Tumors need a steady supply of sufficient nutrients to be able to grow. In order to secure the nutrient availability, they secrete messenger compounds to stimulate neighboring blood vessels to proliferate and sprout. Scientists from the Max Planck Institute for Neurological Research in Cologne, Germany, have now identified a new positive feedback loop involving the Vascular Endothelial Growth Factor (VEGF) and its receptor ‘VEGFR-2’ in human lung adenocarcinoma. When VEGF binds to VEGFR-2 on cancer cells, secretion of the growth-factor itself is boosted consequently accelerating tumor growth. In experiments on mice with lung cancer, the scientists switched off the growth-factor and proteins responsible for this signaling thereby slowing down tumor growth. The tumors were even reduced in size by employing other inhibitors in combination. The researchers thus proved the existence of VEGF Receptor-2 on tumor cells and described a new signaling pathway in lung cancer cells that triggers the sprouting of new blood vessels. In addition, they also learnt from examinations of lung cancer patients that therapy with these inhibitors only makes sense if the cancer cells express large numbers of VEGFR2. These results can contribute to developing new cancer therapies.
Tumor cells often remain in a dormant state before dividing in an uncontrolled manner. During this dormant period, approximately as many cells die off as regenerate. Change in the tumor cell genetics leads to messenger compounds being secreted that stimulate proliferation of blood vessels. Only then the tumor can begin to expand. Without this transition from dormant to active state, the growth of cancer cells would be limited to a dimension harmless for the body.
Scientists at the Max Planck Institute for Neurological Research want to use this as a point of attack for tumor therapy. To this end, they investigated the effect of VEGF, which enables blood vessels to expand. According to the research group led by Roland Ullrich, VEGF also acts directly on the secreting tumor cells. These cells re-absorb it via VEGFR-2 and thus produce even more VEGF. “This positive feedback loop causes more and more new blood vessels to generate and the cancer to grow even faster,” explains Ullrich. “We therefore wanted to find out what happens when we interrupt them.” The scientist’s idea: “to cut off the tumor from the supply of nutrients – simply starving it out.” Ullrich compares the fight against cancer with the siege of a fortress: “You don’t have to necessarily storm the castle to overcome the enemy. It is sufficient to turn off the water-supply.”
In the second part of their study, they therefore experimented with mice that exhibited a specific form of lung cancer and blocked their VEGFR-2. “And we did detect a deceleration of the cancer growth in the animals,” says Ullrich. “An even more impressive result was obtained when we administered an additional inhibitor.” This inhibitor disrupts what is known as the MAPK signaling pathway, which drives growth of tumor cells, among other things. Administered individually, both inhibitors only slowed down the cancer growth, while in combination they were able to actually shrink the tumor. The scientists therefore assume a connection between the MAPK signaling pathway and VEGFR2 inhibition. “If the supply of nutrients to the cells is cut off, they simply begin to grow more vigorously,” explains Ullrich, “and we can prevent that with the help of the second inhibitor.”
However, not all types of cancer are suited to this kind of treatment. These inhibitors can only be effective if the cancer cells also express the receptors for VEGF (VEGFR-2) on their membranes in moderate to high numbers. According to the results of the Cologne scientists, about every fifth lung cancer patient has VEGFR-2 on the tumor cells and could therefore be treated in this way.
Illustration: The feedback loop of the tumor: The cancer cells secrete the growth-factor VEGF (yellow) in order to stimulate nearby blood vessels to introduce small sprouts into the tumor. At the same time, the cells also express VEGFR-2 on their surface, which the VEGF binds to. In this way, the cancer cells are stimulated to produce even more VEGF. – Max Planck Institute for Neurological Research.
Max Planck Institute for Neurological Research News Release (03/14/13)
Abstract (The Journal of Clinical Investigation; 123(4), 1732-1740 (04/01/13))