Illuminating metastases

Researchers at the MDC and the Charité have discovered that the presence of a protein indicates whether some colorectal cancers will lead to metastases, the main cause of death from the disease. The groups are working to turn the discovery into a tool for diagnosis and better therapies for cancer patients. Their findings may also shed light on a current debate about why metastases happen. The work appears in the January 2009 issue of Nature Medicine.

The protein was identified by research group leader Ulrike Stein and Peter Schlag, Director of the Charité Comprehensive Cancer Center, working with Walter Birchmeier's group at the MDC. Stein and her colleagues compared samples from metastatic and non-metastatic colon cancer tissues. Only tumor cells from patients whose cancers metastasized produced a protein that Stein and her colleagues call MACC-1 (for Metastasis-Associated in Colon Cancer 1).

Follow-up studies have shown that the molecule is a reliable sign that a colorectal tumor has metastasized or will do so in the future. Patients whose tumors don't produce the protein usually have good prospects for a lasting recovery and a longer life expectancy. But when the tissue reveals high levels of the molecule, metastases are almost sure to develop.

The researchers are still unsure as to why cells in some tumors produce the molecule and other's don't. But they have gained some insights into why MACC-1 causes cells to detach themselves from a tumor and wander through the body. Stein and her colleagues thought that the protein might be involved in triggering cell migrations. They grew cancer cells in laboratory cultures and watched their behavior. When the cells began to produce MACC-1, they cast off ties to their neighbors and crawled away from each other. If MACC-1 was disabled, the cells stayed put. In another set of experiments, the scientists added human MACC-1 to animal tumors. This led to metastases, a process which could be stopped again by shutting down MACC-1.

The study adds an intriguing bit of information to an ongoing debate about the causes of metastases. Colorectal cancer (CRC) is the second most common form of cancer world-wide and the second most frequent cause of cancer deaths. Researchers believe that the disease begins with stem cells in the intestine, whose job is to replenish the lining of the gut. They undergo random mutations which cause them to lose control of their growth and develop in an abnormal way. Instead of inserting themselves into the lining, they balloon into large polyps.

The growths usually remain benign unless something else happens; most scientists believe that additional mutations allow a small fraction to metastasize. This is surely the case in many patients, but recently scientists have hypothesized that there may be another path to metastasis. As tumors grow, they develop various types of cells. Some of these may be "cancer stem cells" which have the potential to metastasize from the very beginning.

MACC-1 does not resolve the debate. But the protein can be detected even in an early stage of cancer and has proven to be a reliable indicator of the long-term course of the disease. So in some cases, a sub-group of colorectal tumor cells seems predestined to metastasize because for some reason, they have begun to produce MACC-1.

Schlag says that reliable markers such as MACC-1 can be crucial tools as physicians make decisions about patient treatment. "A tumor that is likely to metastasize must be monitored much more carefully than one that is unlikely to, and treated longer and more aggressively," he says. "With a reliable prognosis, we can recognize when this aggressive approach is necessary and when it is not – because if we can identify patients who are not at risk, it is unnecessary and often comes with unpleasant side-effects."

Highlight Reference:

MACC1, a newly identified key regulator of HGF-Met signaling, predicts colon cancer metastasis Ulrike Stein, Wolfgang Walther, Franziska Alt, Holger Schwabe, Janice Smith, Iduna Fichtner, Walter Birchmeier, Peter M. Schlag Nat Med. 2009 Jan;15(1):59-67. Epub 2008 Dec 21.

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