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This article is the second of a 2-part series on cancer virology. An introduction to the infectious causes of cancer can be found here.

Human tumor viruses account for an worldwide. Viruses can lead to cancer by , proliferating when the human immune system is weakened, and hijacking proliferating human cells. Compared to other viruses, human tumor viruses are unusual because they infect, but do not kill, their host cells. This allows human tumor viruses to establish persistent infections.

Epstein-Barr Virus: Burkitt’s Lymphoma, Hodgkin’s Disease, and Nasopharyngeal Carcinoma

Because human tumor viruses sometimes depend on weakened host immunity, environmental factors, and host cellular mutations, one type of viruses is able to cause various types of cancer. For example, EBV is associated with Burkitt’s lymphoma, nasopharyngeal carcinoma, and some forms of . EBV can readily infect and alter the genetic code of human B cells, and may predispose immunosuppressed patients to malignant tumors.

Its early discovery () and monoclonal genome made Epstein-Barr virus (EBV) one of the best studied examples of a cancer-causing virus. Burkitt’s lymphoma is caused by , which codes for a transcription factor that modulates genes related to . Infection by EBV may lead to a MYC mutation that allows human B cells to proliferate indefinitely. Depending on the stage of B cell development during EBV infection, EBV infection may also lead to different forms of Burkitt’s lymphoma. indicate that the development of Burkitt’s lymphoma may be polymicrobial in nature. For example, children with recent infection by the malaria-causing Plasmodium falciparum were more likely to develop Burkitt’s lymphoma.

In patients with Hodgkin’s disease, EBV may directly trigger tumorigenesis, especially through . The association of EBV with Hodgkin’s disease is multifactorial, and includes factors such as country of residence, histological subtype, sex, ethnicity, and age.

Finally, EBV can cause nasopharyngeal carcinoma, which might be a in nasopharyngeal epithelial cells. The genetic mutations caused by EBV infection depend on the viral type and strain, but smoking has been associated with nasopharyngeal carcinoma and possibly leads to .

Pathologists have been able to harness recent advances in viral oncology to visualize cancer under the microscope. Double labelling of malignant cells, as in Figure 1, shows co-expression of Epstein-Barr virus early RNAs (brownish black in color) and latent membrane protein 1 (LMP1; red in color). LMP1 is a well-established , and is seen in Figure 1 via immunohistochemistry staining of EBV infected cells.

Human Papillomaviruses 16 and 18: Cervical Carcinoma, Anal Carcinoma, Oropharyngeal Carcinoma, Penile Carcinoma

Human papillomavirus (HPV) is the in the world, and is present in up to . The HPV genome is : the noncoding upstream regulatory region; the “early” region, involved in viral replication and oncogenesis; and the “late” region, which encodes structural proteins for the viral capsid. When the HPV genome becomes integrated into human chromosomes, it disrupts an open reading frame and causes the overexpression of two . These oncogenes decrease the expression of tumor suppressor protein p53 (also known as the “”) and dysregulating the (pRB), which can eventually lead to cancer.

In countries with accessible preventive health services, there has been a . This is due to the development and widespread acceptance of cervical cancer screening (Pap tests). Further, the HPV vaccination is now available for individuals up to , which prevents approximately .

Kaposi’s Sarcoma-Associated Herpesvirus: Kaposi’s Sarcoma, Primary Effusion Lymphoma, Multicentric Castleman’s Disease

Kaposi’s sarcoma is is the most common cancer in untreated individuals with . Kaposi sarcoma-associated herpesvirus is also known as .  KSHV infects endothelial cells and modulates pathways that control cell proliferation, gene expression, and metabolism. KSHV may selectively activate and suppress its lytic replication cycles during co-infections with other microbes by sensing resources and cellular conditions. In Figure 2 (left), one can visualize Kaposi sarcoma, caused by KSHV, on the lungs of a patient with AIDS. Infection by multiple viruses is likely to be synergistic, an important consideration for immunocompromised individuals because they are more likely to develop infections.

Hepatitis B Virus and Hepatitis C Virus: Hepatocellular Carcinoma

Hepatitis B virus (HBV) is an enveloped DNA hepadnavirus that can cause hepatocellular carcinoma (HCC). HCC is . HBV can integrate itself into the human genome and replicate within liver cells, directly increasing carcinogenic activity through in the liver. Hepatitis B surface antigen (HBsAg), a popular marker for the medical , accumulates within the endoplasmic reticulum inducing oxidative stress to cause liver damage. HBsAg also increases cell motility and decreases apoptosis.

At least two viral proteins (including HBV X protein and Hepatitis B surface antigen) and several human mRNAs (such as miR-122) have been linked to hepatocellular carcinoma. HBV X protein is found at high cytosolic concentrations in HBV-infected hepatocytes. HBV X protein has a complex role in hepatocellular carcinoma.  It has been shown to decrease apoptosis induced by several cell mediators, such as , but it has also been shown to increase apoptosis by promoting the production of reactive oxygen species (ROS) that damage hepatocytes.

Hepatitis C virus (HCV), an RNA virus, is the of hepatocellular carcinoma. Like the Hepatitis B virus, HCV has a in the development of liver cancer. For example, HCV can activate pathways that lead to , impact apoptosis and cellular survival, interact with immune cells, and affect metabolic processes. In contrast with HBV, HCV cannot integrate into the human genome. The progression of HCV can take up to 20 to 40 years, and involves progressive liver fibrosis through irreversible genetic and epigenetic alterations. The malignant transformation of liver cells in HCC involves a variety of pathways, and may cause mutations of genes such as . Liver cancer risk appears to be dependent on viral genotype, and HCV genotype 3, 25, 26, and 27 are more carcinogenic.

Human Adult T-cell Leukemia Virus Type 1 (HTLV-1): T-cell Leukemia

HTLV-1 is a retroviral infection that affects white blood cells known as T cells. Although HTLV-1 infection rarely causes serious disease, it may lead to or HTLV-1-associated muscle disorders in 0.25-2% of infected people. Despite the association of HTLV-1 with cancer, its cancer-causing mechanisms are poorly understood due to difficulties propagating this virus in tissue culture. However, T cells that are infected by HTLV-1 can undergo . Additionally, Gag polyprotein may be a major player because it is responsible for the . In Figure 3 (right), HTLV-1 is visible via cryogenic transmission electron microscopy. Through cryogenic TEM, the lattice-like structure of Gag proteins can be studied and compared to other retroviruses (such as HIV).

Merkel Cell Polyomavirus: Merkel Cell Carcinoma

The final virus linked to human cancers is the Merkel cell polyomavirus (MCV). A rare skin cancer, (MCC) was the first human cancer to be with a polyomavirus. To date, it is the only polyomavirus with a supporting its classification as a causative agent of a human malignancy. MCC is considered a neuroendocrine cancer that commonly occurs in sun-exposed individuals with weakened immune systems (for example, in the elderly). Some subtypes of MCV are residents of the skin microbiome, but studies of the MCV viral life cycle .

Further Reading

White Martyn K et al. (2014).
Schlom and Gulley (2018).
Vrinten et al. (2017).
Rolls et al. (2010).
McLaughlin-Drubin et al. (2007).