Cancer Microbiology: Connecting the Dots
It is well known that microorganisms play an important role in normal health and disease. Cancer—disease that originates when cells in any tissue start to divide abnormally and uncontrollably, with the possibility of spreading (metastasizing) to other parts of the body—is no exception. Several intriguing historical studies have shown links between microorganisms and cancer/tumor development. In fact, research suggests that 15% of cancers, primarily in developing countries, are caused by microbes.
While the majority of microbe-cancer links have been based on gut microbiome studies, growing data suggest that metabolic activity of the microbiome in tumor environments may be used to inform the diagnosis and even prognosis of cancer. Furthermore, researchers are beginning to investigate ways in which certain microbes may facilitate cancer treatment and prevention. Here, we attempt to delineate how microbial existence influences the resilient and cryptic nature of cancer.
How Do Microbes Impact Cancer Cells and Tumor Microenvironment?
Cancer cells often form their own ‘microenvironment’ around a tumor to support its growth, and any microbes residing in and around that tumor have the potential to directly and indirectly alter its microenvironment in ways that influence cancer cell development. For example, microbes, and the metabolic factors they produce, can damage host cell DNA through various mechanisms and epigenetic changes. Furthermore, microbial proliferation and/or biofilm formation can significantly alter the local environment. And research indicates that cancer cells and microbes can even provide resources for one another through symbiotic association—sharing immune system protection and growth factors amongst several other factors.
What Kinds of Microbes Have Been Associated With Cancer?
Twelve microbial species, including viruses, bacteria and even fungi have been classified as human carcinogens by the International Agency for Research on Cancer or the National Toxicology Program (IARCNTP), and several additional (and unaccounted) microbial species are suspected of possessing carcinogenic properties.
Some microbial species and their associated cancer risks are highlighted below. Notably, these microorganisms may or may not directly cause cancer but have potential to exacerbate the conditions and/or increase the likelihood of getting the disease.
It is suggested that viruses are the most common pathogens associated with cancers including anal, cervical, hepatocellular (liver) etc. Recent reports suggested that about 1.5 million global cases of cancer are caused by tumor viruses. Examples of viruses that are associated with tumor development include Epstein Barre Virus (HBV), Human Papillomavirus (HPV), Hepatitis B (HBV) and Hepatitis C (HCV). The mechanism of carcinogenesis differs depending on the type of virus. For instance, HBV can fuse with human genome and grow in the liver cells and increase carcinogenic activity in the liver by manipulating signal pathways causing liver cancer.
Several species of bacteria have been shown to reside inside of tumor cells and may, therefore, influence the progression of cancer. For example, Fusobacterium nucleatum alters the gut microbiome and increases cancer gene expression associated with colorectal cancer.
Increased ubiquity of Helicobacter pylori is directly associated with stomach cancer, the 5th most common cancer worldwide. It does so by producing cancer-causing proteins (oncoproteins) that actually change the cell properties of the stomach.
Chlamydia trachomatis and other sexually transmitted infection-causing bacteria are associated with ovarian cancer, and so on.
Some fungi have also been associated with certain types of cancer. Long-term Candida infections promote oral cancer through secretions of various metabolites. Even commensal fungi could induce carcinogenesis, in the presence of certain lifestyle changes. For example, upon excessive alcohol intake, oral Candida albicans can produce enzymes that are associated with cancer development.
Even certain eukaryotic and multicellular parasites are known human carcinogens. Examples of carcinogenic parasites include liver flukes, blood flukes, Clonorchis sinensis and Toxoplasma gondii, which together can result in cancers such as liver, bladder, colorectal and brain cancer.
Can Microbes Be Beneficial in the Treatment and Prevention of Cancer?
Though many microbial agents can increase cancer risk, the microbiome also presents immense, untapped potential when it comes to understanding, treating and possibly even preventing cancer. While certain microbes have been labeled procarcinogens (cancer causing agents), several other microbes and microbe-derived drugs have been found to be anticarcinogens (capable of treating and/or suppressing cancer progression). For example, commensal flora may be used to control cancer proliferation; probiotics from bioactive food can aid in metabolism and immune system modulation—which in turn can even prevent cancer cell growth and division. Taking this a step further, some studies have suggested that probiotic microbes and their metabolic products may be involved in chemoprevention of several types of cancer.
As mentioned earlier, several infectious diseases from various causative agents (i.e., bacteria fungi, viruses and parasites) promote tumor growth and development. Therefore, prevention of transmission of infectious disease could also help prevent cancer. Vaccine treatment is one proven way to prevent/treat some cancers, the most common successful example of which is the HPV vaccine for prevention of cervical cancer. In other promising applications, the Mycobacterium bovis strain from the BCG vaccine has been applied for the treatment of bladder cancer with high success rate (>80%), when the cancer is detected at early stages.
Meanwhile, industries (pharmaceutical and biotech) are attempting to develop new approaches and molecules to prevent and treat infectious diseases. It is suggested that certain types of cancer could be treated via microbiome management and/or administration of new antimicrobials. For example, a recent study underscores a method that employs human skin ‘engineered’ commensals like Staphylococcus epidermidis to impede tumor growth by activating immune response resulting in cancer cell death. Additionally, several microbes and metabolic products from microbes are being considered for potential anti-cancer therapeutics. Oncolytic agents, such as T-VEC, Oncorine, RIGVIR, are viruses that target and kill tumor cells and are being actively considered as a therapy.
In order to tap into this potential, increased awareness and funding is needed for cancer microbiology research and development. Seeding graduate level programs and courses to teach cancer microbiology is a good place to start. Such programs should be accompanied by funding/research support and followed by outreach endeavors to disseminate knowledge about the link between infectious diseases and chronic diseases like cancer. Undoubtedly, the advancement of cancer microbiology is necessary in order to provide new treatment and preventative options.
Want to know more about the role of viruses in cancer? This next article gives a brief history of cancer virology.