ONCOGENIC MICROBES
The microbial nature of some cancers can trigger a revolution in cancer prevention
Many people view oncology as a specialty for the dying, but there is no subspecialty of internal medicine that promises more advances in the coming years than the field of oncology. With fresh ideas emerging and challenging old concepts, the direction of cancer treatment will move from palliation to cure.
One idea that just might be the next step of oncology is microbial oncogenesis. Although the notion of cancer being caused by microbes is not entirely a new concept, recent studies taking this notion as a launch point are proving that cancer may indeed be preventable and curable.
Fibiger's tumor
The idea that infections can cause cancer started in the 1900s with a Danish pathologist named Johannes Andreas Grib Fibiger. His research involved dissecting rats infected with tuberculosis. While conducting research, he found malignant growths in the stomach of these animals and wondered whether these lesions could be caused by their diet. This led him to the discovery of a spiral worm now known as Gongylonema neoplasticum--a worm that infected cockroaches, which in turn, were eaten by the rats. The spiral worms, he believed, when consumed by the rats, would irritate the lining of the stomach, and set off the neoplastic process.
To test his hypothesis, Fibiger fed laboratory rats with cockroaches infected with the worm, and, to his surprise, he was able to induce the gastric tumors each time. He published his results in 1913, and garnered the Nobel Prize in Medicine in 1926 for achieving the first controlled induction of cancer in laboratory animals. His discovery was considered a development of profound importance to cancer research.
How big is the problem?
Recent epidemiologic data show that over 1.2 million new cases of cancer worldwide may be attributed to infectious agents, accounting for 15 percent of all cancers. This number reflects a substantial portion of cancers in the world that are preventable. In developing countries, the proportion of cancers caused by infectious agents is even higher, rising to almost a quarter of all cancers. This reflects perhaps the high carrier rates of oncogenic microbes in these regions.
Cancer can be induced by persistent infection from many microbes, but only four agents cause roughly 90 percent of cancers due to infection: the hepatitis B and C viruses, the human papillomavirus (HPV), and Helicobacter pylori.
Gastric, cervical, and liver cancers
The discovery of H. pylori in 1982 by Marshall and Warren changed the treatment of upper gastrointestinal disease radically.
H. pylori is acquired by ingesting contaminated food and water. Prevalence of H. pylori infection varies from region to region, ranging from 30 percent in developed countries to as high as 90 percent in countries with poor sanitation.
Epidemiologic data have shown that persons harboring this organism, which causes inflammation of the stomach lining, is at a higher risk of developing gastric cancer than those who don't. By inducing inflammation of the inner lining of the stomach, H. pylori increases the formation of free radicals by inflammatory cells and production of nitric oxide, nitrates, and nitrosamines by macrophages. This encourages cell turnover and the formation of gastric carcinoma.
With epidemiologic data substantiating the association of H. pylori to gastric cancer, the World Health Organization and the International Agency for Research on Cancer consensus group declared H. pylori as a class 1 carcinogen in 1994. Aside from gastric cancer, H. pylori is also associated with a rare type of lymphocytic tumor of the stomach called MALT lymphoma.
HPV has long been known for its ability to immortalize cells in vitro. More than a hundred types of HPV exist, most of them harmless. However, there are several types of HPV that possess the ability to transform the normal cervical epithelium into genital warts or cancers. Low-risk varieties, such as types 6 and 11, are associated with genital warts (or condyloma acuminate), which do not usually progress to invasive disease. In contrast, high-risk varieties, such as types 16, 18, 31, 33, and 35, are associated with moderate to severe cervical dysplasia-intraepithelial cervical lesions that may potentially progress to invasive cervical cancer.
HPV initiates the cancer process by producing viral proteins called E6 and E7. In cells infected with the virus, these proteins bind to tumor-suppressor (p53) proteins and enhance their degradation, stripping the cell of the ability to regulate the cell cycle. Thus, the process of malignant transformation in cervical cancer begins.
The hepatitis virus induces carcinogenesis through direct and indirect mechanisms. The hepatitis virus initiates carcinogenesis directly by integrating viral DNA near protooncogenes or tumor-suppressor genes. Viral DNA disrupts normal gene functions and induces transformation of hepatocytes into malignant cells.
On the other hand, hepatitis infection induces carcinogenesis indirectly by allowing chronic inflammation of the liver. Continuous cycles of necrosis and regeneration lead to spontaneous mutations and induces malignant transformation of liver cells.
Implications
The concept that cancer can arise from a treatable etiology such as an infection carries a variety of implications. New approaches to the problem of cancer will eventually focus on prevention rather than cure.
Primary preventive strategies by vaccination have been shown to affect the prevalence of infections. For example, administration of hepatitis-B immunoglobulin to newborns of infected mothers immediately after birth reduces the carrier rate in children by as much as 90 percent. A decade of mass vaccination against HBV in Taiwan has been show to decrease the incidence of primary liver cancer. Setting up national programs of immunization against hepatitis-B virus and, in the future, developing vaccines against other hepatitis viruses will ultimately reduce the prevalence of hepatocellular carcinoma.
Eradication of H. pylori in patients with peptic ulcer disease has likewise made a dent on the incidence of gastric carcinoma. Furthermore, in patients with gastric cancer treated by resection, eradication of H. pylori prevents the development of new cancer or the continued growth of occult cancer.
Secondary prevention by closer monitoring of infected patients will allow detection of earlier stages of cancer--stages where cure can still be achieved. For example, in carriers of the hepatitis virus, measuring serum alpha-fetoprotein levels and performing UTZ might lead to the discovery of tumors that could be removed via surgery. Likewise, frequent endoscopy of individuals in areas with a high incidence of gastric cancer may result in the discovery of early-stage cancer.
Vaccine against microbes was first used more than 200 years ago, which led to the eradication of smallpox. With the fusion of oncology and microbiology, research on cancer cure and prevention will focus on the development of vaccines against the microbial etiologies of cancer. It is not far-fetched that eventually, we will view gastric and hepatocellular carcinoma, as well as cervical carcinoma, in the same light as we view smallpox, and hopefully measles and polio as well--as a scourge of the past.
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