Harnessing Apoptosis to Destroy Cancer Cells

Nearly 150 years ago, the German physician Rudolph Virchow first proposed a connection between inflammation and cancer. Noting that cancerous tissue also contains the cells and factors that are hallmark features of the body's inflammatory response, Virchow hypothesized that cancer begins at sites of chronic inflammation. At the time - and for many years to follow - the scientific community disavowed this idea because few could envision how the body's first line of defense against tissue injury and infection could also cause harm.

Over the past decade, however, scientists have uncovered increasing evidence to support Virchow's claim. They have determined that the very factors recruited by the body to prevent infection and encourage healing at an injured site can misfire and produce damage. And, if the triggering bacteria, virus, or chemical irritant lingers in the body, a state of chronic inflammation can arise.

Polarized light micrograph (PLM) of prostaglandin B1. Prostaglandin is a hormone-like substance that influences metabolism, blood pressure, smooth muscle activity, and modulation of inflammation. Magnification: 10x.

Today, research indicates that chronic inflammation underpins a host of diseases, including cancer:

• Studies have shown that inflammatory cells promote tumor growth by producing a favorable growth environment, stimulating DNA instability and damage, enabling blood vessel development (angiogenesis), and facilitating the spread of cancer.
• About 15 percent of cancers throughout the world are linked to infectious agents that provoke chronic inflammation - for example, Heliobacter pylori with gastric cancer and hepatitis B and C viruses with liver cancer.
• Cancer may be associated with chronic inflammation caused by long-standing exposure to chemicals such as those found in cigarettes or asbestos.

But the most established and elucidated connection between chronic inflammation and cancer is with colorectal cancer.

Drug Therapy Establishes the Link
Evidence supporting a link between chronic inflammation and colon cancer came together from multiple paths of scientific discovery. For years, scientists observed that patients with long-term chronic inflammatory bowel disease, a group of disorders causing chronic and recurring inflammation of the intestines, often develop colorectal cancer. Population studies confirmed this association.

At the same time, scientists studying the effects of non-steroidal anti-inflammatory drugs (NSAIDs) were also finding evidence to support this link. NSAIDs, which include aspirin, are among the oldest and most widely used drugs in history.

• In a 1980 animal study and a 1983 case study in humans, scientists observed that NSAIDs caused the regression of intestinal polyps - non-cancerous growths that often lead to cancer.
• Several studies reported reduced rates of colorectal cancer in arthritis sufferers who treated their pain with daily doses of aspirin and other NSAIDs.
• And two large population studies found that regular use of NSAIDs over several years reduced the occurrence and mortality for colorectal cancer in the populations studied.

The weight of this collective evidence prompted various research teams throughout the country to explore how NSAIDs act on the body and how this action results in reduced polyp growth and colon cancer risk.

Colonic polyp. Colonoscope (endoscope) view of a benign (non-cancerous) polyp in a 67-year-old man's colon (large intestine). This is a tubulovillous adenoma, a tumor arising from the epithelial tissue lining an organ. Unlike more common polyps, which are attached on a stalk, this type (tubulovillous) forms in a tube shape. If the polyp causes discomfort, or it is suspected that it may turn cancerous, it is removed surgically. In this case, after removal the polyp was found to contain high-grade dysplasia (HGD), the medical term for cell abnormality, which could indicate that the polyp was becoming cancerous.

The Search for a Common Thread
With a chemically diverse group of drugs like NSAIDs sharing the same therapeutic qualities and adverse side effects, it was assumed that they also share a common mode of action. The activity of these drugs was determined in 1971 when Dr. John Vane and his colleagues demonstrated that aspirin and all NSAIDs restrict inflammation by inhibiting the body's production of prostaglandins. Vane predicted that NSAIDs accomplish this outcome by blocking the activity of the cyclooxygenase (COX) enzyme, which catalyzes a key step in prostaglandin synthesis.

Vane's Nobel Prize-winning discovery paved the way for future studies confirming the role of COX enzymes in prostaglandin production, and ultimately for the development of drugs that treat inflammatory diseases by blocking the activity of the enzymes. At first, scientists knew of only one COX enzyme. In 1990, however, three research teams became interested in a protein produced by cells that were becoming cancerous.

• Through further research, they found the gene responsible for producing this protein, and noted it was related to the COX enzyme.
• Naming the new protein COX-2, the scientists determined that it is activated only during inflammation, while the "original" COX-1 enzyme is present in cells at all times, and functions to protect the lining of the stomach and intestines by stimulating mucous production.

Scientists recognized that NSAIDs reduce inflammation by blocking the actions of the COX-2 protein, making them potent treatments for inflammation-associated diseases like arthritis. But they still did not have the findings to document why these anti-inflammatory agents reduce colorectal cancer risk. In 1994, a key piece to this puzzle - the link between COX-2 and colorectal tumors - was provided by Charles Eberhart and Raymond DuBois, who observed that COX-2 (but not COX-1) levels are elevated in as many as 80 percent of colorectal tumors. This finding, since replicated by animal studies, suggests a role for COX-2 and inflammation in tumor development.

Promising Therapies and Future Paths
The potential of NSAIDs as chemoprevention agents for colon cancer is considerably limited by the fact that these drugs can cause serious adverse effects. Because they block the actions of both COX proteins, dosing can lead to excessive stomach acid production, ulceration, and gastrointestinal bleeding.

Scientists thought that a better chemoprevention drug would need to selectively target only the COX-2 enzyme, thereby reducing the most harmful effect of NSAIDs while capitalizing on their benefits. In a milestone NCI-sponsored cancer prevention trial, researchers reported on such a drug, celecoxib, an arthritis medicine that selectively targets the COX-2 enzyme, substantially reducing the number of polyps in patients with an inherited disorder of the colon and rectum that causes polyp growth and almost always progresses to cancer.

Recent studies suggest that elevated levels of COX-2 may contribute to the development of tumors originating at other sites in the body, including the breast, skin, lung, esophagus, bladder, cervix, head and neck, stomach, liver, and pancreas. Based on this information, through 11 clinical trials, scientists are now working to determine if these tumors may be vulnerable to the effects of COX-2 inhibitors.

More recently, three research teams found that daily intake of low doses of aspirin reduced the recurrence of colon polyps among people with previous colon cancers or polyps. These data suggest that daily aspirin may be an appropriate supplement to regular surveillance procedures in individuals who have an increased risk for colon cancer that is similar to the level of risk among the trial participants. It is important to note that:

• Long-term aspirin therapy is not appropriate for everyone. Most people do not have the same elevated risk for colon cancer as those observed in these clinical trials.
• Aspirin, like many drugs, can have side effects. All people aged 50 and older should continue to get colorectal cancer screening exams regularly.

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