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Why chemotherapy fails
A single molecule may explain why our most powerful cancer drugs can’t always halt tumors
Chemotherapy has a lousy reputation. Even the sickest cancer patients are often wary of its many side effects and failure rates.
But new research from Rockefeller University, published last month in the Proceedings of the National Academy of Sciences, may explain why some people don’t respond to the
powerful drugs.
The study, led by Archontoula Stoffel, research assistant professor in Hermann Steller’s Laboratory of Apoptosis and Cancer Biology, examined human cells taken from the tumors of a type of non-Hodgkin’s lymphoma. By looking at how specific molecules interact with two different cell growth pathways, Stoffel and her colleagues found a mechanism that may cause chemotherapy drugs to “jam” before they can take effect.
Most chemotherapy drugs target what was thought
to be a discrete pathway responsible for cell destruction, such as the well-known p53 tumor suppressor protein. But Stoffel and her colleagues showed that proteins that control the function of p53 are also involved in the NF-kappa B (NF-
kB) signaling pathway that is responsible for pushing cells to grow uncontrollably. If p53 is managed or inhibited by proteins that also promote tumor development, chemotherapy will not be effective. (The same interactions could characterize other cancer types beyond lymphoma, the researchers say.)
But it might be possible to target one or both of the genes that link the two pathways.
“Now that we know the proliferation pathway can jam the p53 suicide pathway, we might be able to block specific sections of those pathways,” says Stoffel, whose coauthors include former Rockefeller president and professor Arnold J. Levine, now at the Institute for Advanced Study and the University of Medicine and Dentistry, both in New Jersey.
The trick will be to block only selected portions of the pathways, Stoffel says. Though the NF-kB pathway is linked to a growing list of cancers, it also plays a vital role in the body’s normal immune and inflammatory responses. “It is not possible to shut down NF-kB without causing systemic problems, so we need to find out how to disarm its carcinogenic properties down the signaling pathway, while maintaining its useful functions,” she says.
The Rockefeller University study also presents the first molecular description of a cancer caused by bacteria, and thus represents a model system of how the environment and genetics can lead to a cancer, Stoffel says.
The cancer the researchers used as their model is known as mucosa-associated lymphoid tissue lymphoma (MALT lymphoma), which consists of tumors that originate from cancerous growth of immune cells. MALT lymphoma most often occurs in the stomach and usually arises when immune system B cells respond to inflammation provoked by the bacterium Helicobacter pylori. Infection by this bacterium is one of the main risk factors for developing gastric cancer, the world’s second most common cancer.
In some people with chronic H. pylori infection, the immune cells that respond to the infection acquire genetic changes, called chromosomal translocations, which produce MALT lymphoma. The most common translocation occurs when a gene known as the apoptosis inhibitor 2 gene, API2, on chromosome 11 breaks in half and moves over to a similarly broken gene, MALT1, on chromosome 18. The MALT1 protein helps activate NF-kB in immune cells.
The so-called fusion protein created by this translocated gene was key to understanding the two different pathways. The researchers discovered that the fusion protein acts like a cancer-causing gene, capable of promoting unrestricted cell growth. When they studied the proliferating cells by microchip gene expression analysis, they found more than 80 percent of the genes were involved in regulating proliferation and were known to be involved in NF-kB immune responses. “That makes sense because lymphoma is a tumor of the immune system and abnormal activation of the NF-kB pathway, which is normally involved in setting up an immune response, leads to abnormal proliferation,” Stoffel says.
More startling was the scientists’ finding that five genes were known to be involved in a cell suicide process called apoptosis. When they checked with databases of gene products, the researchers found that three of these five have been shown to block the function of the p53 protein.
“That surprised us,” says Stoffel. “We began to think that maybe the fusion proteins work in a bilateral sense, by turning on NF-kB and inhibiting p53. There have been suggestions in previous research that these pathways might be interrelated, but no one has seen that in a model of cancer.”
To check whether fusion proteins inhibited p53, Stoffel exposed cells to ultraviolet radiation, which is known to stimulate the activity of p53 and kill cells. “But our cells did not die. That meant something was controlling the action of p53,” Stoffel says.
Next, the researchers treated the cells with molecules they knew would block NF-kB and again exposed them to ultraviolet radiation. This time, the cells died.
“The NF-kB pathway, which is the hallmark of all immune responses, tells cells to grow, and abnormal activation of this pathway leads to abnormal proliferation and cancer,” Stoffel says. “If this pathway also inhibits p53, which normally helps clear cells that are damaged, then you can’t eliminate these cells.”
The team concluded that p53 was not inhibited by the NF-kB pathway. The fusion proteins were promoting cancer development by encouraging cell growth through the NF-kB pathway, which, in turn, repressed p53 and inhibited cell death.
The results suggest different ways to inhibit the NF-kB pathway for cancer control. “Many people are now trying to knock out NF-kB, but that produces systemic effects in patients because this pathway plays such an important function in normal cells. It is active in disease but also needs to be intact for normal immune and inflammatory responses,” Stoffel says.
The goal now is to identify molecules downstream of the NF-kB pathway that could be targets for new drugs able to activate tumor suppressor genes without upsetting the body’s other cells.

July 16, 2004



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