William Coley, M.D., the 19th century New York surgeon known as the "Father of Cancer Immunology," had an interesting theory about what causes cancer: he thought cancer was caused by a microbe. Some tiny organism originating outside the body had invaded and caused the cancer—much like bacteria invading the lungs cause tuberculosis (TB). This "parasitic theory of cancer" became popular at the end of the 19th century, when many common diseases such as tuberculosis, cholera, anthrax, and smallpox were shown to be caused by identifiable "germs." Cancer too, many believed, was likely microbial in origin.
"The evidence in favor of the microparasitic origin of cancer has been steadily and rapidly accumulating until at the present moment it rests little short of absolute demonstration," Coley wrote confidently in 1893.
The parasitic origin of cancer had many things going for it. For one, it helped to make sense of Coley’s clinical experience with bacterial toxins ("Coley’s toxins") as a treatment for cancer. If bacterial toxins were able to kill cancer, that must be because cancer itself was caused by a microbe.
There were also clear cases of infections causing cancer-like growths in plants, and many people who looked at tumors under the microscope claimed to find evidence of the presence of bacteria and other microbes.
The parasite theory ran into trouble in the early 20th century when direct causal links between such bacterial infections and human cancers were hard to find. While it was easy to isolate bacteria from tumors, there was no single, identifiable "cancer germ" analogous to the specific bug that causes TB.
Powerful figures in the cancer community stood up to pronounce the parasitic theory dead. James Ewing, head of Memorial Hospital and William Coley’s boss, "sounded the death knell for microbial theories of cancer," writes science historian David Hess, author of Can Bacteria Cause Cancer? (2000).
So strong was the opposition to the parasitic theory that even when The Rockefeller Institute biologist Peyton Rous, in 1911, provided clear evidence that a microscopic parasite—a virus—was able to cause cancer in farm animals, no one believed him. It was not until 1966 that Rous’s discovery of chicken sarcoma virus was vindicated, by a Nobel Prize, when Rous was 86 years old.
With the recognition that Rous's finding was genuine came a renewed interest in viruses as a cause of cancer. In 1964, the National Cancer Institute established its Special Virus Cancer Program to look for viral causes of cancer. It was this research effort that led, eventually, to our current understanding of the role of oncogenes and tumor suppressors in cancer.
Today, we now know that about 15%-20% of cancers have a viral cause, including Burkitt's lymphoma (Epstein-Barr virus), cervical cancer (human papillomavirus), and liver cancer (hepatitis B and C viruses).
The Return of Bacteria
If, by the 1960s, viruses were accepted as a contributing cause of cancer, the same could not be said of bacteria. A long history of dubious research by fringe scientists claiming to have found the cancer “germ” had likely predisposed the medical establishment to ignore bacteria as a contributing factor in cancer. In 1965, the American Cancer Society included Coley’s toxins on its damning list of “Unproven Methods in Cancer Treatment,” a reflection of the negative establishment view of bacterial theories of cancer.
It would not be until relatively recently, within the past decade, that bacteria would (re)emerge as an intense area of interest among cancer biologists. A clear link between bacterial infection and cancer was established in the early 2000s when it was shown that the bacterium Helicobacter pylori is a major cause of gastric cancer. The stage for this discovery was set by the finding by Barry Marshall and Robin Warren, in 1982, that H. pylori could be blamed for most cases of gastric ulcer, work for which they won a Nobel Prize in 2005.
These days, one can barely open a newspaper without reading about some newly recognized role for bacteria in health or disease, from using fecal transplants to treat antibiotic-resistant bacterial infections, to the role of our gut microbiome in establishing our propensity for diabetes or obesity.
Some of the hottest contemporary research concerns the role of bacteria in cancer and cancer treatment. Michael Karin, Ph.D., a professor of molecular biology at the UC-San Diego School of Medicine and winner of last year’s Coley Award, has helped to draw attention to the link between bacteria and cancer. Karin, an expert in signaling pathways that control inflammation, has shown that inflammation is an underappreciated cause of both cancer development and progression.
"Inflammation is believed to account for about 20% of all cancers but it probably plays a role in more than 80%-90% of all cancers," says Karin.
Inflammation occurs when tissues are damaged, as a result of trauma or infection. Acute inflammation in response to tissue damage is a natural part of wound healing—helping to promote new tissue growth and kill damaging bacteria that have invaded a cut, for example. Chronic inflammation, which does not subside and goes on for months or years, is much less benign. Epidemiological research has clearly established that chronic inflammation is linked to approximately 15%-20% of cancers, including and especially colorectal cancer (CRC). People who have chronic inflammatory bowel diseases are at a much higher risk of developing colorectal cancer.
The human intestine contains tens of trillions of bacterial cells. In the right set of circumstances, it appears the wrong kind of bacteria can lead to chronic inflammation, which can predispose to cancer.
Exploring exactly how bacteria cause inflammation and how inflammation leads to cancer is an active area of research being pursued by current CRI scientists. CRI investigator Wendy Garrett, M.D., Ph.D., of the Harvard School of Public Health, for example, is studying the role of a strain of bacteria called Fusobacterium nucleatum in the early stages of colorectal cancer development. She has found that stool samples from CRC patients are enriched in this type of bacteria. April Price, Ph.D., a CRI postdoctoral researcher in Greg Barton’s lab at UC-Berkeley, is studying cell surface receptors in the gut that distinguish good bacteria from bad bacteria—a necessary step in understanding what lights the fuse of inflammation. Joshua Ziel, Ph.D., a CRI postdoctoral researcher in Dan Littmann’s lab at NYU, is studying the molecular signals that trigger inflammation, in the hopes that by better understanding the this chain of events, they may be able to intervene in this process through targeted drug therapies.
"We may also find things along the way that can suggest lifestyle alterations or microbial alterations that can lower the incidence of cancer and so keep people from going through that experience altogether," adds Ziel.
The role of inflammation in promoting certain types of cancers has led some doctors to recommend prophylactic treatment with anti-inflammatory drugs, like NSAIDs and aspirin, to help prevent CRC. Therapies designed to alter levels of inflammatory molecules are likely to become an important treatment avenue for patients in coming years, predicts UCSD's Karin.
This is a very different way of thinking about cancer than was common just a decade ago, when the focus was more on what happens inside the tumor cell rather than outside it. Yet the recognition that inflammation plays a role in cancer is not new. More than 150 years ago, the German biologist Rudolf Virchow proposed that cancer occurred at sites of chronic inflammation after observing that many tumors were infiltrated by inflammation-promoting immune cells known as macrophages. Virchow’s idea was that cancer resulted from a form of chronic "irritation."
Today, scientists realize that Virchow was largely correct. Chronic inflammation, triggered by bacteria, can lead to the production of DNA-damaging molecules that cause mutations; this, combined with signals to produce new cells and grow new blood vessels—hallmarks of wound healing—can create a fertile ground for the emergence and growth of cancer.
Science is rarely linear. Sometimes yesterday’s heresies turn out to be the source of today’s most powerful advances.