Mini-reviewVirus induced inflammation and cancer development
Introduction
Viruses contribute significantly to cancer development worldwide, with up to 15% of human cancers attributed to chronic viral infection [1], [2]. Human papillomavirus (HPV) and hepatitis B virus (HBV) are the most significant contributors, but the list of tumourigenic viruses is much longer [1]. Epstein–Barr virus (EBV), human T-lymphotropic virus-I (HTLV-I), hepatitis C virus (HCV), Kaposi’s sarcoma herpesvirus (KSHV) and Merkel cell polyomavirus (MCV) all have confirmed roles in cancer induction, with a significantly longer list of viruses also suspected to play a role in tumourigenesis.
The acute inflammatory response to virus infection is an essential component of the antiviral response, inducing genes responsible for antiviral activity, immune cell recruitment and cell fate [3]. Unfortunately, excessive inflammation can arise during persistent infection and is generally damaging, having mutagenic effects on the host genome [4]. Chronic inflammation plays a role in a number of disease states, including diabetes, arthritis, Alzheimer’s disease, and over a longer period, cancer [5]. In the context of cancer development, chronic inflammation has been linked not only to tumourigenesis, but also to increased cell proliferation, survival, invasion, angiogenesis and metastasis [5], [6].
Tumourigenesis usually follows the accumulation of mutations in gene coding regions, resulting in uncontrolled cell growth. It is estimated that around 100 coding region mutations are present in a typical cancer genome, including 10–20 in genes actively contributing to oncogenesis [7], [8]. This implies that cancer development is usually a slow process, largely unaffected by acute infections which resolve. For this reason, viruses and bacteria with the potential to develop chronic infections are significantly over-represented among tumourigenic pathogens [9].
Cancer initiation during viral infection can generally be divided into two categories, based on the capacity of the virus to directly contribute to oncogenesis. Oncogenic viruses encode proteins that stimulate cell proliferation and/or interfere with cell apoptosis, and therefore play a direct role in carcinogenesis [10]. Most viral oncogenes target similar cell growth pathways to counteract the growth arrest that occurs in response to viral infection. Other viral oncogenes inhibit apoptosis and immune cell recognition, thus allowing ongoing viral replication.
Viral carcinogenesis can also occur indirectly, if chronic infection leads to oxidative stress and inflammation [10]. Cytokine secretion by the infected cell and surrounding tissues creates an inflammatory milieu which can promote cancer development, principally mediated by IL-1B, TNF-α and IL-6 [4], [11]. Inflammatory stimuli and direct effects of the virus activate signalling pathways responsible for cancer development, including NF-κB, STAT3 and the MAPKs [12], [13].
Inflammation alone can increase the oncogenic potential of a cell, but the combination of direct and indirect factors present during chronic viral infections explains the high rates of virus-associated cancers. This review will focus on the role of virus-induced inflammation in cancer development, highlighting the similarities and differences among oncogenic viruses.
Section snippets
Oncogenic viruses of the liver: HBV and HCV
HBV and HCV are both hepatotropic viruses which can establish persistent infection. HCV is unusual among oncogenic viruses, as it does not integrate into the host genome or demonstrate viral latency, yet sustains chronic infection in approximately 50–80% of untreated individuals [14]. Chronic HCV infection dramatically increases the likelihood of developing liver fibrosis (scarring) and steatosis (fat accumulation), with approximately 20% of patients developing cirrhosis, and 4% developing
Human T lymphotropic virus (HTLV-1)
Following an exhaustive worldwide search for a human retrovirus, HTLV-1 was identified in 1980 [60], [61]. HTLV-1 was the first retrovirus to be associated with human cancer, termed adult T-cell leukaemia (ATL) [62]. The HTLV-1 genome is positive sense RNA, which is reverse transcribed and integrates randomly into the genome of predominantly CD4+ T cells [63]. Following integration, clonal expansion of the infected T cells is induced by the viral trans-activator protein Tax, which interferes
EBV
EBV infects 90% of the world’s population, primarily as an asymptomatic infection in childhood [83]. Infection at a later stage (often adolescence) results in infectious mononucleosis, characterised by fever, pharyngitis and/or tonsillitis, and tender cervical lymphadenopathy [84]. EBV preferentially infects B lymphocytes, but has also been shown to infect other cells types, primarily epithelial cells [85], [86]. Following acute infection, EBV establishes latent infection in B lymphocytes,
KSHV
Like EBV, KSHV is a gamma herpes virus that usually remains latent as a nuclear episome, with occasional viral reactivation followed by lytic replication. However unlike EBV, KSHV is usually oncogenic only in immunosuppressed patients, either as a result of AIDS or following organ transplant [112], [113], [114]. KSHV is associated with the development of Kaposi’s sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castleman’s disease (MCD) [115]. KSHV infection is more common in HIV
HPV
HPVs belong to the Papillomaviridae family, and are a diverse group of small non-enveloped dsDNA viruses. The ∼120 types of HPV identified to date can be subdivided based on their tissue tropism, infecting either cutaneous or internal mucosal surfaces [135]. The mucosal HPV types have further been divided based on their oncogenic potential, with low risk types generally causing benign genital warts, and high risk types associated with neoplasia and subsequent cancers. High risk HPV types 16 and
Conclusions
Chronic viral infection is increasingly being recognised as a leading cause of cancer worldwide. As well as the direct oncogenic role of some viruses, ongoing inflammation stimulated by chronic viral infections also contributes significantly to tumour formation. In addition to the viruses discussed above, mounting evidence now implicates other viruses in the development of human cancers. These include Merkel cell polyomavirus, which has been associated with the majority of Merkel cell
Conflict of interest
None.
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