Pathogens causing cancer – an overview

Cancer can be caused by both physiological and environmental conditions. Infections with certain viruses, bacteria and parasites have been associated with carcinogenic activity in humans and play an etiologic role in approximately 20% of the cancer cases worldwide.[1]

There are currently seven known viruses, one bacterium and three parasites identified as cancer-related pathogens.[1] This article aims to give a short overview of these pathogens and their corresponding cancer types (Table 1).

Table 1. An overview of pathogens that cause cancer and corresponding cancer types.

Five viruses (HPV, EBV, KSVH, HTLV-1, and MCPyV) are identified as direct carcinogens, which express their protein products. A portion of the viral genome can be detected in each cancer cell, which results in the expression of viral oncogenes that affect several cellular pathways, including DNA repair, proliferation, and apoptosis.[1,2] The indirect carcinogenic pathogens (HBV, HCV, H. pylori, S. haematobium, O. viverrini, and C. sinensis) do not induce expression of oncogenes but cause chronic inflammation leading to the release of cytokines, chemokines, and prostaglandins. This can result in deregulation of the immune system and promotion of neovascularization.[2]

Viruses

Hepatitis b and c virus

HBV and HCV are different types of hepatitis viruses. In highly endemic areas, hepatitis B is most commonly spread through perinatal transmission, but it can also be horizontally transmitted through bodily fluids. HCV is mainly transmitted through blood transfusion and intravenous drug use. Both HBV and HCV cause liver disease, including hepatocellular carcinoma (HCC). The exact molecular mechanisms of how they cause cancer are unknown, although chronic inflammation and DNA damage have been shown to contribute.[2]

The global burden of HCC is high. It is the third leading fatal cancer worldwide, and its incidence continues to increase. According to the WHO, about 296 million people live with HBV infection and 58 million with HCV infection.[3,4] This leads to about 661,000 cases of cancer every year.

The worldwide incidence of HCC is heterogeneous because of the variable prevalence of other underlying risk factors. It is estimated that 72% of cases occur in Asia (more than 50% in China), 10% in Europe, 7.8% in Africa, 5.1% in North America, 4.6% in Latin America and 0.5% in Oceania.[5]

Human papillomavirus (hpv)

HPV is a DNA virus that belongs to the papillomaviridae family. It is associated with cancers of the cervix, oropharynx, vulva, vagina, penis, anus and anogenital tract. The route of transmission is through skin-to-skin, skin-to-mucosa, and mucosa-to-mucosa contact. A difference was found between high-risk and lower-risk subtypes of HPV. HPV-16 and -18 are two of those high-risk subtypes and are associated with cervical carcinoma.

HPV is believed to cause cancer by integration of its DNA into the host genome, altering cellular functions and promoting transformation, and the expression of viral genes acting as oncogenes.[2]

Epstein-barr virus and kaposi’s sarcoma-associated herpesvirus

Epstein–Barr Virus (EBV) or human gamma herpesvirus 4 (HHV-4) is a DNA virus. It mainly spreads through bodily fluids, especially saliva. Other minor but significant routes of transmission are through blood and semen, and using objects recently used by an infected person. All this makes EBV extremely widespread, with more than 90% of people getting infected.[6] Although EBV is a poor and inefficient carcinogenic agent, it is associated with a number of malignancies and contributes to about 1.5% of cancer worldwide.[3] The types of cancer with the highest EBV-related case burden are nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), Hodgkin’s lymphoma (HL), Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and extra nodal NK/T-cell lymphoma, nasal type (ENKTL-NT).[6]

Another DNA virus belonging to the gamma herpesvirus family is Human herpesvirus 8 (HHV-8) or Kaposi’s sarcoma-associated herpesvirus (KSHV), which causes Kaposi’s sarcoma.

The prevalence of KSHV varies greatly, ranging from about 3% in the UK up to almost 80% in some areas of sub-Saharan Africa.[7] It is strongly associated with advanced HIV/AIDS. It is thought to spread by mother-child transmission and through saliva. Various environmental factors, such as co-infection with malaria, seem to increase the replication of KSHV and thus lead to enhanced transmission.[7] KSHV is rarely associated with cancer, except in immunocompromised patients.

Human t-lymphotropic virus 1 (htlv-1)

The human T-lymphotropic virus type 1 (HTLV-1) is a retro virus that can cause adult T-cell leukaemia/lymphoma (ATL) and a progressive nervous system condition known as HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP). HTLV-2 has virological and pathological similarity to HTLV-1 and is mainly associated with HAM/TSP. Both infect CD4 cells and thus stimulate cell proliferation leading to ATL. HTLV-3 causes death of CD4 cells and was later renamed as the human immunodeficiency virus (HIV).

HTLV-1 is transmitted primarily through direct contact via cell-containing bodily fluids including blood, breast milk and semen. While breast feeding is associated with ATL, HAM/TSP is related to transmission by blood transfusion.

The WHO estimates that the total number of people living with HTLV-1 infection range from 5 to 10 million, although this is likely an underestimation due to a scarcity of reliable data.[8] Seroprevalence of HTLV-1 in Europe and the USA is low (1%), while in certain areas in Japan it is as high as 30%.[9] Although most people do not develop conditions that can be linked to the infection, there are several serious diseases thought to be caused by or strongly associated with the virus. The lifetime risk of developing ATL among people with an HTLV-1 infection is about 5%, although this again may be an underestimation. There is currently no vaccine or recommended treatment for asymptomatic HTLV-1. Treatment should instead focus on the symptoms of associated diseases.

Merkel cell polyomavirus (mcpyv)

Merkel cell polyomavirus is a DNA virus that is widely prevalent and can be detected on the skin of most healthy adults. It usually causes asymptomatic infection in the skin, but occasionally leads to an aggressive type of neuroendocrine skin cancer called Merkel cell carcinoma (MCC), also known as trabecular carcinoma of the skin. More than 80% of MCC tumours can be related to MCPyV[10], although the exact mechanism that leads to carcinogenesis is not yet fully understood.

The prognosis of MCC is poor, with a 5-year overall survival of around 51% for patients presenting with local disease at the time of diagnosis, and worse prognoses for those with more advanced stages of disease.[10] The incidence of MCC varies according to geographic regions but has tripled over the last 20 years and is expected to increase further in the future.[10] Risk factors associated with MCC are advanced age, immunosuppression, fair skin, and exposure to ultraviolet light. Skin pigmentation appears to protect against MCC.[11]

Helicobacter pylori bacterium (photo Shutterstock)

Bacterium

Helicobacter pylori

H. pylori is a spiral shaped, Gram-negative bacterium that selectively colonies the epithelial layer of the stomach. H. pylori colonization is very common, with the Centers for Disease Control and Prevention (CDC) in the United States estimating that approximately two-thirds of the world’s population is infected.[12] In most people, H. pylori colonization does not cause any symptoms. However, long-term infection causes chronic inflammation and significantly increases the risk of developing duodenal and gastric ulcer disease and gastric cancer. Infection with H. pylori is the strongest known risk factor for gastric cancer, which is the second leading cause of cancer-related deaths worldwide. Approximately 1-3% of carriers develop gastric adenocarcinoma.[13]

Other malignancies that H. pylori is thought to contribute to are gastric mucosa-associated lymphoid tissue (MALT) lymphoma and hepatobiliary tumours.

MALT lymphoma is a rare type of non-Hodgkin lymphoma in the stomach lining. Normally, the lining of the stomach lacks lymphoid tissue, but as a response to colonization with H. pylori this tissue is stimulated. Nearly all patients with MALT lymphoma show signs of H. pylori infection, and the risk of developing this tumour is more than six times higher in infected people than in uninfected people.[12] Although there are multiple studies that show a positive association between H. pylori infection and the development of HCC and biliary tumours, this evidence is limited, and a causal relationship has not yet been confirmed.[14]

H. pylori infection can be treated with antibiotics and eradication has been shown to greatly decrease the risk of developing gastric cancer, with a decreased incidence of almost 40%.[12] However, due to the development of antibiotic resistance, treatment is becoming a challenge.

Parasites

Schistosoma haematobium

S. haematobium is a trematode parasite and one of the schistosomiasis species that causes schistosomiasis. People can get infected via contact with infested water, where the larval form of the parasite is excreted by freshwater snails and can penetrate the skin.

Schistosomiasis is a public health problem in certain areas and has been reported in 78 countries, mainly in sub-Saharan Africa. It affects around 240 million people worldwide, and more than 90% of all cases occur in Africa.[15]

There are 2 major forms of schistosomiasis – the intestinal and urogenital form. S. haematobium causes the urogenital type and is known to cause squamous cell carcinoma and urothelial carcinoma of the bladder if it remains untreated. Tumours are mostly found in a young age group (reflecting exposure since early childhood) and have a poor prognosis. The WHO strategy for control is implementing mass drug administration (MDA) with praziquantel in endemic areas as preventive chemotherapy.[15]

Opistorchis viverrini and clonorchis sinensis

O. viverrini and C. sinensis are trematodes that can be contracted by eating raw or undercooked fish, crabs or crayfish, and can infect the liver, gallbladder, and bile ducts. Most infections are asymptomatic but if untreated can cause severe diseases of the liver, including cancer of the bile duct (cholangiocarcinoma, CCA).[16] CCA is found in the epithelial lining of the bile ducts and is untreatable in most cases.[16] C. sinensis is mostly found in rural areas of Korea and China and therefore known as the oriental liver fluke. O. viverrini is found in Thailand, Laos, Cambodia, Vietnam, Germany, Italy, Belarus, Russia, Kazakhstan, and Ukraine and is especially common in the north-east of Thailand, where at least 70% of people are infected. This leads to a high number of CCA. Worldwide, bile duct cancers make up 15% of the primary liver cancers, compared to 90% in Khon Kaen province, Thailand.[16]

Hymenolepis nana

There is one case report on malignant transformation of infection with H. nana, a tape worm, in an HIV infected individual.[17]

Conclusion

Infections are an important source of human malignancies. It is important to note epidemiological differences; while S. haematobium infection is restricted to Africa, liver flukes such as O. viverrini and C. sinensis are mainly found in South-East Asia. HIV/AIDS related cancers such as KS and non-Hodgkin lymphoma reflect the endemicity of HIV infection, particularly in Africa, while HTLV-1 prevalence is highest in Japan.

Reducing the incidence of pathogen-driven cancers can be done by prevention or early treatment. For instance, HBV can be prevented by vaccination which is becoming widely available. S. haematobium infection prevention requires mass drug administration and early treatment with praziquantel. However, although infectious agents contribute significantly to the overall global cancer burden, it is important to realize that most infected people will not develop malignancies. Most at risk are people in underserved communities in LMICs and immunosuppressed patients.

References

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9. Mueller N, Okayama A, Stuver S, et al. Findings from the Miyazaki Cohort Study. J Acquir Immune Defic Syndr Hum Retrovirol. 1996;13 Suppl 1:S2-7. doi: 10.1097/00042560-199600001-00002. PMID: 8797696.
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