carcinogenesis are still not fully clarified. Different stud- cancer evolution, by controlling cell cycle progression ies suggest a role for the hepatitis B virus × antigen [103]. (HB×Ag) in this context. Indeed, in addition to a physical There is emerging interest in the polyomaviruses as binding and functional inactivation of p53, HB×Ag pro- possible human carcinogens [80,83,104-107]. SV40, motes fibrogenesis by stimulating fibronectin expression, which naturally infects the rhesus monkey, was inadver- inhibits apoptosis mediated by Fas and tumor necrosis tently introduced into the human population as a con- factor-alpha (TNF-α) and its expression correlates with taminant of early poliovirus vaccines, whereas the BK and the development and progression of CLD [102,103]. In JC polyomaviruses are natural human pathogens associ- particular, HB×Ag expressed by HBV genome integrated ated with disease processes in the urinary tract or brain, into chromosomal DNA is often functional in trans-acti- respectively. Genomic sequences of these three polyoma- vation assays [102]. Moreover, it can alter patterns of host viruses, which are tumorigenic under experimental con- gene expression, contributing to carcinogenesis, by acti- ditions, have been detected in human mesothelioma, vating signal transduction pathways in host-infected cells osteosarcoma, NHL, brain tumors, and prostate cancer. [102,103]. HB×Ag transforms cell lines in vitro, giving In addition, an integrated form of a new polyomavirus, rise to liver cancer in transgenic mice [103]. A role in the MCPyV, was recently observed in Merkel cell carcinoma, Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 8 of 11 http://www.infectagentscancer.com/content/5/1/11 a rare but aggressive human skin cancer of neuroendo- γ-herpesvirus infection, few viral genes are expressed. crine origin [39,84]. Whereas EBV latent proteins contribute to cell immortal- EBV and HHV-8 are two members of the Herpesviridae ization, HHV-8 lytic genes play an important role in can- family that are classified as cancerogenic agents. These cer development and progression. An Italian study viruses can establish long-term viral infections in their investigated the latent and lytic antibodies seropreva- target cells, promoting cellular immortalisation and lence in elderly subjects, and the possible correlation with transformation [80,81]. EBV is the most important aetio- clinical stage and disease progression in classical KS logical factor in classic BL [108], and it is also detectable [118,119]. While the antibody levels against HHV-8 latent in undifferentiated nasopharyngeal carcinomas, in a sub- antigens were observed in all KS cases, antibody levels set of HL, and in some cases of NHL, notably in immuno- against HHV-8 lytic antigens increase with the progres- suppressed patients [79,80,108]. sion of KS, and higher HHV-8 antibody levels were The alteration of cell signaling represents the molecular observed in the fast progressive form of the disease [119]. basis for cellular proliferation occurring in association According to the literature, these results support the with several viral infections. In particular, both EBV and hypothesis that active viral replication probably contrib- HHV-8 target important cell signaling pathways involved utes to progression of KS. In addition, HHV-8 DNA was in oncogenesis, such as the β-catenin pathway that plays a constantly detected in saliva and PBMC samples of classi- key role in the control of cell adhesion and tissue mor- cal KS but without any correlation with the clinical stage phogenesis [109,110]. The level of β-catenin protein is of the disease, suggesting that oral shedding is likely to subject to tight regulation, particularly through ubiq- occur in these patients and contributes to viral transmis- uitin-mediated proteasomal degradation. Latent mem- sion [119]. brane protein-1 (LMP-1) and latent membrane protein- 2A (LMP-2A) of EBV affect the β-catenin stabilization Conclusive remarks and activation avoiding the ubiquitination [110], as many By the first decade of the 21st Century, much evidence other oncoproteins of tumorigenic viruses, such as T had accumulated pointing out at least six human viruses, antigen in JCV [105]. It is beginning to emerge that tumor namely HPV, HBV, EBV, HHV-8, HCV, and HTLV-1, as viruses modulate the ubiquitination of specific cell fac- aetiologic agents of human cancers. As mentioned above tors for their needs [111,112] by employing different these viruses are responsible of roughly 20% of all human strategies. Among them, viruses encode their own ubiq- tumors worldwide [45]. Moreover, oncogenic viruses uitin ligases and deubiquitinating enzymes (DUBs), as have also proved to be powerful tools for dissecting fun- recently demonstrated in the case of herpesviruses damental pathways and proteins involved in cell cycle [112,113]. Indeed, since the discovery that the largest teg- progression and regulation. For example, a number of ument protein of Human Herpes Virus-1 (HSV-1), UL36, oncogenes have been identified through studies focused contains a deubiquitinating activity it has been reported on RNA tumor viruses, while essential tumor suppres- that all members of the Herpesviridae family, including sors, such as p53 and Rb, were discovered and character- EBV and HHV-8, encode UL36 homologues, suggesting ized through DNA tumor viruses. In the future, it is an important role of this protein in the viral life cycle expected that the characterization of new tumor viruses [111,114]. On the other hand, the presence of the viral will contribute in clarifying relevant aspects of cell biol- latency-associated nuclear antigen (LANA) in all HHV-8- ogy and carcinogenesis. Indeed, other candidate human associated tumors significantly correlates with β-catenin tumor viruses have been proposed [120]. Particularly over-expression. In this context it has been demonstrated intriguing in this context is the study of human endoge- that introduction of anti-LANA small interfering RNA nous retroviruses role in seminomas, breast cancer, (siRNA) into primary effusion lymphomas (PEL) cells myeloproliferative disease, ovarian cancer, melanoma, eliminated β-catenin accumulation, while LANA itself and prostate cancer [121]. Moreover, as demonstrated in upregulated expression of β-catenin in transfected cells. the case of HBV and HPV, prophylactic vaccines offer the LANA stabilizes β-catenin by binding to its negative reg- potential to prevent cancers having a viral aetiology. ulator GSK-3β, causing a cell cycle-dependent nuclear Thus, the development of new vaccines against other accumulation of GSK-3β [115]. The importance of this human tumor viruses should be a must for the future pathway to HHV-8-driven cell proliferation is highlighted research. by the observation that LANA stimulates entry into S Competing interests phase. The authors declare that they have no competing interests. In the past 10 years much effort has been devoted to the Authors' contributions study of HHV-8. HHV-8 is consistently detected in all All authors have contributed in writing the review. All the authors read and forms of KS, in PEL, and in a subset of multicentric Cas- approved the final manuscript. tleman's disease [116,117]. During the latency program of Bergonzini et al. Infectious Agents and Cancer 2010, 5:11 Page 9 of 11 http://www.infectagentscancer.com/content/5/1/11 Author Details 25. 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