New therapy method against cancer metastasis

DKFZ: Combination of low-dose chemotherapy and antibodies reduces the development of metastases

09/01/2015

Mice with malignant tumors receiving low dose chemotherapy in combination with an antibody to a central blood vessel cell control protein develop less metastases and survive longer. This is the result of a study by the German Cancer Research Center (DKFZ) and the Medical Faculty of the University of Heidelberg. According to the scientists, the combination therapy even acts several times against the establishment of metastases. This prevents blood vessels from supplying the newly formed metastases. At the same time, the treatment reduces the number of certain immune cells, which in turn promotes the colonization of cancer cells, according to a statement by the DKFZ.

New therapy combats metastases and is gentler on the patient
If a tumor is surgically removed, the patient is considered cancer free. However the malignant tumor has often already scattered. To fight these cancer cells, doctors usually recommend chemotherapy. However, this treatment is extremely stressful for the patient. In addition, the cells are undetectable and thus it is not clear which patient actually benefits from the chemo. „This is a big dilemma for many cancer patients: should they opt for high-dose chemotherapy with all the serious side effects or instead be at higher risk for metastases?“, says Professor Hellmut Augustin from the DKFZ. His group was therefore looking for more gentle methods that prevent the formation of metastases.

In doing so, the scientists took into account new research findings that attribute great importance to the wall cells of the blood vessels (endothelial cells) for tumor growth. The background is the process of angiogenesis, in which tumor cells cause blood vessels to form new capillaries that supply the tumor and promote its growth.

In addition, the endothelial cells themselves are also factors that favor the growth of tumors. Therefore, the researchers around Augustin not only wanted to prevent the formation of vascular tumors, but also suppress the production of these growth factors. They chose the molecule angiopoietin-2 as a starting point for their study, which is formed by endothelial cells and plays an important role in angiogenesis.

Mice lived longer due to the new metastatic therapy
The researchers performed their investigation in mice to which breast or lung cancer cells were transferred. After the tumors reached an early stage of growth, they were surgically removed. Then the experimental animals received different types of chemotherapy. Some mice were also treated with a blocking antibody to angiopoietin-2.

As it turned out, chemotherapy alone was not effective. However, in combination with the antibody, the mice developed significantly fewer metastases than the untreated animals. Most effective was a combination therapy with the antibody and a so-called metronome chemotherapy, in which the cytostatic substances are administered permanently in low doses. In contrast to conventional high-dose chemotherapy, metronome chemotherapy does not primarily act against the tumor cells themselves, but prevents the colonization of certain cells from the bone marrow in the tumor, which also promote tumor growth. The animals treated with this combination therapy lived longer than the mice that received only the antibody.

Inhibition of angiopoietin-2 prevents immigration of cancer-promoting immune cells into the environment of the tumor
Tissue analyzes showed that angiopoietin-2 promotes vascular growth on the one hand, but also stimulates the endothelial cells to attract tumor-promoting macrophages (leukocytes, cells of the immune system) to the vicinity of the cancer cells. The blocking of angiopoietin-2, on the other hand, caused significantly fewer cancer-promoting immune cells to migrate into the tumor environment.

„With our combination therapy, we are therefore at the same time against the establishment of metastases from several sides: First, we throttle their vascular supply. On the other hand, we prevent the growth of tumor-promoting macrophages, which create an inflammatory environment and thus to a certain extent prepare the ground for a permanent colonization of the cancer cells“, explains Augustin. „Of course, we can not predict whether the results of these preclinical studies can be translated one-to-one into humans, but in our experiments we learned a lot about how metastases develop. We want to translate this knowledge into a clinical application.“ (Ag)