Decreased blood vessel leakage can improve cancer therapy and reduce tumor spread

Cancer therapy is often hampered by the accumulation of fluids in and around the tumour, which is caused by leakage from the blood vessels in the tumour. Researchers at Uppsala University now show how leakage from blood vessels is regulated. They have identified a novel mechanism whereby leakage can be suppressed to improve the result of chemotherapy and reduce the spread of tumours in mice. The results have been published in the scientific journal Nature Communications.

When a tumour grows, new blood vessels are formed that supply the tumour with nutrients and oxygen. However, these vessels are often malfunctioning and fluids and other molecules leak out of the vessels. This results in edema in the tissues, which in turn makes it more difficult for drugs to reach into the tumour during cancer therapy. The malfunctioning vessels can also contribute to the spread of metastases from the tumour.

The leakage from the blood vessels is controlled by specific protein complexes that connect the cells in the blood vessel walls. By regulating these protein complexes, the cells are joined more or less tightly, which affects the leakage from the vessels.

Recent findings from Uppsala University show how a specific alteration of the protein complex in the vessel walls can reduce leakage, without affecting any other vessel functions.

We have studied mice that have a mutation in a certain part of one of the proteins in the protein complex. The regular blood vessels in these mice function normally, but vessels in tumours showed less leakage, and there was a decrease in edema formation. In addition, the mutant mice responded better to treatment with chemotherapy‘, says Lena Claesson-Welsh, professor at the Department of Immunology, Genetics and Pathology,at Uppsala University and Science for Life Laboratory, who led the study.

The growth factor VEGFA functions as a signalling molecule, regulating the protein complexes in the blood vessel walls. One way of treating cancer is by inhibiting VEGFA, which decreases leakage and edema and improves the effects of chemo- and radiation therapy. However, VEGFA affects blood vessels in several ways and sustained anti-VEGFA therapy deteriorates vessel function and can cause increased metastasis.

The specific mutation that we have studied allowed us to examine one of the signalling pathways in which VEGFA is involved. An important finding was that mice with the mutated protein complex also showed a reduced spread of metastases. We, therefore, believe that a targeted inhibition of this specific signalling pathway, which controls how the cells in the vessel walls are connected, might work better as a cancer therapy than the more general VEGFA inhibition that is used today,’ says Lena Claesson-Welsh.

Li et al. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nature Communications. 2016;7:11017 doi:10.1038/ncomms11017 [Article]

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Next-generation immunotherapy offers new hope for beating brain cancer

High-grade glioma is the most aggressive form of brain cancer. Despite improvements in surgical procedures, chemotherapy, and radiotherapy, this type of brain tumour is still notoriously hard to treat: less than 10% of patients survive beyond five years. Researchers from KU Leuven, Belgium, have now shown that next-generation cell-based immunotherapy may offer new hope in the fight against brain cancer.

Cell-based immunotherapy involves the injection of a therapeutic anticancer vaccine that stimulates the patient’s immune system to attack the tumour. Thus far, the results of this type of immunotherapy have been mildly promising. However, Abhishek D. Garg and Professor Patrizia Agostinis from the KU Leuven Department of Cellular and Molecular Medicine have now found a novel way to produce more effective cell-based anticancer vaccines.

The researchers induced a specific type of cell death in brain cancer cells from mice. The dying cancer cells were then incubated together with dendritic cells, which play a vital role in the immune system. The researchers discovered that this type of cancer cell killing releases ‘danger signals’ that fully activate the dendritic cells.

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The researchers induced a specific type of cell death in brain cancer cells from mice. The dying cancer cells were then incubated together with dendritic cells, which play a vital role in the immune system. The researchers discovered that this type of cancer cell killing releases ‘danger signals’ that fully activate the dendritic cells. “We re-injected the activated dendritic cells into the mice as a therapeutic vaccine”, Professor Patrizia Agostinis explains. “That vaccine alerted the immune system to the presence of dangerous cancer cells in the body. As a result, the immune system could recognize them and start attacking the brain tumor.”
CREDIT©KU Leuven Laboratory of Cell Death Research & Therapy – Dr. Abhishek D. Garg

We re-injected the activated dendritic cells into the mice as a therapeutic vaccine“, Professor Patrizia Agostinis explains. “That vaccine alerted the immune system to the presence of dangerous cancer cells in the body. As a result, the immune system could recognize them and start attacking the brain tumour.

Combined with chemotherapy, this novel cell-based immunotherapy drastically increased the survival rates of mice afflicted with brain tumours. Almost 50% of the mice were completely cured. For the sake of comparison: none of the mice treated with chemotherapy alone became long-term survivors.

The major goal of any anticancer treatment is to kill all cancer cells and prevent any remaining malignant cells from growing or spreading again“, Professor Agostinis continues. “This goal, however, is rarely achieved with current chemotherapies, and many patients relapse. That’s why the co-stimulation of the immune system is so important for cancer treatments. Scientists have to look for ways to kill cancer cells in a manner that stimulates the immune system. With an eye on clinical studies, our findings offer a feasible way to improve the production of vaccines against brain tumours.”

Garg et al. Dendritic cell vaccines based on immunogenic cell death elicit danger signals and T cell–driven rejection of high-grade glioma. Science Translational Medicine, 2016;8:328ra27 DOI: 10.1126/scitranslmed.aae0105 [Abstract]

Study shows broccoli may offer protection against liver cancer

Consumption of broccoli has increased in the United States over the last few decades as scientists have reported that eating the vegetable three to five times per week can lower the risk of many types of cancer including breast, prostate, and colon cancers.

A new study from the University of Illinois reports that including broccoli in the diet may also protect against liver cancer, as well as aid in countering the development of fatty liver or nonalcoholic fatty liver disease (NAFLD) which can cause malfunction of the liver and lead to hepatocellular carcinoma (HCC), a liver cancer with a high mortality rate.

The normal story about broccoli and health is that it can protect against a number of different cancers. But nobody had looked at liver cancer,” says Elizabeth Jeffery, a U of I emeritus professor of nutrition. “We decided that liver cancer needed to be studied particularly because of the obesity epidemic in the U.S. It is already in the literature that obesity enhances the risk for liver cancer and this is particularly true for men. They have almost a 5-fold greater risk for liver cancer if they are obese.”

Jeffery says that the majority of the U.S. population eats a diet high in saturated fats and added sugars. However, both of these are stored in the liver and can be converted to body fat. Consuming a high-fat, high-sugar diet and having excess body fat is linked with the development of NAFLD, which can lead to diseases such as cirrhosis and liver cancer.

Previous research suggests that broccoli, a brassica vegetable containing bioactive compounds, may impede the accumulation of fat in the liver and protect against NAFLD in mice. Therefore, Jeffery and her team wanted to find out the impact of feeding broccoli to mice with a known liver cancer-causing carcinogen. The researchers studied four groups of mice; some of which were on a control diet or the Westernized diet, and some were given or not given broccoli.

We wanted to look at this liver carcinogen in mice that were either obese or not obese,” Jeffery explains. “We did not do it using a genetic strain of obese mice, but mice that became obese the way that people do, by eating a high-fat, high-sugar diet.

Although the researchers were predominantly interested in broccoli’s impact on the formation and progression of cancerous tumors in the liver, Jeffery explained that they also wanted to observe the health of the liver and how the liver was metabolizing lipids because of the high-fat diet. “There is almost no information about broccoli and high-fat associated diseases,” she says.

The study shows that in mice on the Westernized diet both the number of cancer nodules and the size of the cancer nodules increased in the liver. But when broccoli was added to the diet, the number of nodules decreased. Size was not affected.

That was what we really set out to show,” Jeffery says. “But on top of that we were looking at the liver health. There are actually two ways of getting fatty liver; one, by eating a high-fat, high-sugar diet and the other by drinking too much alcohol. In this case, it is called non-alcoholic fatty liver, because we didn’t use the alcohol. And it is something that is becoming prevalent among Americans. This disease means you are no longer controlling the amount of fat that is accumulating in your liver.”

With NAFLD, lipid globules form on the liver. During the study, the researchers observed these globules in the livers of the mice on the Westernized diet. “We found that the Westernized diet did increase fatty liver, but we saw that the broccoli protected against it. Broccoli stopped too much uptake of fat into the liver by decreasing the uptake and increasing the output of lipid from the liver,” she says.

Jeffery notes that adding broccoli to the diet of the mice did not make them “thin,” or affect their body weight, but it did bring the liver under control, ultimately making them healthier. “This is one of the things that makes this very exciting for us,” she says. “I think it’s very difficult, particularly given the choices in fast food restaurants, for everybody to eat a lower-fat diet. But more and more now you can get broccoli almost everywhere you go. Most restaurants will offer broccoli, and it’s really a good idea to have it with your meal,” Jeffery adds.

Jeffery’s previous research shows that eating broccoli freshly chopped or lightly steamed is the best way to get to the vegetables’ cancer-fighting compound, sulforaphane. Although the researchers only used broccoli in the study, Jeffery adds that other brassica vegetables, such as cauliflower or Brussel sprouts, may have the same effect.

Chen et al. Dietary Broccoli Lessens Development of Fatty Liver and Liver Cancer in Mice Given Diethylnitrosamine and Fed a Western or Control Diet. J. Nutr. 2016;146:542-550 doi: 10.3945/​jn.115.228148 [Abstract]