- Open Access
View and review on viral oncology research
© Bergonzini et al; licensee BioMed Central Ltd. 2010
- Received: 15 January 2009
- Accepted: 24 May 2010
- Published: 24 May 2010
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 terms of their prevention, diagnosis, and therapy. In the 21st 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.
- Acquire Immune Deficiency Syndrome
- Merkel Cell Carcinoma
- Rous Sarcoma Virus
- Acquire Immune Deficiency Syndrome Patient
- Viral Oncology
Animal retroviruses have been characterized earlier, starting from the RSV studies. Indeed, one of the major breakthrough in understanding the molecular mechanisms behind the ability of RNA viruses to cause cancer came from the RSV field. In particular, the observation that cellular transformation and viral replication by RSV were dissociable properties  suggested that the virus was encoding a cancer-causing gene, dispensable for viral replication. In 1970, Duesberg and Vogt by comparing the genomes of two closely related replication-competent RSV variants, one of which could transform cells and the other which could not  demonstrated that the transformation-competent RSV variant exhibited at the level of the 3'-end additional sequences accounting for a genome 20% larger than the one of transformation-defective RSV variant. This cancer-causing gene (oncogene) was named src according to the type of tumor caused by RSV in chickens, the sarcoma. The established dispensability of the src gene for RSV replication lead to the hypothesis that oncogenes have a cellular origin and that carcinogenic events activate cellular genes to promote cancer. Thus, the reverse transcriptase-dependent life cycle typical of most RNA oncogenic viruses, like RSV, would allow the viral genome to capture a cellular oncogene. In 1976, Bishop and Varmus proved that this hypothesis was correct . Indeed, they were able to obtain src specific probes, starting from transforming RSV genome, and demonstrated its hybridization with the DNA of normal chicken cells and with the DNA of other avian species, even though with lower stringency. This evolutionary conservation of src sequences provided strong evidence that src was indeed a cellular gene acquired by RSV from the chicken genome, rather than being a viral gene. Moreover, this finding suggested that the cellular gene, designated a proto-oncogene, must sustain a mutation to cause cancer thus associating tumors with mutagenic events. Supporting this view, it was then demonstrated that ras oncogenes present in human bladder carcinoma cell lines, and rat mammary carcinomas contained a mutation crucial for inducing cellular transformation absent in ras proto-oncogene present in normal cells [43, 44]. Viral oncogenes carry as well mutations or are constitutively expressed with negative effects on cell proliferation control. Indeed, to date, more than 70 cellular proto-oncogenes have been identified through studies of oncogenic retroviruses, and nearly all of these genes code for key cell signaling proteins involved in the control of cellular proliferation and apoptosis . The ability to encode viral oncogenes is not the only mechanism by which RNA viruses can cause cancer. It has been demonstrated that retroviruses not carrying oncogenes in their genome may influence expression/function of cellular oncogenes by insertional mutagenesis .
Among human retroviruses, the earliest oncogenic virus identified was HTLV-1, associated with the ATL, an aggressive clonal malignancy of mature CD4+ T lymphocytes that presents after a 20-40 years period of clinical latency . Interestingly, HTLV-1 still represents the only known human retrovirus directly linked to a specific human malignancy. Indeed, several epidemiological and molecular evidence implicates HTLV-1 as the aetiologic agent of ATL: i) the geographic distribution of ATL in different world areas, from Japan to Central African, the Caribbean basin, Taiwan, and Papua New Guinea matches that of HTLV-1 infections ; ii) when checked, ATL patients always underwent HTLV-1 infection; iii) leukemic cells cultured derived from ATL patients are positive for HTLV-1; iv) HTLV-1 infection of normal human T cells induced cellular transformation and immortalization.
Interestingly, by contrast to mechanisms typical of animal retroviruses, HTLV-1 does not cause cancer by insertional mutagenesis or by capturing and activating cellular proto-oncogenes. Rather, the major oncogenic determinant of HTLV-1 is the viral Tax gene that encodes a protein essential for viral replication . In particular, it has been demonstrated that Tax associates with centrosomes, causing their fragmentation , and it is crucial for transactivation/repression of viral and cellular gene expression. Oncogenic transformation of infected and transfected cells would hence be due to the interaction with various transcription factors . Furthermore, Tax induces genome instability by deregulation of cell cycle checkpoints. According to the chromosomal alterations observed in ATL patients, it has been described that Tax is able of inducing a delay in the cellular recognition and response to DNA damage, and of suppressing the DNA repair machinery activation . Thus, Tax drives genome instability and cellular transformation by interfering with cell cycle checkpoint pathways and DNA repair mechanisms. Hence, Tax can be considered a viral oncoprotein, since Tax alone transforms rat fibroblasts and primary human T lymphocytes, while transgenic mice expressing Tax develop tumors . Moreover, recent evidence supports a role for the HTLV-1 basic leucine-zipper factor (HBZ) as an additional viral player in cancer development [53, 54]. Interestingly, HBZ expression in transgenic mice confers a phenotype similar to the one observed in ATL patients, and in particular the infiltration of lymphocytes into skin and lung [53, 54]. A schematic representation of HBZ role in HTLV-1 mediated oncogenesis is reported in Figure 1. Finally, it has been shown that HTLV-1 is able of altering the major histocompatibility complex class-I (MHC-I) and the T cell receptor (TCR) cascade activation through the accessory protein p12. p12 targets the free MHC-I chain and increases Signal Transducer and Activator of Transcription-5 (STAT-5) protein activation and calcium release . Furthermore, p12 decreases viral expression in TCR-stimulated T cells and is recruited to the immunological synapse . Besides, HTLV-1 accessory proteins p13II is able to target the mitochondria and to induce changes in its morphology. In particular, the effects on mitochondria result mainly at the membrane permeability level, altering the inner membrane potential, and the oxygen consumption (respiration), thus affecting cellular proliferation, apoptosis, and reactive oxygen species (ROS) production [57, 58].
The hypothesis of an HIV-1 involvement in tumor pathogenesis is based on the evidence that AIDS-related tumors have been described, such as KS, non-Hodgkin's lymphomas (NHLs), and invasive cervical carcinoma (ICC) . HIV-1 infection can play a direct and/or indirect role in HIV-1-related tumorigenesis. Among the HIV-1 proteins of particular importance with regard to a possible role in the carcinogenesis is the accessory protein Tat . In this context, it has been proposed that the Tat-induced DNA repair deficiencies may play a significant role in the development of AIDS-associated cancers . In particular, in the case of ICC, HIV-1 Tat, besides enhancing the activity of HPV oncogenes, by upregulating HPV E6 and E7 gene expression , could also promote cell cycle progression . Moreover, it has been suggested that Tat, by physically interacting with pRb2/p130, might alter pRb2/p130 cell growth-suppressive properties, leading to the loss of cell cycle control .
Besides, considering clinical data about HIV-1-associated primary cerebral lymphoma, several important differences of AIDS to non-AIDS related primary cerebral lymphomas have been described [59, 63, 64]. Among them are the higher aggressiveness, the presence of multi-focal lesions, the reduced percentage of therapy responders, and an elevated mortality [63, 64].
In addition to the retroviruses, HCV, a member of the Flaviviridae family, is associated with human cancer. HCV infection affects more than 170 million individuals worldwide and represents one of the main causes of chronic liver disease (CLD) that can evolve in HCC . Among patients infected with HCV, it is almost exclusively those with cirrhosis (roughly 20%) who develop HCC, revealing a major risk factor for malignant progression. For these patients, the annual risk for developing HCC is 1% to 4%, with patients from Japan having an even higher risk. Chronic inflammation and cirrhosis are believed to play key roles in promoting HCV-associated HCC, although the underlying mechanisms of this process are not yet understood. In addition to HCC, HCV is also involved in polyclonal B lymphocyte activation  and epidemiological studies show that HCV seropositive individuals have a 5.5 times higher risk developing NHL compared to HCV-seronegative individuals . Clonal B cells may evolve to overt HCV-related NHL as result of an antigen-driven process triggered by the E2 protein [66, 67]. Noteworthy, the characterization of clonal B cells activation mechanisms may represent a suitable target to develop a therapy for HCV-associated NHL [66, 67].
By contrast to RNA viruses, usually oncogenes of DNA tumor viruses lack any recognizable sequence similarities to cellular genes and how the products of these viral genes were able to transform cells was not elucidated till late 1970s [68, 69]. It has been demonstrated few years earlier that SV40 was capable to induce tumor formation in experimentally infected hamsters, by the expression of the viral large tumor (T) antigen, the major oncogenic determinant of SV40 [70–72]. By employing co-immunoprecipitation techniques, it was shown that the SV40 large T antigen was interacting with a cellular protein having an approximate molecular weight of 53 kDa. Based on its size, this cellular protein was named p53. This finding represented the first evidence that products of DNA tumor virus oncogenes could function through physical/direct interactions with cellular proteins. By cloning p53 genes from neoplastic rodent and human cells it was possible to demonstrate that in all cases the coding sequences differed from those present in normal cells, by carrying important gain-of-function mutations. Indeed, p53 is mutated or lost in almost 50% of all human cancer cases worldwide, representing the most commonly mutated gene in human tumors. This finding suggests that p53 acts as a tumor suppressor gene, which in contrast to proto-oncogenes function to prevent rather than to promote cancer . Several studies have contributed to demonstrate that a wide variety of cellular stress stimuli, such as DNA damage but also viral infection, induce the activation of p53, which binds to and regulates the activity of several important cellular factors . In this way, p53 controls cell cycle progression, senescence, apoptosis, and DNA repair thus preventing tumor formation by reducing the accumulation of genetic lesions. In the case of viral infection p53 activation represents the attempt of the host cell to block viral replication, by inducing, for instance, apoptosis. Thus, several DNA viruses have evolved proteins, such as the SV40 large T antigen, to bind and inactivate p53, in order to escape the cellular antiviral response , with cell transformation as a consequence.
Inactivation of p53 is not the only mechanisms evolved by DNA oncogenic viruses which induces tumors. A second tumor suppressor genes, was discovered by studying the childhood tumor retinoblastoma (Rb) . Rb susceptibility was linked to a single recessive trait and the gene encoding the specific tumor suppressor gene was identified and cloned [75, 76] and the protein named Rb. In 1988, Harlow, Livingston and co-workers, demonstrated that the Rb protein immunoprecipitates with adenovirus E1A and with SV40 large T antigen from transformed cells [77, 78].
Studying the interactions among human adenovirus E1A and SV40 large T antigen with Rb was essential for understanding the cellular tumor suppressor function  with the demonstration that a hypophosphorylated form of Rb negatively regulates G1 to S phase progression through the cell cycle by binding to and blocking the activity of E2F, a transcriptional factor activating several genes involved in cellular DNA replication. Cell progression through G1 to S phase depends on the G1 cyclin-dependent kinases activity, which directly hyperphosphorylate and inactivate Rb leading to the release of active E2. Viral oncoproteins specifically bind to and inactivate the hypophosphorylated form of Rb. Thus free active E2F accumulates, with consequent uncontrolled cellular proliferation.
To date, the DNA viruses consistently associated with human tumors, are the HBV, HPV, EBV, and HHV-8 [80, 81]. In addition, several evidence suggest a causative role in some human cancers also for SV40, BK Virus (BKV) and JC Virus (JCV) [80–83].
HPV represents a typical example of human oncogenic DNA virus. Specific genotypes have been clearly linked to different forms of tumors, mainly cervical cancer, but also some penile and upper aerodigestive tract carcinomas [45, 84]. Being the viral aetiology of the above tumors so well established, as for HBV, it is expected that the recently tested HPV vaccines [45, 84] will have a profound impact on their prevention [45, 84–90]. The HPV E6 and E7 oncoproteins play an important role in cervical tumors development, and are continuously expressed in the lesions, while tumor arises only several years after the initial cellular immortalising events. In fact, the continuous expression of E6 and E7 is required for maintenance of the transformed phenotype, and prevention of cell growth arrest and/or apoptosis [91, 92]. The best-characterised HPV16 E6 activity is its ability to induce degradation of the tumour suppressor protein p53 via the ubiquitin pathway . Moreover, among additional functions, E6 protein can also interfere with cellular differentiation and cell cycle progression . E7 is an acidic phosphoprotein of 98 amino acids, which is structurally and functionally related to a gene product of other DNA tumour viruses, the adenovirus E1A protein and SV40 large T antigen. As mentioned above, all three proteins are capable of binding to the tumour suppressor protein retinoblastoma (pRb1) and its related proteins p107 and p130, involved in cell cycle regulation. By doing so, and thanks to other functions, E7 controls cell cycle progression . In addition to E6 and E7, HPV E5 protein, a small hydrophobic protein, localized in the endomembrane compartments of the Golgi apparatus and endoplasmic reticulum could play a role in HPV carcinogenesis. Indeed it has been demonstrated that HPV E5 down-regulates surface MHC-I, thus preventing its transport to the cell surface; hence, E5 can potentially allow infected cells to escape adaptive immune response of cytotoxic T lymphocytes (CTL), thus favouring viral persistence [95, 96].
As for HCV, HBV chronic infection represents an important risk factor for the development of HCC, a malignant tumor frequently observed in some countries of Asia and Africa [97, 98]. It is important to underline how major achievements in the prevention of virus-induced cancers may be attributable to strategies to control infection in human populations. In fact, HBV vaccination has dramatically decreased the number of HCC [45, 99–101]. However, the molecular mechanisms of HBV carcinogenesis are still not fully clarified. Different studies suggest a role for the hepatitis B virus × antigen (HB×Ag) in this context. Indeed, in addition to a physical binding and functional inactivation of p53, HB×Ag promotes fibrogenesis by stimulating fibronectin expression, inhibits apoptosis mediated by Fas and tumor necrosis factor-alpha (TNF-α) and its expression correlates with the development and progression of CLD [102, 103]. In particular, HB×Ag expressed by HBV genome integrated into chromosomal DNA is often functional in trans-activation assays . Moreover, it can alter patterns of host gene expression, contributing to carcinogenesis, by activating signal transduction pathways in host-infected cells [102, 103]. HB×Ag transforms cell lines in vitro, giving rise to liver cancer in transgenic mice . A role in the ability of HB×Ag to modulate specific cell pathways has been linked to the upregulated gene clone 11 (URG11) cellular protein, which appears to be a direct effector of the viral protein. Indeed, URG11 is upregulated in HB×Ag-positive liver cells and seems to be involved in cancer evolution, by controlling cell cycle progression .
There is emerging interest in the polyomaviruses as possible human carcinogens [80, 83, 104–107]. SV40, which naturally infects the rhesus monkey, was inadvertently introduced into the human population as a contaminant of early poliovirus vaccines, whereas the BK and JC polyomaviruses are natural human pathogens associated with disease processes in the urinary tract or brain, respectively. Genomic sequences of these three polyomaviruses, which are tumorigenic under experimental conditions, have been detected in human mesothelioma, osteosarcoma, NHL, brain tumors, and prostate cancer. In addition, an integrated form of a new polyomavirus, MCPyV, was recently observed in Merkel cell carcinoma, a rare but aggressive human skin cancer of neuroendocrine origin [39, 84].
EBV and HHV-8 are two members of the Herpesviridae family that are classified as cancerogenic agents. These viruses can establish long-term viral infections in their target cells, promoting cellular immortalisation and transformation [80, 81]. EBV is the most important aetiological factor in classic BL , and it is also detectable in undifferentiated nasopharyngeal carcinomas, in a subset of HL, and in some cases of NHL, notably in immunosuppressed patients [79, 80, 108].
The alteration of cell signaling represents the molecular basis for cellular proliferation occurring in association with several viral infections. In particular, both EBV and HHV-8 target important cell signaling pathways involved in oncogenesis, such as the β-catenin pathway that plays a key role in the control of cell adhesion and tissue morphogenesis [109, 110]. The level of β-catenin protein is subject to tight regulation, particularly through ubiquitin-mediated proteasomal degradation. Latent membrane protein-1 (LMP-1) and latent membrane protein-2A (LMP-2A) of EBV affect the β-catenin stabilization and activation avoiding the ubiquitination , as many other oncoproteins of tumorigenic viruses, such as T antigen in JCV . It is beginning to emerge that tumor viruses modulate the ubiquitination of specific cell factors for their needs [111, 112] by employing different strategies. Among them, viruses encode their own ubiquitin ligases and deubiquitinating enzymes (DUBs), as recently demonstrated in the case of herpesviruses [112, 113]. Indeed, since the discovery that the largest tegument protein of Human Herpes Virus-1 (HSV-1), UL36, contains a deubiquitinating activity it has been reported that all members of the Herpesviridae family, including EBV and HHV-8, encode UL36 homologues, suggesting an important role of this protein in the viral life cycle [111, 114]. On the other hand, the presence of the viral latency-associated nuclear antigen (LANA) in all HHV-8-associated tumors significantly correlates with β-catenin over-expression. In this context it has been demonstrated that introduction of anti-LANA small interfering RNA (siRNA) into primary effusion lymphomas (PEL) cells eliminated β-catenin accumulation, while LANA itself upregulated expression of β-catenin in transfected cells. LANA stabilizes β-catenin by binding to its negative regulator GSK-3β, causing a cell cycle-dependent nuclear accumulation of GSK-3β . The importance of this pathway to HHV-8-driven cell proliferation is highlighted by the observation that LANA stimulates entry into S phase.
In the past 10 years much effort has been devoted to the study of HHV-8. HHV-8 is consistently detected in all forms of KS, in PEL, and in a subset of multicentric Castleman's disease [116, 117]. During the latency program of γ-herpesvirus infection, few viral genes are expressed. Whereas EBV latent proteins contribute to cell immortalization, HHV-8 lytic genes play an important role in cancer development and progression. An Italian study investigated the latent and lytic antibodies seroprevalence in elderly subjects, and the possible correlation with clinical stage and disease progression in classical KS [118, 119]. While the antibody levels against HHV-8 latent antigens were observed in all KS cases, antibody levels against HHV-8 lytic antigens increase with the progression of KS, and higher HHV-8 antibody levels were observed in the fast progressive form of the disease . According to the literature, these results support the hypothesis that active viral replication probably contributes to progression of KS. In addition, HHV-8 DNA was constantly detected in saliva and PBMC samples of classical KS but without any correlation with the clinical stage of the disease, suggesting that oral shedding is likely to occur in these patients and contributes to viral transmission .
By the first decade of the 21st Century, much evidence had accumulated pointing out at least six human viruses, namely HPV, HBV, EBV, HHV-8, HCV, and HTLV-1, as aetiologic agents of human cancers. As mentioned above these viruses are responsible of roughly 20% of all human tumors worldwide . Moreover, oncogenic viruses have also proved to be powerful tools for dissecting fundamental pathways and proteins involved in cell cycle progression and regulation. For example, a number of oncogenes have been identified through studies focused on RNA tumor viruses, while essential tumor suppressors, such as p53 and Rb, were discovered and characterized through DNA tumor viruses. In the future, it is expected that the characterization of new tumor viruses will contribute in clarifying relevant aspects of cell biology and carcinogenesis. Indeed, other candidate human tumor viruses have been proposed . Particularly intriguing in this context is the study of human endogenous retroviruses role in seminomas, breast cancer, myeloproliferative disease, ovarian cancer, melanoma, and prostate cancer . Moreover, as demonstrated in the case of HBV and HPV, prophylactic vaccines offer the potential to prevent cancers having a viral aetiology. Thus, the development of new vaccines against other human tumor viruses should be a must for the future research.
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