RESEARCH. Previous attempts to stop tumours from gaining access to new blood vessels have not been successful. But what if the blood vessels not only expand by branching out, but also by splitting lengthwise? The idea breathes new life into a 50-year-old idea in cancer research and offers hope of a better treatment for malignant melanoma, an aggressive form of cancer.
Tumours need blood just as our organs do. As far back as 50 years ago, American physician and researcher Judah Folkman proposed that tumours that do not have access to blood vessels can grow to only a few millimetres in diameter. For many years cancer researchers looked intently for ways to inhibit tumour access to blood vessels. Finally, during the 1990s they identified the growth factor VEGF as a signal to nearby blood vessels to send out a new branch. Adults have only limited formation of new vessels, but the physiological mechanism is misused by tumours needing more oxygen to grow so that they gain access to the circulatory system.
Those who thought that the discovery of VEGF would cure cancer were destined to be disappointed, however. Drugs that block this growth factor turned out to not be as effective as researchers had hoped.
‘Blocking VEGF can inhibit the tumour’s access to new blood vessels for a little while, but this procedure did not work at all as well as people thought it would. But one might ask if this was such a stupid idea. Why didn’t the drugs work better? Can there be another explanation?’ asks Max Levin, who seems to be on to a possible answer.
Oncologist and vascular biologist
As an oncologist at Sahlgrenska University Hospital, he often meets patients with metastatic malignant melanoma, on which surgery, immunotherapy, chemotherapy or radiation have no longer have an effect.
‘Malignant melanoma is a very aggressive form of cancer, and if the tumours spread, it’s common for them to develop resistance to the treatments that are available,’ says Max, showing an image from one of his former patients.
‘Look at this tumour and you clearly see that it has a reddish surface, which indicates that there are a lot of blood vessels in the tumour. The tumour is growing rapidly, and it requires a lot of oxygen and energy. No treatment helped, and the patient died shortly after the second image was taken. Imagine if we had been able to stop vascular growth in aggressive tumours. That could have been an amazing treatment.’
Max received his PhD in vascular biology at Wallenberg Laboratory and for a number of years was also a postdoc at the University of California, San Francisco (UCSF), on a team with expertise in how cells build structures, such as tubes and spheres. The team at UCSF works with models in which cells are allowed to grow three-dimensionally (3D). Cells then spontaneously assume the three-dimensional shapes found in the body’s organs. When Max cultured blood vessel cells in 3D, he realized that there is another possible way the tumour can gain access to oxygen-rich blood.
When blood vessels send out new branches, vascular biologists call this ‘sprouting,’ but during prenatal life, blood vessels rapidly form new vascular spheres or networks by splitting lengthwise, something called ‘splitting angiogenesis’ or intussusceptive angiogenesis.
‘It’s a relatively unknown process. Many researchers in vascular biology don’t even know that it occurs. In scientific databases there are about 80,000 articles on vascular formation, but fewer than a hundred deal with splitting angiogenesis,’ says Max, who recently was named to one of the advanced ALF positions in Gothenburg to develop his focus of research.
Here in Gothenburg he is building a team investigating whether it’s possible that tumours also send signals for splitting angiogenesis. Thanks to well-functioning collaboration with surgeons at the hospital, the team has access to carefully handled samples from tumours surgically removed from patients with malignant melanoma.
A frozen moment
The first step in their work is to show that splitting angiogenesis actually occurs in human tumours. This is a case where persistent effort has also produced results. Matias Ekstrand, a doctoral student in Max Levin’s team, has spent countless hours at the confocal microscope, which can be used to generate 3D images. Together with resident physician Ankur Pandita, Matias has been looking for signs that indicate the blood vessel is about to split – the thin pillar that first forms inside the blood vessel, which later grows into a new blood vessel wall.
‘We’re looking for a frozen moment in blood vessels that are thinner than a strand of hair, so it really is like looking for a needle in a haystack,’ says Matias. ‘But about a year ago, after several months of work, we found the first pillar, which obviously felt great! And once we found the first one, we soon found more, and at various stages of splitting,’ says Matias.
Idea about drugs
The team is now working on a well-supported article that they hope to get published in a high-quality journal.
The next step for the team will be to search for drugs that can block splitting angiogenesis, which can be tested both in animal models and in clinical studies in collaboration with other researchers. To find a suitable animal model, the team is collaborating with researchers at Sahlgrenska Cancer Center, including Jonas Nilsson and Martin Bergö.
During his time as a postdoc at UCSF, Max conducted screening experiments to find drugs that stop the vascular splitting process and saw that MMP inhibitors seem to produce the results he seeks. MMPs are enzymes that perforate the supporting tissue and that are important in all the processes involved when the tissue is about to change shape. There are drugs for joint pain that have been tested for rheumatoid arthritis that inhibit MMP and that are interesting to study for treating malignant melanoma as well.
‘If we can combine a new drug that prevents blood vessels from splitting in half with the blockage of VEGF, I think we can arrive at a much more effective treatment for depriving tumours of access to new blood vessels,’ says Max Levin. ‘Today there are very few patients with metastatic cancer disease that we oncologists can cure, even though we now have immune therapy that, especially in case of metastatic melanoma, increases the survival and even cures some patients. I don’t really think that our findings in themselves will lead to a cure, but along with other treatments they have the potential to offer cures.’
Of course, there are several years of research ahead before the results may be of benefit to patients, but Max is hopeful. After a long uphill climb, when he at times doubted his own ideas himself, the team is now in a creative and fruitful period.
‘Now we see in samples from our own patients that splitting angiogenesis is occurring in their tumours, and we have important new findings to publish. Research has never been more fun than now.’
TEXT AND PHOTO: ELIN LINDSTRÖM CLAESSEN