Sabotage of Cancer Defense

12. September 2006

Some recruits of the human immune defense are behaving completely different from their original programming, when directly facing tumor cells. Instead of doing the rampant tissue in, they raise its aggressiveness and support it to spread.

Normally, the mission of macrophages in the immune system is clearly defined: Detect and destroy bacteria, viruses, protozoans, but also cancer cells. That the latter manage to reprogram the natural destination, the team of Claudia Binder at the hematology and oncology department of Göttingen University has proven. Already in earlier experiments, the researchers had discovered, that the invasivity increases, if bred together with breast cancer cells in one dish. The tumor cells obviously are using the proteolytic abilities of the guards. When in contact with the transformed cells, the macropahes are releasing matrix metalloproteases (MMP), which are weakening the surrounding connective tissue.

Key Role for Wnt

With the latest experiments, published in the American professionals magazine “Proceedings of the National Academy of Sciences” (PNAS) by the Göttingen hematologists, they point out the way how the cancer cells are interfering with the control of the opponents. Again they let human breast cancer cell lines meet with macrophages in a dish. Via suitable inhibitors the team showed, that in immune cells molecules are activated, which are playing a key role especially in the transmission of signals into the cell nucleus.

This so-called Wnt-family plays a role in the cell activities, having to do with development, survival, building of tissue, but also mobility. For that purpose, the Wnt-glycoproteine docks on to a receptor in the cell membrane. Via a chain reaction this connection leads to an increased reading of genes being concerned with cell activation. This cascade of signal transmission is detected in all metazoans thus playing a key role in the reaction of messages from the cell's environment. Wnt defects occur in different types of cancer, but also in disorders of the bone structure or retinal vessel ailments.

One family member takes over a most important role in this sabotage of the immune defense. Up to now Wnt 5a was considered as a molecule with predominantly tumor suppressor features. But in their model, the Göttingen oncologists found out, that the factor does not only contribute to increase the aggressiveness of the tumor, but even takes over the role of the macrophages completely, replacing them in the test-tube.

These in-vitro statements as well reflect the reality at the tumor front fairly certain. If the researchers used tissue samples of tumors and according lymph node metastases instead of cell lines, Wnt 5a was histologically verified in macrophages.

Regain of Schismatic Macrophages

Very similar processes happen with other cancer types, because
Wnt 5a appears in aggressive melanoma as well. Just how important the new results are for an understanding of metastasis of cancer tissue, the director of hematology and oncology at the department human medicine of the Göttingen University, Lorenz Trümper, explain: “It was known for quite some time, that macrophages immigrate in tumors. What was not clear so far is what exactly they are doing there.” Building on the results, the Göttingen working group is hoping to be able to study the role of Wnt 5a and its relatives in tumor development and to discover further important factors, with the help of newly applied for research funds. “If we succeed”, says Trümper, “we might be able to develop therapeutic approaches applicable to put the schismatic macrophages back into service of the body.”

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