Cancer and Microbiology

HeLa cell

Slightly more than 20% of the global cancer burden can presently be linked to infectious agents majorly but not exclusively viruses- bacteria and parasites have also been implicated.

There seems no better time to shine the spotlight on the link between cancer and infectious disease than today, February 4th, as the globe marks World Cancer Day. The International Agency for Research onCancer (IARC) lists 11 infectious agents– 7 viruses, 3 parasites and 1 bacterium- as Group 1 agents carcinogenic to humans.

I’ve been reading the Nobel lecture presented by German virologist Harald zur Hausen on December 7, 2008. He won the prize for Physiology/Medicine for his discovery of the link between Human Papilloma Virus and cervical cancer.( His co-awardees were Luc Montaigner and Françoise Barré-Sinoussi who discovered the Human Immunodeficiency virus). The lecture later published in the journal, Virology , provides insight as to why it took such a long time to establish the connection between infections and cancers, how the link was eventually made and the mechanisms by which infections cause cancers.

Harald zar Hausen

The importance of infectious agents as human carcinogens has only recently been acknowledged, precisely only in the last three decades. This is relatively recent compared to the identification of physical and chemical carcinogens and considering the fact that the search for an infectious cause for at least some human cancers dates back to the second half of the 19th century. The first hints of a role for infectious agents in the causation of cancer were evident by the beginning of the 20th century but indubitable proof only surfaced some 65 years later.

What made it difficult to identify infectious agents as causative factors for human cancers?

1. No human cancer arises as the acute consequence of infection. The latency periods between primary infection and cancer development are frequently in the range of 15-40 years
2. But for rare exceptions, no synthesis of infectious agents occurs in cancer cells.
3. Most infections linked to human cancers are common in human populations. They are ubiquitous with only a small proportion of infected individuals developing the respective cancer types.
4. Mutations in host cell genes or within viral genome are mandatory for malignant conversion.
5. Chemical and physical carcinogens facilitate selection of specific mutations and frequently act synergistically with carcinogenic infectious agents
6. Some infectious agents act indirectly without persistence of their genes within respective cancer cells (HIV, H.pylori, Hepatitis B virus, Hepatitis C virus)

Despite these, epidemiology provided hints for the successful search for connections. Geographic coincidence of Hepatitis B infection and liver cancer led to the original suspicion that the infection predisposed to hepatocellular carcinoma. Cholangiocarcinomas in south east Thailand, bladder cancer in the Nile delta or along the Nile river and Burkitt’s lymphoma in equatorial Africa, all raised early suspicions of an infectious origin. As far back as 1842, Rigoni-Stern documented the role of sexual contact in the causation of cervical cancer.

So, how do infectious agents cause cancer?

1. Some act as direct carcinogens by introducing viral oncogenes into host cells e.g high risk papilloma viruses, Epstein-Barr virus
2. Others such as Human Immunodeficcy Virus act as indirect carcinogens by activating other latent potentially tumorigenic viruses
3. Some agents, notably the bacterium, Helicobacter pylori and the parasites, Clonorchis sinensis, Opistorchis viverrini and Schistosoma haematobium, induce chronic inflammation resulting in production of oxygen and nitrogen radicals which can result in random genetic and epigenetic modifications of the host cell genome with eventual malignant growth.

What is the implication of infectious aetiology on prevention of human cancers?

The establishment of a causal relationship between the presence of specific infective agents and certain type of human cancer represents a key step in the development of novel therapeutic and preventive strategies for cancers. Diagnostics, vaccines and drugs that target infectious agents are revolutionising cancer prevention.

Screening for high risk HPV types can now be done and cervical cancer prevented using Qiagen HPV DNA detection kits.

The first vaccine to prevent cancer was Hepatitis B vaccine developed in Taiwan in 1984. More recently, HPV vaccines have drastically reduced the incidence of cervical cancer. Two HPV vaccines are available, Gardasil and Cevarix. Both target HPV types 16 and 18 which are known to cause 70% of cervical cancers. In addition, Gardasil induces immunity to HPV types 6 and 11 which cause 90% of genital warts.

Novel direct acting antiviral agents, such as Sofosbuvir, that cure Hepatitis C virus infections are now available and will go a long way to reduce deaths from hepatocellular carcinoma.

Microbes and Cancer: The Future

Prof. zar Hausen is of the opinion that more links between cancer and infection will be uncovered in future. He is currently researching early childhood cancers and colorectal cancers for possible contributions from microbes. With respect to colorectal cancers, he notes that “the gut is a huge repository of microbes. Many viruses in the gut are bacterial viruses — bacteriophages”. He also acknowledges that it is a slow paced journey from hypothesis to proof-

“…. it is a complicated story that will take a long time to disentangle. Plus it is a long way from initial isolation of a virus to final identification and determination of whether a virus is pathogenic or oncogenic. We need functional tests to determine the relationship between a virus and cancer. For instance, we started to work experimentally on HPV in 1972. We isolated HPV strains 16 and 18 (the oncogenic ones) in 1983 and 1984, so that took 11–12 years before we could be sure that those were the causative agents.”

References:

1. H. zur Hausen. Infections Causing Human Cancer. Wiley-VCH, Weinheim/New York (Publ.), pp. 1-517, 2006.

2. H. zur Hausen. The search for infectious agents of human cancers: where and why. Nobel lecture. Virology, 392: 1-10, 2009.