This is how tumors inhibit the formation of metastases – and give hope to cancer patients

In many types of cancer, the often life-threatening metastases only appear after the original cancer focus has been surgically removed. Because as long as the so-called primary tumor persists, the growth of the daughter tumors is often suppressed. A team from the German Cancer Research Center (DKFZ) in Heidelberg has now elucidated the exact mechanism behind this phenomenon. In the journal "Journal of Experimental Medicine" it reports on the metastasis-inhibiting effect of the molecule nANGPTL4 and its potential for use in cancer therapy.

Cancer is one of the leading causes of death in industrialized countries. While the original cancer focus - the so-called primary tumor - can often be treated well, most patients succumb to the daughter tumors known as metastases. In many patients, such metastases only appear after the primary tumor has been surgically removed. How can that be?

Doctors refer to this phenomenon, which occurs particularly frequently in breast cancer and black skin cancer - melanoma - as "concomitant tumor resistance". Accordingly, the primary tumor is able to suppress the growth of metastases. Although the causes of this are still largely unclear, experts assume that there are at least two control mechanisms: the body's own immune system and so-called angiogenic factors - these regulate the formation of blood vessels and thus the nutrient supply of tumors.

The molecule angiopoietin-like protein 4 (ANGPTL4) is one such angiogenic factor. However, there are controversial publications on this messenger: In most studies, ANGPTL4 is described as stimulating the formation of new blood vessels and thus as carcinogenic, while other studies attested to the molecule's anti-cancer effect. These contradictory results prompted the DKFZ team led by Hellmut Augustin to examine the messenger more closely.

The researchers were able to decipher the mode of action of ANGPTL4 through extensive series of experiments on tumors from both humans and mice. They found that as tumor growth progressed, more ANGPTL4 was present in the tissue. The molecule is formed in the cells of the primary tumor and promotes their growth locally.

It is also known from previous studies that ANGPTL4 has two cleavage products: cANGPTL4 and nANGPTL4. Augustin and colleagues found that the c-fragment, like the full molecule, is mainly found in the primary tumor tissue, while the n-fragment is found in blood serum. They also proved that the two fission products have opposite effects. cANGPTL4 promotes the formation of new blood vessels and thus promotes the growth of metastases. On the other hand, the nANGPTL4 circulating in the blood inhibits the formation of new blood vessels and thus suppresses the growth of metastases.

"Advanced-stage melanoma patients had significantly less nANGPTL4 in the serum than patients with fewer metastases," explains Augustin. "We therefore assume that a higher serum concentration of the n-fragment could help to delay the malignant development of the metastases." Tumor-affected mice that were treated with nANGPTL4 also had fewer metastases and survived significantly longer than animals in an untreated control group.

The team writes that many more studies are still needed. However, the therapeutic administration of nANGPTL4 could represent a long-term strategy for high-risk patients with tumor diseases. In the study, Augustin and colleagues primarily researched skin tumors, but according to the scientists, the effect of nANGTPL4 is probably not tumor-specific - it could therefore also be transferred to other types of tumors.

The findings on the two ANGPTL4 fragments now explain the contradictory results of earlier publications. In addition, physicians can now better understand the mechanism of the "accompanying resistance": In the experiments, the removal of the primary tumor meant that the source of the metastasis-suppressing n-fragment was also removed.

"Nevertheless, surgical removal of the primary tumors remains the gold standard in the treatment of most types of cancer," emphasizes Augustin. “In addition, it is worthwhile to continue researching active substances such as ANGPTL4. Because drugs that effectively suppress the formation and growth of metastases represent an enormous benefit for cancer patients.”