Once Established, Cancers Get By With Less

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Anti-Cancer Drug Development

Researchers at the Duke Comprehensive Cancer Center have discovered that initiating cancer and maintaining its growth are very different processes, a finding that could impact the development of new anti-cancer drugs.

Their study, published in the Nov. 15, 2005, issue of the journal Cancer Cell, counters a longstanding belief that cancer cells become "addicted" to the cancer-causing gene RAS and cannot grow without it. They found that while RAS is indeed important for promoting the start of a tumor, tumors rely on RAS far less once they are established.

"Once tumors are established, the cancer takes on a life of its own" said Christopher Counter, Ph.D., associate professor of pharmacology, cancer biology and radiation oncology and the study's principal investigator. "This study shows that once a tumor has created its own neighborhood, it is much easier for it to keep growing."

The results could alter the development of cancer therapies now aimed at inhibiting RAS, said the researchers.

Counter and graduate student Kian-Huat Lim, Ph.D., studied the role of RAS, a gene that, when mutated, is a key player early in the complex series of events that lead to cancer. An aberrant form of RAS is found in nearly all pancreatic cancers, half of colon and thyroid cancers and one-third of all lung cancers, among others. The gene has been found to turn on numerous pathways in a cell that lead to abnormal changes in cell shape, its ability to grow independently, resist the normal process of cell death, and recruit new blood supply to the tumor.

But the Duke researchers wanted to understand the role of RAS once the tumor is already established and growing, the point at which cancers are diagnosed and treated.

"A lot of research has gone into understanding what it takes to start a tumor," Counter said. "We wanted to know what it takes to keep a tumor going and perhaps, then, what it takes to make it stop."

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So, the scientists designed a series of experiments using human cells growing in the laboratory. They used a combination of molecules that selectively activated one RAS pathway at a time while turning off the main RAS signal. The experiment was similar to turning off a water main, then individually opening one downstream water valve at a time to see whether it alone could supply enough water for a town.

In normal cells, they found that tumors did not form unless all of the RAS pathways were activated. However, tumors that were already established no longer needed most of the functions of RAS, except one. The required signal is called AKT, a factor that allows cancer cells to avoid cell death.

"What we found is that once cancer cells get going, they set up their own neighborhood of feeder cells that can supply a lot of what the tumor needs drive tumor growth," Counter said. "If tumor cells lose some of these growth signals, the cells in the tumor microenvironment can pick up the slack and keep tumors going."

This finding clarifies the commonly held notion that cancer cells become completely "addicted" to RAS and cannot grow without it. The Duke researchers were able to show that only one arm of RAS signaling, the AKT pathway, was critical to maintaining the growth of established tumors.

"AKT appears to be a linchpin for RAS oncogenic activity in established tumors," said Counter. "There is already active interest in AKT inhibitors, and this finding certainly underscores its importance."

In addition, the study demonstrates the critical role of the tumor neighborhood or "microenvironment" in maintaining active tumors. The tumor microenvironment contains a network of cells and blood vessels that support the growing tumor. The Duke team demonstrated that the tumor microenvironment can substitute for some of the RAS functions, making tumor cells less reliant on the presence of activated RAS.

"Our work shows that tumors behave much differently once they are established," said Counter. "Since cancers are treated once you already have a tumor, we need to understand how tumors keep growing, which appears to be a different question than how tumors get established."

The study was funded by the National Cancer Institute.

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