Promising insight: Doctors have found out why cancer metastases often only appear after the main tumor has been removed – and have thus found a new approach to cancer therapy. Accordingly, the primary tumor releases a messenger substance that promotes its growth locally. In the blood, however, this messenger substance is split and an inhibitor for metastases is created. This inhibitor could also be used medically to prevent metastases.
Metastases are the most feared consequence of cancer. They occur when cancer cells break away from the primary tumor and form metastases elsewhere in the body. Once a cancer has spread in this way, it is often difficult to fight. Whether a tumor forms metastases depends on its genetics, but also on external factors such as stress, diet, mechanical injuries or even chemotherapy.
But why do metastases often only appear when the primary tumor has already been eliminated by surgery or chemotherapy? Such delayed metastasis formation is particularly common in breast cancer and melanoma. According to a common theory, this is because the original cancerous focus suppresses the growth of secondary tumors. “Primary tumor and metastases form a bidirectional communication system,” explain Corinne Hübers from Heidelberg University and her colleagues.
The molecular mechanisms of this communication – and thus also the inhibitory effect of the primary tumor – were previously unclear. Hübers and her colleagues have therefore used fluorescence markers in mice, among other things, to investigate which messenger substances the primary cancer tumor releases and what effect these messenger substances have on metastases. The focus was primarily on messenger substances that regulate the blood supply to the primary tumor and metastases.
It turned out that the researchers identified one particular candidate among the 38 messenger substances examined. Because previous studies had already suggested that the messenger substance ANGPLT4 can have opposite effects depending on the context and condition. “While ANGPLT4 was initially described as promoting the formation of new blood vessels and thus also as promoting cancer, other studies were able to prove the exact opposite and show that ANGPLT4 inhibits the development of metastases,” reports co-author Hellmut Augustin from the German Cancer Research Center.
Now the scientists have been able to clarify what is behind it. At the primary tumor, the molecule it produces promotes the blood supply to the tumor and thus its growth. However, if the messenger gets into the bloodstream, it is split by the enzymes active there. For reasons that have not yet been clarified, the blood serum then contains almost exclusively one of the two cleavage products, the n-fragment (nANGPLT4).
This was also confirmed by blood samples from cancer patients: “nANGPTL4 dominated the systemic blood circulation and showed an inverse correlation with the progression of the disease,” the researchers report. This means that the more nANGPTL4 a cancer patient had in their blood, the better their prognosis.
The researchers determined the reason for this positive effect of the messenger substance cleavage product nANGPTL4 in further analyses. Thus, nANGPLT4 binds to a different receptor than the intact molecule or the second fragment. This receptor change in turn leads to vascular growth in the vicinity of the metastases being suppressed – and thus also the growth of these secondary tumors.
This also explains why metastases often only develop after the primary tumor has been removed: “We now understand that the source of the metastasis-suppressing n-fragment also dries up at the same time,” says senior author Moritz Felcht from Heidelberg University. “If nANGPLT4 is missing, individual dormant metastatic tumor cells can become active and grow into dangerous macrometastases.”
The new findings could also have practical uses for cancer therapy. Because the inhibitor nANGPLT4 or a molecule with a similar mechanism of action could help prevent the formation of metastases. This form of metastasis inhibition has already worked in mice: mice with cancer that were treated with nANGPLT4 developed fewer secondary tumors and survived the cancer longer than untreated conspecifics.
“Many cancer patients could benefit from drugs that effectively suppress the outgrowth of metastases. Given the tremendous benefit that such a drug could bring to those affected, it is worthwhile to further research ANGPLT4 preclinically and then clinically,” says Augustin. (Journal of Experimental Medicine, 2022; doi:10.1084/jem.20202595)
Source: German Cancer Research Center
This article was written by Nadja Podbregar
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The original of this article “Promising knowledge provides a new approach for cancer therapy” comes from scinexx.
