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Skin cancer viruses: bench to bedside – HPV, HHV8 and Merkel cell carcinoma virus

Drug Discovery Today: Disease Mechanisms, 3-4, 10, pages e91 - e94

Viral infection in cancer is common. Although there is still debate whether viruses alone can cause tumors, the discovery of tumor viruses has enlightened many fields of tumor biology and viral oncogenesis. With the advances of biotechnology, the list of tumor viruses will grow in the coming decades. However, to determine if a candidate virus causes cancer, the key is to combine epidemiological and molecular biologic data. Recently, promising viral targeted therapies include anti-latent viral drugs and immunological therapies. In this article, we review the current knowledge of the role of human papillomavirus, human herpesvirus 8, and Merkel cell polyomavirus in skin cancer carcinogenesis, with a focus on recent literature.


Approximately 15–20% of cancers worldwide have been attributed to infectious agents, including viruses [ 1 ]. These tumor viruses cause malignant transformation through both direct and indirect mechanisms. Direct mechanisms involve viral-encoded proteins that disrupt the cell cycle, leading to malignant transformation. Indirect mechanisms include insertional mutagenesis, in which integration disrupts cellular oncogenes, or chronic infection and inflammation that eventually leads to carcinogenic mutations in host cells. These viruses are rarely complete carcinogens and seem to interact with cofactors such as chemical carcinogens, UV radiation, genetic predispositions and immunosuppression [ 2 ]. They target tumor suppressor genes, which facilitate viral replication and contribute to unlimited cell growth as well as genomic instability. The causative relationship between viruses and cancer in immunosuppressed patients, such as in AIDS and organ transplantation patients, has been an area of intensive investigation.

Human papilomavirus

HPVs are small DNA viruses belonging to the family Papillomaviridae with a circular genome typically containing 8 genes. The late genes: L1 and L2, code for proteins that form the capsid. The nucleotide sequence of L1 constitutes the basis for HPV classification. The early genes, E6 and E7, are involved in transcription and replication and are expressed in the basal epithelium and differentiating cells in virally infected cells. More than 120 types of HPV have been discovered and they are divided into alpha, beta and gamma HPVs, which comprise the majority of cutaneous HPVs [ 3 ]. The different HPV types are generally divided into those preferentially infecting the skin versus mucosal surfaces, the latter being associated with neoplastic disease of the anogenital tract and of head and neck squamous cell carcinomas. Among the mucosal HPVs, 15 types are considered high risk, in particular, HPV 16 and 18 which are responsible for >70% of the HPV induced cancers [ 4 ]. In addition to verrucous carcinoma, bowenoid papulosis and epidermodysplasia verruciformis, HPV has been associated with cutaneous squamous cell carcinoma (SCC), especially in immunocompromised individuals [ 5 ]. Higher copies of HPV DNA are detected in SCC from immunosuppressed patients. Moreover, HPV is found in up to 80% of SCC in organ transplant recipients. However, attempts to link cutaneous squamous cell carcinoma (SCC) in immunocompetent patients and HPV have yielded contradictory results. Not all cutaneous SCCs are infected with HPV and prevalences vary widely depending predominantly on detection methods [ 6 ]. Moreover, many types are identified in the same lesion. Therefore, HPV may act only as an initiating factor early during carcinogenesis or may merely be a bystander with no role in UV-induced SCC. Interestingly, β-papillomavirus species 2 is present more commonly in SCC from immunocompetent patients when compared with the healthy skin of the same individual. The relevance of HPV to the pathophysiology of SCC remains unclear.

The mechanism of HPV induced carcinogenesis is not completely understood. Integration of the virus is an important event in malignant transformation induced by high risk genital HPV types. The best documented mechanism in HPV related malignant transformation is the persistent overexpression of HPV E6 and E7. E6 interferes with p53 resulting in p53 degradation and E7 inactivates Retinoblastoma (Rb) signaling. Thus, acting synergistically, not only do they promote inhibition of apoptosis and dysregulation of the cell cycle leading to abnormal cell growth, but also induce cellular genomic instability and contribute to carcinogenesis. Interestingly, SCCs derived from mice with deletion of Rb or p53 gene only in skin exhibit similar molecular signatures to that of HPV-tumors, suggesting a role of HPV in the carcinogenesis of SCC.

Human herpesvirus

HHV-8, also known as Kaposi sarcoma (KS) associated herpesvirus (KSHV), is a large double-stranded DNA virus. Its discovery as the causative agent in KS was made in 1994 using representational difference analysis comparing Kaposi's sarcoma and healthy tissue genome from the same patient [ 7 ]. It is transmitted through saliva and replicates in oropharyngeal cells. It is the causal factor in all variants of KS and certain lymphoproliferative disorders [8 and 9]. The risk of these diseases is significantly higher during acquired or iatrogenic immunosuppression, in the setting of HIV coinfection and organ transplantation.

KSHV in Kaposi's sarcoma and HPV in cervical cancer are two examples where viruses are necessary for tumorigenesis as the viruses are universally present in these tumors; however, cofactors exist. Although there is a higher prevalence of KS in HIV infection, its detection in other immunosuppressed settings supports the role of KSHV in KS pathogenesis. Similar to HPV E6 and E7, KSHV-encoded cyclin, viral FLICE inhibitory protein and KSHV latency-associated nuclear antigen (LANA) target Rb, p53 and interferon signaling, which promote cell proliferation and prevent apoptosis. Moreover, cells harboring KSHV undergoing lytic replication express lytic viral proteins including K1, viral interlukin-6, viral Bcl-2, viral G protein coupled receptors, K17 and viral chemokines, which lead to cytokine and growth factor secretion. Collectively, a proliferation of endothelial-type cells and abnormal leaky blood vessels eventuates. However, the fact that KS fails to develop in HIV-negative KSHV-infected individuals argues for a role for host genetic factors such as genetic polymorphisms of inflammatory and immune response genes in KS development.

The detection of HHV-8 infection in tumor cells is a prerequisite for a diagnosis of KS. The gold standard to detect HHV-8 is immunohistochemistry with antibodies against the HHV-8 LANA [ 10 ].

Promising approaches to the treatment of KS in addition to HAART include radiotherapy, systemic chemotherapy with daunorubicin, taxanes and HIV protease inhibitors that also have direct anti-tumor activity [ 11 ]. Despite the success of HAART in reducing incidence of AIDS-KS and inducing AIDS-KS regression, KS achieves resolution only in 50% of patients. Radiotherapy is effective for isolated disease, while systemic chemotherapy with daunorubicin and taxanes are useful for disseminated diseases. New therapeutics target signaling pathways are essential in vascular and lymphovascular proliferations, such as VEGF, PDGF, Notch and NF-κB pathways. Interestingly, rapamycin demonstrates clinical efficacy in post-transplant KS through inhibition of PI3K-Akt-mTOR pathway.

Merkel cell polyomavirus

Merkel cell carcinoma (MCC) is an aggressive skin cancer with rising incidence, 1500 cases per year in the US. Moreover, MCC incidence is approximately 11-fold greater in AIDS patients and 5-fold greater in organ transplant patients. 50% of patients have metastases at presentation with a 5-year disease-associated mortality rate of 46%, far exceeding that of melanoma. Nevertheless, there is no effective treatment so far.

The most recent breakthrough is the discovery of Merkel cell polyomavirus (MCV). Polyomaviruses are small, nonenveloped, double-stranded, circular DNA viruses first identified in 1954, by Gross, with the discovery of murine polyomavirus [ 12 ]. In 1960, simian vacuolating virus 40 (SV40) was identified in rhesus monkey cells used for the production of vaccines [ 13 ]. Although SV40 is an asymptomatic infection in primates, the virus was shown to be oncogenic in mice and rodents. SV40 is now a workhorse for cancer biology. In 2008, MCV was identified by a technique called digital transcriptome subtraction [ 14 ]. In the initial study, MCV was detected in 8/10 (80%) of MCCs, as compared to 9/84 (11%) of non-MCC tissues. Analogous to HPV, clonal integration of MCV in the host genome is detected in both primary and metastatic MCCs, indicating that the viral infection is present before clonal expansion because MCV can neither replicate nor are transmissible [ 15 ].

The role of MCV in MCC pathogenesis

It is widely accepted that MCV is causally association with MCC; however, it is not sufficient for MCC carcinogenesis. As with other viruses, MCV, together with additional cellular events and loss of immunosurveillance, contributes to MCC development. Similar to SV40, MCV encodes a multiply spliced tumor (T) antigen protein complex that targets several tumor suppressor genes. Studies have demonstrated that both MCV large T antigen (LT) and small antigen (ST) play a role in MCC pathogenesis. Almost all MCV genome isolated from MCCs has mutations in LT distal to pRb-binding site, which eliminates DNA replication and avoids cell lysis and death. Moreover, it has been shown that expression of T antigens is necessary for the maintenance of MCV-positive MCCs both in vivo and in vitro. LT and ST dysregulate cell proliferation and prevent apoptosis through interactions with Rb and mTOR pathways, respectively. Furthermore, knockdown of MCV ST expression in MCC cell lines arrests cell proliferation. However, the initial event in MCV-driven MCCs is the evasion of immune surveillance because MCC is common in the elderly and immunosuppressed individuals.

MCV infection prevalence

The presence of MCV in MCCs varies depending on the methods used [15 and 16]. Several groups have reported the rate of MCV detection in MCC at between 40 and 80%. In studies where MCV DNA is detected by PCR amplification, viral copy numbers per cell varied among cases by many orders of magnitude [ 17 ]. Immunohistochemistry with antibodies specific for MCV LT and ST antigen can be used to detect MCV in MCC. Recently, Rodig et al. developed a new monoclonal antibody against the LT antigen which detected MCV in 97% of unique MCC tumors [ 18 ]. The benefits of immunohistochemistry are high amplification of the signals, robust, diffuse nuclear staining and lack of lymphocyte staining. However, commercial available antibodies used to detect MCV are against the LT antigen of MCV. It is known that a subset of MCC express ST antigen in the absence of LT positivity. Collectively, immunohistochemistry is faster and cheaper, and qPCR is more expansive.

MCV serology has been based largely on antibodies reacting to the late structure proteins VP1 and, to a lesser extent, VP2. Variable seroprevalence of MCV in MCC patients has been reported. Similar to other polyomavirus, MCV seroprevalence is 9% in children younger than 4 years of age and increases to 35% by 4–13 years of age. Using virus-like particle as antigens for immunoassays, Tolstov et al. found that 80% of healthy North American blood donors showed evidence for past MCV exposure [ 19 ]. Furthermore, MCV is detected in 80% of cutaneous swabs from healthy volunteers, suggesting that it commonly inhabits the human skin [ 20 ]. Although MCV is detected in a small fraction of non-melanoma skin cancers, no connection had been drawn [ 21 ]. Interestingly, Mittelford et al. identified MCV in two combined MCC–SCC tumors. HPV 6 was also detected, which led to the hypothesis of cocancerogenesis of two oncogenic viruses in non-melanoma skin cancer [ 22 ]. Extensive efforts sought to find an association between MCV and other diseases have largely failed. However, a recent report identified MCV in 6 of 18 (33%) of chronic lymphocytic leukemia/small cell lymphoma, suggesting a potential role of MCV in hematologic malignancies [ 23 ].

Clinical implications of MCV in MCC

It is still unclear whether MCV has any, if at all, prognostic impact in MCC. Conflicting data exist regarding the presence of MCV and viral load on clinical implications in MCC. Therefore, it is proposed that at least two subtypes of MCC exist: one clinically less aggressive subtype, with clear MCV etiology as demonstrated by high viral load, LT expression and high titers of MCV antibodies, and a second subtype that is clinically more aggressive with a different etiology, with a low viral load, lack of LT expression and MCV titers that are similar to the general population [ 24 ]. Recently, several studies have identified MCV-specific CD8 and CD4T cells in MCC patients that have shed light on immunotherapeutic targeting, peptide vaccine and adoptive immunotherapy, of MCV.


The burden of viral infection in cancer is high, but has been underappreciated by cancer research community. With the advance of mordent technology, more cancer viruses will be discovered in coming years. However, determining whether a virus causes cancer is challenging. Substantial progress has made in understanding the biological, etiological and clinicopathological features of tumor viruses, as exemplified by the development of vaccines against hepatitis B virus and HPV. Failure to recognize the contribution of virus in cancer minimizes the opportunities for cancer control, such as in the case of EBV and KSHV. Although gaps remain in our knowledge relating to viral agents and their role on carcinogenesis, tumor prevention and treatment, future research may lead to direct antiviral agents or small molecule inhibitors of viral proteins to prevent interaction with and disruption of cell cycle proteins or the ultimate goal of protective vaccines which could result in a 15–20% reduction of human malignant tumors worldwide.

Conflict of interest

The authors have no conflict of interest to declare.


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Department of Dermatology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA

lowast Corresponding author.