Chronic Infections and Cancer: How Infectious Agents May Play a Role in Carcinogenesis

Although cancer is commonly linked to genetic mutations, lifestyle and environmental factors, aging, and inherited risk, chronic infection may be an equally important factor.

It is estimated that chronic infections may cause 15% of all cancers around the globe, although this is highly region dependent. Some estimates claim that as many as two million cases of cancer could be attributed to chronic infections. Plummer et al., 2016, de Martel et al., 2012.

The relationship between chronic infections and cancer is not casual. The majority of infections may never lead to the development of cancer. Some persistent infections may lead to the development of pre-cancerous conditions that may ultimately result in cancer.

It is important to study this relationship because many infection-related cancers are potentially preventable.

How May Infections Lead to Cancer?

There are several pathways followed by cancer-causing infections. Different microbes affect the host in different ways.

Some of the important pathways are:

• chronic inflammation
• disruption of cellular growth control mechanisms
• immune evasion

Chronic inflammation may lead to mutagenesis

Infection leads to inflammation and an immune response. During inflammation, cells secrete chemicals that help to eliminate the invading microbes. Once the infection is cleared, the inflammatory response typically subsides.

But when the infection is chronic and prolonged, the inflammatory response may become chronic.

Chronic inflammation promotes angiogenesis

Chronic inflammation and infection also lead to the formation of new blood vessels that facilitate the process of tumor growth.

Immune cells produce inflammatory mediators and reactive oxygen and nitrogen species. Both aid the body in fighting infection, but overexposure causes damage to DNA, proteins, and cell membranes.

Affected tissue is subject to repeated cycles of:

• inflammation
• cellular damage
• tissue repair
• cell proliferation

Cellular division also necessitates the replication of DNA. Thus, increased cycles of cellular damage and regeneration allows for the accumulation of genetic alterations.

Over the years, these changes may impact genes that control cell growth and division, repair of genetic material, and programmed cell death, all of which is related to tumor development.

This is especially relevant to cancers related to chronic bacterial and parasitic infections.

Some pathogens can affect cancer-related genes

Some viruses go beyond causing inflammation.

There are viruses that manipulate human cells by reprogramming the growth and division cycles of cells, and by controlling factors that sustain cell survival.

Some viral proteins inactivate tumor suppressor proteins. Others stimulate pathways that promote cell growth and proliferation, as well as pathways that interfere with cell death.

Important oncogenic viruses are:

• human papillomavirus (HPV)
• Epstein-Barr virus (EBV)
• hepatitis B virus (HBV)
• hepatitis C virus (HCV)
• Kaposi sarcoma-associated herpesvirus (KSHV/HHV-8)
• human T-cell lymphotropic virus type 1 (HTLV-1)

Infection with high-risk HPV presents a strong example. Viral proteins interfere with multiple tumor suppressor mechanisms within infected cells. Persistence of infection and the buildup of additional changes may ultimately result in the development of cancerous cells.

Infection alone is typically not enough. Cancer requires multiple changes happening at different times.

Some infections weaken immune surveillance

Our immune system should not only be thought of as our defense against pathogens, but also has the task of surveying the body for abnormal cells.

Abnormal cells can sometimes be recognized and potentially harmful abnormal cells be eliminated before they become a clinically detectable cancer.

Many infections weaken this process.

Of the many examples, HIV is perhaps the best understood case. HIV will never be able to transform a cell into a cancer cell, and HIV is not that kind of infection. It drives the immune system to extremes and eventually becomes unable to control other infections that are oncogenic.

In relation to this, the reason for the increased incidences of cancers associated with viruses such as HPV, EBV, and KSHV is due to the significant HIV-related immunodeficiency.

In this case, cancer risk may result from trade-offs between infection, immune dysfunction, and other cancer-associated pathogens.

Which Infections Are Most Proximate To Cancer?

Most cancer-associated infections can be attributed to a relatively smaller group of infectious agents.

Infectious Agent	Major Associated Cancers
Helicobacter pylori	Gastric cancer and gastric MALT lymphoma
HPV	Cervical, anal, penile, vulvar, and vaginal cancers and some oropharyngeal cancers
HBV	Hepatocellular carcinoma
HCV	Hepatocellular carcinoma and some lymphomas
EBV	Several lymphomas and gastric cancers, and nasopharyngeal carcinoma
KSHV / HHV-8	Kaposi sarcoma
HTLV-1	Adult T-cell leukaemia/lymphoma
Schistosoma haematobium	Bladder cancer
Opisthorchis viverrini	Cholangiocarcinoma
Clonorchis sinensis	Cholangiocarcinoma

Together, infection-related cancers due to H. pylori, HPV, and hepatitis B and C viruses account for a significant fraction of cancer burden attributable to infection. Plummer et al., 2016

Helicobacter pylori: From Stomach Infection to Cancer Risk

Helicobacter pylori is a paradigmatic case of bacterial infection linked to cancer.

This bacterium has the ability to colonize the stomach for decades. In some cases, this infection induces chronic gastritis and alters the gastric environment and ultimately destroys the gastric mucosa.

Over time, chronic inflammation generates a series of tissue alterations that increase the risk of developing gastric adenocarcinoma.

H. pylori infection also induces gastric MALT lymphoma.

The key point is that H. pylori infection is treatable, thus, identifying and clinical elimination of this infection are essential to cancer prevention.

HPV: One of the Most Preventable Causes of Infection Related Cancer

Almost all cervical cancers and many other cancers are caused by persistent HPV infection. HPV has high types that tend to cause cancers and low types that do not. Most infections caused by HPV go away on their own. The type of infection we are most concerned about is persistent high-risk HPV.

HPV infection persists when the virus stays in the cells of the cervix for many years. The proteins of HPV infection stimulate the cells of the cervix to multiply without control, and reverse the cells of the cervix to normal. Changes that start a cancer cell can begin while a person is infected with HPV, and, even if the infection goes away, cancer may still develop.

HPV infection can also cause cancer of the anus, vagina, penis, vulva, throat, and liver.

The combination of vaccination against HPV and screening is more effective against HPV related cancers than it is against any other type of cancer.

Hepatitis B and C: Chronic Infection and Liver Cancer

Hepatitis B and C infections that become chronic can cause many decades of infection and inflammation of the liver. Eventually, damage to the liver can cause scarring, and the growth of new and abnormal cells in the liver. This increases the risk for cancer. HBV and HCV can increase the risk of liver cancer.

Hepatitis B can cause cancer through the viral DNA.

Hepatitis B infection has the potential to do far more and cancel out many of the other methods that can reduce the risk of cancer.

Parasites Can Also Cause Cancer

There are many parasites like bacteria and viruses that also can cause cancer.

Many parasites are also carcinogens like sin nombre virus and Plasmodium.

Prolonged infection with Schistosoma haematobium induces chronic inflammation of the urinary tract and can cause bladder cancer.

Opisthorchis viverrini and Clonorchis sinensis can reside in bile ducts, leading to chronic inflammation and subsequent tissue damage and increasing the incidence of cholangiocarcinoma.

This phenomenon illustrates an important point: chronic infections establish environments that lead to cancer development.

What About Other Bacteria and the Microbiome?

The study of a cancer microbiome is in its infancy. Additional microorganism involvement in cancer development is currently the focus of study.

Fusobacterium nucleatum has been implicated in colorectal cancer and is currently being studied for its role in inflammation, tumor biology, and local immune cell environments.

Other bacteria like Salmonella Typhi and some Chlamydia spp. have been studied regarding a possible connection with cancer.

We must be careful to differentiate well-established carcinogenic infections from new associations.

Just because a microorganism is found more often in a certain type of cancer does not mean it causes that cancer. Tumors can manipulate their ecosystems, including their microbiome.

This is an area of intensive research in cancer biology.

It is possible that co-infections may impact cancer risk

Human biology does not operate via a single factor.

One can be infected with several chronic infections at the same time and one pathogen can have a positive or negative impact on the immune response to other pathogens.

Immune suppression may result in the persistence or reactivation of oncogenic viruses. Infection induced chronic inflammation can create a new normal in a tissue that can appreciate and positively impact another pathogen.

Modern researchers view infection-associated carcinogenesis as an integrated system of:

• host-pathogen interactions
• immunology
• genetics
• the microenvironment
• the balance of other factors and infections

We may be able to explain why only a portion of those infected with cancer-associated pathogens develop cancer using this viewpoint.

This area of research is global.

In high income countries, infection attributable cancers represent a small percentage of all cancers. In many areas of sub-Saharan Africa and South Asia, this percentage is much higher. Plummer et al., 2016; de Martel et al., 2012

Some factors that might help explain these differential statistics include:

• access to vaccines and treatment
• certain chronic infections
• level of sanitation
• screening programs
• access to treatment for infectious diseases
• socio-economic factors

This variation illustrates that infection-related cancers have a large preventable burden.

Can Infection-Related Cancers Be Prevented?

Infection-related cancers, in many instances, can be prevented.

As opposed to inherited genetic variants or aging, some of the main infectious causes of cancer are either preventable, treatable, or can be controlled.

Some of the main strategies are:

• Vaccination. Hepatitis B vaccinations and vaccines against high-risk HPV can prevent many thousands of cancer-causing infections.
• Screening. Precancerous lesions of the cervix can be detected by cervical screening, which can be used to intervene before an invasive cancer can develop.
• Seeing and controlling. Infection of H. pylori can be detected and treated to control the infection, and complications, including cancer, can be prevented.
• Preventing exposure. Several infectious pathogens responsible for cancer can be controlled by PCP practices, screening blood, the use of medical equipment, and public health measures.
• Controlling infections. Chronic infections can be controlled.

Infection is one small piece of the cancer puzzle

It should not be construed that infection definitely causes cancer. This is not true.

Most people are exposed to cancer-related pathogens and still do not get cancer. There are many environmental, behavioral, and genetic factors that can influence cellular and molecular changes that cause cancer, some of these include age, genetic makeup, immune function, lifestyle, and environmental and random factors.

Chronic infections can permanently change the biological environment.

Years of sustained inflammation and increasing DNA damage can weaken immune control, enhance cancer cell signaling, suppress anti-cancer genes, and ultimately increase the survival and growth of cancer cells.

Why This Matters

Despite the well established association between cancer and lifestyle, the infection-cancer link provides evidence that cancer prevention cannot be fully addressed through lifestyle changes alone.

It is important to study the process that can take decades and occur prior to the first signs of a cancer growth.

This is especially important with the new emerging focus in personalized prevention, detection and treatment of cancer.

In comparison to the rest of cancer research, infection-related cancers have greater potential to generate prevention guidelines through existing methods.

Prevention of cancers caused by chronic infections can be achieved through the use of vaccines, screening, the proper management of chronic infections, and effective public health programs.

References

• Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Global Health. 2016.
• de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncology. 2012.
• Kuper H, Adami HO, Trichopoulos D. Infections as a major preventable cause of human cancer. Journal of Internal Medicine. 2000.
• de Martel C, Franceschi S. Infections and cancer: established associations and new hypotheses. Critical Reviews in Oncology/Hematology. 2009.
• Yasunaga J, Matsuoka M. Oncogenic spiral by infectious pathogens: cooperation of multiple factors in cancer development. Cancer Science. 2018.
• Hatta MNA, Hanif EAM, et al. Pathogens and carcinogenesis: a review. Biology. 2021.

This article is just meant for informational and educational purposes and does not give advice for diagnosis or treatment for an infection or cancer. For concerns about chronic infections and their association with an increased risk for cancer, please consult with a health care professional.