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Cell Growth And Death Controlled By Single Pathway In Lymphoma Cancer Model

Date:
June 4, 2004
Source:
Rockefeller University
Summary:
New research at Rockefeller University, published this week in the online edition of the Proceedings of the National Academy of Sciences, helps explain why some people do not respond to chemotherapy and offers a possible solution.

New research at Rockefeller University, published this week in the online edition of the Proceedings of the National Academy of Sciences, helps explain why some people do not respond to chemotherapy and offers a possible solution.

The cell culture study shows that in a type of lymphoma, molecules involved in the NF-kappa B (NF-kB) signaling pathway -- responsible for pushing cells to grow uncontrollably -- also control the function of the p53 tumor suppressor protein whose function is demolishing those harmful cells. The same interactions could characterize other cancer types, the researchers say.

Most chemotherapy target what was thought to be a discrete "pathway" responsible for cell destruction, such as the p53 protein, but if these proteins are managed -- even protected -- by other key cancer-promoting molecules, the chemotherapy will not work.

Instead, the researchers say it may be possible to target one or both of the genes they found that link both molecular pathways, like intersections joining two highways together in different spots.

"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 the lead researcher, Archontoula Stoffel, Ph.D., a research assistant professor at Rockefeller University.

Blocking only selected pieces of these pathways will be important, Stoffel says, because the NF-kappa B pathway plays a vital role in the body's normal immune and inflammatory responses, although it is also linked to a growing list of cancers. "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. "This study may help."

The study also is important because it 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," says Stoffel.

Stoffel studied a type of non-Hodgkin's lymphoma known as MALT (mucosa-associated lymphoid tissue), which consists of tumors that originate from cancerous growth of immune cells. MALT lymphoma most often occurs in the stomach and usually arises when B lymphocytes respond to inflammation provoked by the bacterium Helicobacter pylori (H. 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 (the apoptosis inhibitor 2 gene, or 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.

When this translocation takes place, a new chimeric gene forms, which produces a new fusion protein that has unique functions. This fusion protein offered researchers a way "to uncover the relationship between two major pathways involved in cancer development," says Stoffel.

The researchers first discovered the fusion protein acts like an oncogene, or cancer-causing gene, that can promote unrestricted cell growth. To identify the pathway involved in this ability to continually grow, they studied those cells by microchip gene expression analysis and found more than 80 percent of the genes are involved in regulating proliferation and "were known to be involved in NF-kB immune responses," Stoffel says. "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."

But the scientists also discovered five genes they say are known to be involved in a cell suicide process called apoptosis, but which had never been described as genes associated with the NF-kB pathway.

Checking with databases of gene products, the researchers found that three of the five genes 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 (UV) radiation. "It is very well known that UV stimulates the activity of p53, which then kills the damaged cells. But these cells did not die. That meant something was controlling the action of p53."

The team now had to determine whether this resistance to cell death was dependent on activation of the NF-kB pathway, so they treated the cells with molecules they knew would block NF-kB.

They then exposed the transfected cells -- those in which NF-kB was inhibited -- to UV radiation. If the cells died, that meant p53 was "free" of NF-kB's control and could kill the damaged cells. If the cells did not die, p53 was not being inhibited by the NK-kB pathway.

Sure enough, the cells died, leading the team to conclude that the fusion proteins promote cancer development by both pushing cell growth through activation of NF-kB, which, in turn, repressed p53, inhibiting cell death.

In addition, the researchers found when NF-kB was blocked, the cells also lost their proliferative advantages. "That meant both the proliferative and the anti-apoptotic potential of the cells was also dependent on NF-kB," Stoffel says.

"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."

These results suggest different ways to inhibit the NF-kB pathway for cancer control, she says. "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," she says.

Now it may be possible to identify molecules that are regulated "downstream" of NF-kB in different cancer sites that could be inhibited by a novel drug, she says. Given this new model of cancer development, striking at this pathway may work to activate tumor suppressor genes that had been inhibited, says Stoffel.

The study was funded by the Lymphoma Research Foundation and the Robert and Harriet Heilbrunn Cancer Fund.

Co-authors include Arnold J. Levine, Ph.D., former president of Rockefeller University who is now at the Institute for Advanced Study in Princeton, N.J., and the University of Medicine and Dentistry of New Jersey; Mira Chaurushiya, a former technician at the Rockefeller University; and Bhuvanesh Singh, M.D., at Memorial Sloan-Kettering Cancer Center.


Story Source:

The above story is based on materials provided by Rockefeller University. Note: Materials may be edited for content and length.


Cite This Page:

Rockefeller University. "Cell Growth And Death Controlled By Single Pathway In Lymphoma Cancer Model." ScienceDaily. ScienceDaily, 4 June 2004. <www.sciencedaily.com/releases/2004/05/040531212843.htm>.
Rockefeller University. (2004, June 4). Cell Growth And Death Controlled By Single Pathway In Lymphoma Cancer Model. ScienceDaily. Retrieved August 1, 2014 from www.sciencedaily.com/releases/2004/05/040531212843.htm
Rockefeller University. "Cell Growth And Death Controlled By Single Pathway In Lymphoma Cancer Model." ScienceDaily. www.sciencedaily.com/releases/2004/05/040531212843.htm (accessed August 1, 2014).

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