Researchers at VIB (Flanders Institute for Biotechnology) and KU Leuven say they have discovered a crucial factor in the spread of cancer. A team led by Massimiliano Mazzone, Ph.D., has demonstrated that the metabolism of macrophages can be attuned to prevent the spread of cancer. The key is in making these macrophages more prone to “steal” sugar from the cells forming the tumor's blood vessels. As a result, these blood vessels will be structured more tightly, which can prevent cancer cells from spreading to other organs.
The study (“Macrophage Metabolism Controls Tumor Blood Vessel Morphogenesis and Metastasis”) appears in Cell Metabolism.
Macrophages attack foreign microorganisms and remove harmful substances within the body. As a result, they are an essential part of our immune system. On top of their positive effect on pathogens, macrophages can also play a negative role in cancer biology. Indeed, tumors contain many specific macrophages that play a decisive role in the formation of blood vessels. In tumors, these blood vessels traditionally have a chaotic and dysfunctional buildup. As a result, cancer cells are more likely to escape through the vessels, enter the bloodstream, and invade other organs.
The properties of macrophages have already been studied extensively, but it remained unknown whether changing their metabolism would impact their functions. The team investigated this by blocking a specific gene called REDD1 in the macrophages. This stimulated the cells' glycolysis, the process by which they convert sugar into energy.
According to Prof. Mazzone, from VIB-KU Leuven, “the supply of glucose to a tumor has a negative effect, comparable to giving too much sugar to a child: it causes hyperactivation of many cellular compartments. More specifically, the cells that are forming the blood vessels are getting out of control by this glucose overload. They quickly give shape to a chaotic, irregular vessel network typical to cancer.”
“By changing the macrophages' metabolism, we actually set up a 'glucose competition' between the macrophages and the tumor's blood vessels. As a result, the macrophages can eat the glucose instead of the blood vessel cells. Because the latter are not overstimulated anymore, they are able to create vessels in a gentler way. This forms a structured and strong vessel barrier around the tumor, preventing cancer cells to escape to the bloodstream and invade distant organs.”
Because of research's many aspects, Prof. Mazzone joined forces with the lab of Prof. Peter Carmeliet (VIB-KU Leuven), who specializes in the formation of blood vessels, and with Bart Ghesquière (VIB-KU Leuven), a leading metabolism expert.
Prof. Mazzone's team also investigated the consequences of mechanistic target of rapamycin (mTOR) inhibitors, existing cancer drugs aimed at reducing the growth of tumors.
“These mTOR inhibitors are only partially effective in patients. In mice, we found that these drugs can sometimes increase the spread of cancer because they hinder glycolysis in macrophages. That is why we are currently examining whether we could use our findings to predict people's resistance to mTOR inhibitors,” he said.
