To Stop Cancer From Spreading: Shoot The Messenger

By NoCamels Team April 09, 2015 3 minutes

Cancer Cell via BigStock

Humans need to communicate with each other in order to get things done – at work and at home. But so do the cells inside our bodies, which transmit messages from their outer walls to their inner nucleus. These messages prompt them to take immediate action. Now, it turns out that if cancerous cells don’t receive certain messages, the spread of cancer throughout the body can be halted. How? Israeli researchers have come up with a method of shutting off the overflow of information that creates cancerous mutations.

The average living cell must transmit a constant stream of messages quickly and efficiently from its outer walls to the inner nucleus, where most of the day-to-day “decisions” are made. But this rapid, long-distance communication system leaves itself open to mutations that can give rise to a “spam attack” that promotes cancer. Weizmann Institute scientists have identified a potential drug molecule that stops only cancerous cells (not healthy ones) from getting their “mail.”

Weizmann Institute’s Prof. Rony Seger and his team have proposed a new method of shutting off the overflow of information before it can get to the nucleus. Their method could be used to treat a number of different cancers, especially several that develop resistance to current treatments, and it might possibly induce fewer side effects than those treatments do. These findings were recently published in the scientific journal Nature Communications.

“Spamming” the cell with “messages” leads to disastrous results

There are 15 different pathways for transferring the cell’s main internal messaging (membrane-to-nucleus communication). Seger has identified a number of the proteins involved in these pathways, especially in one particular pathway, called the MAPK/ERK cascade, which is involved in cancer. Dysregulation of this pathway shows up in 85 percent of all cancer types. Following certain mutations, the message sent to the cell becomes “spam.” It gets sent over and over, flooding the nucleus’ “inbox.” The response to this “spam attack” can be disastrous; in the case of such messages as those to grow or divide, the result may be cancerous.

A crucial step in this pathway takes place when a molecule called ERK undergoes a transformation that enables it to pass through the membrane surrounding the nucleus. Seger has revelaed an entire, complex process that must occur for ERK to get its message across. Seger realized that an effective nuclear “spam filter” on the ERK pathway would involve blocking just this step, thus preventing specific ERK “messages” from getting into the nucleus. His team then designed a variety of small molecules to enter the cell and block the transfer of ERK molecules into the cell’s nucleus. Working with Dr. Michal Besser of the Sheba Medical Center, they grew cells from different cancers in culture and then added the different molecules to see which of them would best target ERK.

Leukemia. Photo by Dr. Richard Lee/National Cancer Institute

“The cancer disappeared within days and did not return”

The team identified one potential drug molecule that performed well, even causing many of the cancer cells to die. Seger says that the cancer cells become “addicted” to the constant flow of ERK signals, so adding a filter that cuts this signal off causes them to die. Importantly, this molecule did not affect normal cells, suggesting that it mainly targets the cancer process and therefore might have fewer side effects than the present chemotherapy drugs.While testing the treatment on lab mice, “the cancers disappeared within days and did not return,” Seger says.In addition, the fact that the molecules do not destroy the ERK but only stop it from entering the nucleus may be good news for healthy cells: The ERK can still send a “delivery receipt” back up the relay to the receptors, so they don’t try to resend the message. According to Seger, the method of designing small molecules that can get inside cells and stop certain messages before they become “spam” might be useful in treating other diseases in addition to cancer.

One of the cancers that the molecule eradicated in the experiments was melanoma, an often fatal cancer with few available treatments. The drugs currently used for melanoma usually work for a while and then the cancer becomes resistant to them. Seger envisions the new molecule being added to the drug regimen in rotation with others, so that resistance cannot develop. Says Seger: “All in all, the molecule was completely effective in eliminating a dozen of the cancers the team tested, and many others showed a decline, if not complete destruction, of the cancer cells.”

Photos: Dr. Richard Lee/National Cancer Institute