Highlights • REDD1 deletion enhances glucose uptake and glycolysis in hypoxic TAMs via mTOR • Enhanced glycolysis in REDD1 KO TAMs leads to glucose competition (GC) with tECs • GC by REDD1 KO TAMs stabilizes tumor EC junctions and vessels preventing metastasis • mTOR activation is antitumoral in hypoxic TAMs but protumoral in cancer cells
A team has demonstrated that then 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. On top of their positive effect on pathogens, macrophages can also play a negative role in cancer biology. Indeed, tumors contain a lot of specific macrophages that play a role in formation of blood vessels. In tumors, these vessels have a chaotic, dysfunctional buildup. As a result, cancer cells are more likely to escape through the vessels, enter the bloodstream and metastasize.
While properties of macrophages have already been studied extensively, it remained unknown whether changing their metabolism would impact their functions. The team of prof. Mazzone and Dr. Mathias Wenes 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.
Prof. Massimiliano Mazzone (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 hyper-activation 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.”
Prof. Mazzone joined forces with the lab of prof. Peter Carmeliet, specialized in the formation of blood vessels, and with Bart Ghesquière (VIB-KU Leuven), a leading metabolism expert. Together, they also investigated the consequences of mTOR inhibitors, existing cancer drugs aimed at reducing the growth of tumors.
Prof. Massimiliano Mazzone (VIB-KU Leuven): “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.”
http://www.vib.be/en/news/Pages/Scientists-reveal-link-between-cell-metabolism-and-the-spread-of-cancer.aspx
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