Oncogenic Viruses Volume 1: Fundamentals of Oncoviruses

Oncogenic Viruses: Fundamentals of Oncoviruses provides an overview of the history of human oncoviruses, how to discover and define an oncovirus, how viruses cause cancer in general, their oncogenic mechanisms and epidemiology, and the cancer biology of oncoviruses. The book is organized into five main parts that include history and discovery of virus-tumor complications, taxonomy and classification of oncoviruses, oncoviruses around the world, including epidemiology statistics and current methods. Finally, the book looks at the molecular epidemiology of DNA and RNA viruses and their role in the pathogenesis of human cancers.

• Provides an overview of the history, discovery, taxonomy and biology of oncoviruses
• Offers the fundamentals of viral implications in human tumors
• Covers the molecular epidemiology and oncologic implications and associations of DNA and RNA oncoviruses

• Language: English
• Publisher: Academic Press
• Release date: Sep 14, 2022
• ISBN: 9780323859134

Book preview

Chapter 1

General introduction oncogenic viruses: recent knowledge

Moulay Mustapha Ennaji,    Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco

Abstract

Considerable research into the tumorigenesis factors have confirmed that the oncogenic viruses are a serious cause of some cancers and having a suspected role in other neoplastic growths. This field is full of arguments and controversial conclusions. Even related to one virus, there are different study designs and statements, such as population studied, former clinical and pathological criteria, other viruses implicated, and social status of probands studied. These differences and contradictory conclusions can be seen in the literature, but there is general agreement about the serious suspected roles of viruses in the initiation and development of cancer.

Keywords

Human papilloma virus; Epstein-Barr virus; non-Hodgkin’s lymphoma; hepatitis C virus

Considerable research into the tumorigenesis factors have confirmed that the oncogenic viruses are a serious cause of some cancers and having a suspected role in other neoplastic growths. This field is full of arguments and controversial conclusions. Even related to one virus, there are different study designs and statements, such as population studied, former clinical and pathological criteria, other viruses implicated, and social status of probands studied. These differences and contradictory conclusions can be seen in the literature, but there is general agreement about the serious suspected roles of viruses in the initiation and development of cancer.

One of the most famous oncogenic viruses, human papilloma virus (HPV), is responsible for major cervical cancers, especially in developing countries. HPV 16 and HPV 18 contribute toward malignancy and are classified as high-risk genital types with 70% of all cases in comparison to other HPV types and 20% of the adult population in Western countries (Faridi et al., 2011).

In terms of relationships between oncogenic viruses and other tumors, approximately 4% of human T-lymphotropic virus type (HTLV-1)-infected individuals develop adult T cell leukemia/lymphoma (ATLL). HTLV-1 clinically causes two major diseases: ATLL and tropical spastic paraparesis/HTLV-1-associated myelopathy. This virus is the first retrovirus that has been associated with human diseases, including an aggressive leukemia derived from CD41 T cells, according to Satou et al. (2011).

Another virus that is associated with lymphoma is Epstein-Barr virus (EBV), and many studies have linked it to human immunodeficiency virus (HIV). This relationship is repeated between HIV and development of non-Hodgkin’s lymphoma (NHL), as HIV-infected patients with profound immunodeficiency, are at substantial risk of developing NHL and particularly primary central nervous system lymphoma (Pluda et al., 1993). A positive association between hepatitis C virus (HCV) and risk of NHL has also been suggested (Matsuo et al., 2004).

Other studies have reported different prevalence attribution of these types of lymphoma with HCV (Negri et al., 2004), but HCV prevalence in patients with B cell NHL (B-NHL) is approximately 15%, higher than that reported in general population (1.5%), suggesting a role of HCV in the etiology of B-NHL. It is important to note that some clinical and pathological features of NHL are associated with HCV infection, but the virus does not seem to affect prognosis. In addition, a positive association between hepatitis B virus (HBV) infection and B-NHL raises the possibility that HBV may play an oncogenic role in the initiation of B-NHL (Gisbert et al., 2003; Keegan et al., 2005; Marcucci et al., 2006; Vallisa et al., 1999).

According to the World Health Organization (WHO) the regions with the highest risk of HPV are Eastern Africa, Melanesia, and southern and central Africa. Unless cervical cancer prevention and control measures are successfully implemented, it is estimated that by 2030, approximately 800,000 new cases of cervical cancer will be diagnosed annually. The vast majority of these cases will be in developing countries. Since 2009, the WHO has recommended the inclusion of HPV vaccination in national immunization programs in countries where cervical cancer is a public health priority and where cost-effective and sustainable implementation of the vaccine is feasible (WHO, 2020).

Since late 2019 the world has suffered from a unique pandemic situation caused by SARS-CoV-2, a zoonotic coronavirus that is the cause of COVID-19. This disease leaves its effect on human health even after healing, and new symptoms are being revealed continually. This pandemic situation has alarmed the scientific community because of the serious effects of the viral infections on health and has emphasized the importance of an effective vaccination process.

Neutralizing antibodies are crucial for vaccine-mediated protection against viral diseases. They probably act by blunting the infection, which is then resolved by cellular immunity. The protective effects of neutralizing antibodies can be achieved by neutralization of free virus particles and by several activities that are directed against infected cells. Several viruses have evolved mechanisms to evade neutralizing antibody responses, and these viruses present special challenges for vaccine design that are now being tackled (Burton, 2002).

There are two immune systems. Most organisms possess innate immunity, and vertebrates also have the adaptive system, which is necessary for developing vaccines. The former involves cells such as dendritic cells and macrophages, which also have important roles in the adaptive system. The latter is characterized by lymphocytes, which possess specific receptors that recognize foreign antigens (Gordon, 2007).

Vaccine approaches to infectious diseases are widely applied and appreciated. Among them, vectors based on recombinant viruses have shown great promise and play an important role in the development of new vaccines. The ideal viral vector should be safe and enable efficient presentation of required pathogen-specific antigens to the immune system (Souza et al., 2005).

Scientists know the importance of vaccination for minimizing the chances of developing cancer. Vaccine therapy for cancer is less toxic than chemotherapy or radiation and therefore could be especially effective in older, more frail cancer patients. However, it has been shown that older individuals do not respond to vaccine therapy as well as younger adults do (Gravekamp, 2009). In this book we focus also on the importance of vaccinations against viruses for cancer patients.

Based on current evidence, including clinical and epidemiological studies of various tumors, and because of the similarity with the same serosity of oncoviruses mechanism of action, it might be that the findings will be accumulated, realizing a confirmed oncogenic viruses’ role in the initiation and progression of such tumors. In addition, the underlying tumorigenesis mechanisms in the vast majority of human cancers could be accurately identified. For the reason, it is possible to recommend HPV vaccines or developing other vaccines for other oncogenic viruses to avoid further human tumors, improving the lives of many people.

This book is dedicated to providing an update on the molecular biology of oncogenic viruses and recent findings. It is presented in two volumes. Volume 1, Fundamental of Oncovirus, provides basic knowledge about fundamental of oncogenic viruses. Volume 2, Medical Applications of Oncology Knowledge, discusses the oncogenic viruses in relation to the threat of human cancers.

References

Burton, 2002 Burton DA. Viruses and vaccines. Nature Reviews Immunology. 2002;2:706–713.

Faridi et al., 2011 Faridi R, Zahra A, Khan K, et al. Oncogenic potential of Human Papillomavirus (HPV) and its relation with cervical cancer. Virology Journal. 2011;8:269 https://doi.org/10.1186/1743-422X-8-269.

Gisbert et al., 2003 Gisbert JP, García-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s lymphoma: Systematic review and meta-analysis. Gastroenterology. 2003;125(6):1723–1732.

Gordon, 2007 Gordon A. The importance of vaccination. Frontiers in Bioscience. 2007;12:1278–1290.

Gravekamp, 2009 Gravekamp C. The importance of the age factor in cancer vaccination at older age. Cancer Immunology, Immunotherapy. 2009;58:1969.

World Health Organization ‎, 2020 World Health Organization (2020). Guide to introducing HPV vaccine into national immunization programmes 2020. Available from: www.who.org. (Retrieved on 12 September 2020).

Keegan et al., 2005 Keegan TH, Glaser SL, Clarke CA, et al…. Epstein-Barr virus as a marker of survival after Hodgkin’s lymphoma: A population-based study. Journal of Clinical Oncology. 2005;23(30):7604–7613.

Marcucci et al., 2006 Marcucci F, Mele A, Spada E, et al…. High prevalence of hepatitis B virus infection in B-cell non-Hodgkin’s lymphoma. Haematologica. 2006;91(4):554–557.

Matsuo et al., 2004 Matsuo K, Kusano A, Sugumar A, Nakamura S, Tajima K, Mueller NE. Effect of hepatitis C virus infection on the risk of non-Hodgkin’s lymphoma: A meta-analysis of epidemiological studies. Cancer Science. 2004;95(9):745–752.

Pluda et al., 1993 Pluda JM, Venzon DJ, Tosato G, et al…. Parameters affecting the development of non-Hodgkin’s lymphoma in patients with severe human immunodeficiency virus infection receiving antiretroviral therapy. Journal of Clinical Oncology. 1993;11(6):1099–1107.

Satou et al., 2011 Satou Y, Yasunaga JI, Zhao T, et al…. HTLV-1 bZIP factor induces T-cell lymphoma and systemic inflammation in vivo. PLOS Pathogens. 2011;7(2):e1001274.

Souza et al., 2005 Souza APD, et al. Recombinant viruses as vaccines against viral diseases. Brazilian Journal of Medical and Biological Research. 2005;38:509–522.

Vallisa et al., 1999 Vallisa D, Bertè R, Rocca A, et al…. Association between hepatitis C virus and non-Hodgkin’s lymphoma, and effects of viral infection on histologic subtype and clinical course. The American Journal of Medicine. 1999;106(5):556–560.

Chapter 2

Hepatocellular carcinoma associated with hepatitis B virus and environmental factors

Hanaâ Bazir¹, Hlima Bessi², Mohammed Nabil Benchekroun¹ and Moulay Mustapha Ennaji¹,    ¹Group Research Leader Team of Virology, Oncology, and Biotechnologies, Head of Laboratory of Virology, Oncology, Biosciences, Environment and New Energies (LVO-BEEN), Faculty of Sciences and Techniques Mohammedia, University Hassan II of Casablanca, Casablanca, Morocco,    ²Team of Ecotoxicology and Toxicology, Laboratory of Virology, Oncology, Biosciences, Environment and new Energies, Faculty of Sciences and Techniques, Mohammedia, University Hassan II of Casablanca, Morocco (LVO BEEN)

Abstract

Hepatocellular carcinoma (HCC) accounts for between 85% and 90% of primary liver cancers. It has several interesting epidemiological characteristics. Differences in distribution have been noted between geographic regions and ethnic groups but also according to sex and the presence of several risk factors linked to the environment. A variety of risk factors for HCC have been reported, including hepatitis B and C viruses, aflatoxin B1, alcohol consumption, nonalcoholic fatty liver disease, and hemochromatosis. Hepatitis B virus (HBV) is a ubiquitous virus with worldwide distribution. Hepatitis B is one of the most common and serious infectious diseases in the world. HBV infection causes more than one million deaths each year. It is estimated that more than one-third of the world’s population has been infected with HBV. About 5% of the population are chronic carriers of HBV, and nearly 25% of all carriers develop serious diseases of the liver, such as chronic hepatitis, cirrhosis, and HCC. Hepatocarcinogenesis is a complex and multifactorial process that involves both genetic and environmental factors leading to malignant transformation. HBV is among the most important etiological factors in HCC. In this chapter we will discuss the association between HCC and HBV and the synergy between this viral factor and other environmental factors.

Keywords

Tumor; virology; risk factor; oncology; pathology

2.1 Introduction

Hepatocellular carcinoma (HCC) is a malignant tumor of the liver that develops from hepatocytes. It is the most common primary malignant tumor of the liver, followed by cholangiocarcinoma, which develops from cells of the bile ducts. HCC is one of the leading causes of cancer death worldwide. HCC has a geographic distribution that overlaps that of hepatitis B, with increased frequency in sub-Saharan Africa and Asia, particularly China. However, the risk factors for HCC are changing, and this geographic distribution is fading. With the near-universal use of vaccination against the hepatitis B virus (HBV) and drugs to control the replication of the virus, the number of cases of HCC due to hepatitis B is decreasing. A decrease in the number of cases of HCC due to chronic hepatitis C has been observed, resulting from the discovery of drug combinations that are very effective in eliminating the hepatitis C virus (HCV) in affected patients. On the other hand, there has been an increase in the number of cases of HCC linked to overweight and diabetes. Obesity and type 2 diabetes mellitus are conditions that substantially increase the risk of developing HCC (Lange & Dufour, 2019).

2.2 Hepatocellular carcinoma

2.2.1 Epidemiology and etiological factors

2.2.1.1 Incidence

Primary liver cancer is the seventh most common cancer and the fourth leading cause of cancer deaths worldwide (Bray et al., 2015). While we have seen a decrease in the incidence and impact of many other cancers, the global burden of primary liver cancer worldwide has increased in recent decades (El-Serag, 2012; Tang et al., 2018).

HCC represents more than 90% of primary liver cancers, and in nearly 90% of cases, it develops in the context of chronic liver disease, most often in the stage of cirrhosis (Singal et al., 2020). The etiology of the underlying disease is known in about 90% of cases. Worldwide, these are mainly infections with HBV or HCV and less frequently from excessive alcohol consumption and/or unrelated steatotic liver disease alcohol (Singal et al., 2020).

Exposure to hepatocarcinogenic toxins is also a significant risk factor in some parts of the world. For example, over 90% of the general population in several West African countries is exposed to aflatoxins as a result of improper postharvest processing, while exposure is minimal in Western countries (Hamid et al., 2013).

The incidence and the main etiological factors involved in hepatocarcinogenesis are shown in Fig. 2.1. The highest incidence of HCC is observed in East Asia, with Mongolia having the highest incidence of HCC in the world. HBV is the main causative factor in most parts of Asia (except Japan), South America, and Africa; HCV is the main causative factor in Western Europe, North America, and Japan, and alcohol consumption is the causative factor in Central and Eastern Europe. Nonalcoholic steatohepatitis (NASH), the main etiology included in the Other category is a rapidly increasing risk factor that is expected to become the predominant cause of HCC in income regions in the near future (Sung et al., 2021) (Figs. 2.1 and 2.2).

Figure 2.1 The incidence of HCC by geographic area and etiology. HCC, hepatocellular carcinoma.

Figure 2.2 Age-standardized (world) incidence rates, liver, by sex.

An increase in the incidence of HCC is expected until 2030, when it is possible that a decrease will be observed as a result of the efforts that have been made in recent decades to fight against infections by HBV and HCV, in particular with the generalization of vaccination against HBV and the development of antiviral treatments (Valery et al., 2018). However, the prospect of an increase in the prevalence of obesity and its metabolic complications, such as diabetes, and the increase in per capita alcohol consumption in some regions of the world could lead to an increased risk of HCC, which potentially could offset the decrease in the proportion linked to viral hepatitis (Valery et al., 2018).

Overall, the prognosis for individuals with HCC is grim, with 5-year survival rates of around 10% (Bray, et al., 2015) (Fig. 2.2).

2.2.2 Mortality

As with the incidence, large variations in overall mortality are observed around the world, reflecting the large disparities in access to screening programs and specific treatments for cancer, regardless of the etiology (Figs. 2.3 and 2.4) (Bray et al., 2018). It is estimated that around 85% of HCC cases occur in low- or medium-resource areas, particularly in East Asia and sub-Saharan Africa (Figs. 2.3 and 2.4).

Figure 2.3 Global variation in HCC mortality. HCC, hepatocellular carcinoma.

Figure 2.4 Age-standardized (world) incidence and mortality rates, liver.

2.3 Anatomopathological characteristics

The macroscopic aspects of HCC are extremely variable; in particular, it can range in size from a few millimeters to more than 20 cm in diameter. It is a malignant hepatocyte epithelial tumor (Roncalli, 2004).

2.3.1 Physiopathology

In a patient with chronic liver disease, scar tissue replaces damaged liver cells; this is known as hepatic fibrosis. In cirrhosis, scar tissue surrounds clusters of regenerating liver cells; these clusters constitute regeneration nodules. Depending on the extent of the damage to the liver, the fibrosis can be more or less severe, and there are several stages, from focal fibrosis to cirrhosis (Fattovich et al., 2004). Cirrhosis is present in 80%–90% of patients with HCC and is considered a precancerous condition (Fig. 2.5B). Cirrhosis is defined by mutilating, diffuse fibrosis with the destruction of the architecture of the liver and the formation of parenchymal nodules (regeneration nodules) (Schuppan & Afdhal, 2008).

Figure 2.5 (A) Well-differentiated hepatocellular carcinoma. The diagnosis is based on morphological, architectural, and cytological criteria. Compared to nontumor hepatocytes (bottom), nucleocytoplasmic ratios are increased and cell density is high. On the right, on the Sirius red staining, the sinusoidal network is markedly reduced (top) compared to that of the nontumor liver (bottom). The arrow indicates the production of bile by tumor cells (HES, hematein/eosin/saffron stain). (B) Chronic posthepatitis cirrhosis (Trinchet & Ziol, 2012).

2.3.2 Tumor pathology

Tumor cells are more or less atypical. They can contain Mallory bodies, hyaline globules, glycogen, and fats (tumor cells with steatosis). They can also produce bile. The architecture of tumor proliferation in well-differentiated tumors more or less reproduces that of the hepatic parenchyma with cells organized in rows by sinusoids. Trays of tumor cells are thicker than those in the normal liver (three or more cells), and there is a decrease in the reticulin network, as evidenced by the Gordon Sweet or Sirius red stain (Fig. 2.5A) (Trinchet & Ziol, 2012). The architecture can also be pseudoglandular (formation of acini by dilation of the bile canaliculus) or compact with clumps of tumor cells without span or sinusoid. We can also observe changes like peliosis (dilation of the sinusoids), hemorrhage, or necrosis (Fig. 2.5).

2.4 Nature and history of liver carcinogenesis

Liver carcinogenesis is a dynamic process. HCC develops mostly in chronic liver disease, and liver carcinogenesis is strongly related to the occurrence of cirrhosis. As a result of long-term stimulation by viral or chemical factors (alcohol or bioactive lipids), the liver frequently harbors chronic inflammation (Bishayee, 2014). Meanwhile, three processes have to be distinguished: stimulation of fibroblasts, maturation and deposition of fibers, and catabolism of fibers. These could induce changes in hepatic architecture and damage liver function. In most cases, progression from fibrosis to cirrhosis occurs after an interval of 15–20 years and is influenced by both genetic and environmental factors.

As was mentioned, 80%–90% of HCC arise in the setting of cirrhosis. The microenvironmental composition and organization of cirrhosis can serve as prognostic factors in HCC pathogenesis (Novikova et al., 2017). This environment promotes the evolutional process of dysplasia, from low-grade to high-grade dysplasia, early HCC, progressed HCC, and advanced HCC. A combination of histological characteristics (cellular density, pseudoglandular formation, steatosis, presence of portal spaces, stromal invasion, nuclear atypia, isolated artery, etc.) makes it possible to differentiate premalignant lesions from early HCC. During tumor growth, there is often portal vein thrombosis, a feature of the advanced stage that is associated with poor prognosis.

2.5 Molecular mechanism of hepatocarcinogenesis

The most characteristic impairment in hepatocarcinogenesis is an underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory cell proliferation (hepatocyte regeneration), providing a mutagenic environment that can lead to the development of HCC (Nakagawa & Maeda, 2012). Hepatic carcinogenesis is a multistage process, with chronic hepatitis and cirrhosis being the preneoplastic stages (Sakamoto et al., 1991). In fact, in most cases, especially during the developmental phase of cirrhosis, inflammation and replicative senescence phenomena will lead to an accumulation of genetic alterations that will promote the selection of transformed hepatocytes (Fig.