A roadblock for metastases

Caught at an early stage, many cases of colon cancer come with a fairly good prognosis: 90 percent of patients survive at least five years. But if the diagnosis comes too late, after metastases have formed, the numbers flip. Only about ten percent of such patients reach the five-year mark, making this one of the most frequent causes of cancer death worldwide. Researchers are actively searching for ways of detecting the disease before it becomes deadly and new forms of treatment. A few years ago, Ulrike Stein's group at the MDC and Charité discovered that high levels of a protein called S1004A was a good indicator of whether tumor cells were likely to migrate through the body and form metastases. Now the scientists have found that treating mice with a substance commonly used to rid the body of tapeworms reduces the likelihood that this will happen and improves the prognosis for the animals. They hope that the discovery can now lead to an effective treatment in human patients. Their work was reported in the July 6 edition of the Journal of the National Cancer Institute.

  In a mouse model of metastasis, tumors in the spleen (above, left) metastasize to form large, deadly tumors in the liver (above, right). But when the animals are treated with niclosamide, tumors in the spleen (below left) lead to smaller metastases (below, right) and the animals have a longer life expectancy. 

"In aggressive colon cancer and many other types of tumors, cells produce up to 60 times the normal amount of S100A4 protein," Ulrike says. "The reason lies with the disruption of a biochemical signaling pathway within tumor cells. This route, called the beta-catenin signaling pathway, frequently becomes far too active during cancer. One result to strongly trigger the production of the S100A4 protein."

While S100A4 itself does not cause cancer, it has deadly effects on animals already susceptible to tumors. When mice that produce too much of the protein are crossed with another strain that has a high rate of cancer, tumors spread like wildfire. On the other hand, if mice that don't produce the protein are injected with highly metastatic breast cancer cells, the tumors don't metastasize.

Over the past few years, researchers have discovered some of the reasons: S100A4 helps cells loosen ties to their neighbors and promotes their migration through the body and the formation of new colonies of cells. These processes are vital in the formation of tissues and organs during the development of embryos, but it becomes deadly during cancer.

Until now, Ulrike says, scientists haven't found a substance that can block the expression and thereby the metastatic potential of S100A4. The current study changes that situation. During a research stay at the National Cancer Institute-Frederick in Maryland, USA, Ulrike and Wolfgang Walther carried out a high-throughput screen of 1280 small molecules with Robert Shoemaker's group, to find something that could inhibit the protein's production. The most powerful effect came from a drug called niclosamide, which is already used to treat tapeworm infections in human patients.

With this information, postdoc Ulrike Sack and her colleagues in Ulrike Stein's group first investigated the effects of niclosamide on the behavior of cells in the test tube, including human cancer cells. They discovered that the treatment had a strong impact on cell migration and their ability to form colonies – two steps which are essential to metastases.

Next the scientists turned to mice, using a well-established method of studying metastases. They injected tumor cells into the spleens of control animals and another group that was treated with niclosamide. All the animals developed tumors in their spleens. In the control mice, metastases spread to the liver within just eight days.

But the livers of the treated animals remained almost metastases-free. The size and the number of the metastases that developed in their livers were significantly reduced, and the animals survived about twice as long as their control counterparts. This was true whether they were given the drug for just a few days after injection of the tumor cells or over the entire course of the disease.

The scientists discovered that niclosamide specifically blocks production of high amounts of S100A4 and its metastatic effects. "We're lucky that the drug has already been thoroughly tested in human patients," Ulrike Stein says. "That is normally a huge bottleneck in the development of drugs. So we're hopeful that we can quickly move to human trials, to study the effects of niclosamide on deadly forms of colon cancer."

- Russ Hodge  

Highlight Reference:

Sack U, Walther W, Scudiero D, Selby M, Kobelt D, Lemm M, Fichtner I, Schlag PM, Shoemaker RH, Stein U. Novel effect of antihelminthic Niclosamide on S100A4-mediated metastatic progression in colon cancer. J Natl Cancer Inst. 2011 Jul 6;103(13):1018-36

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