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Locking a biochemical gateway letting fuel into immunosuppressive cells could slow the progression of the tumor and help treat multiple cancers, says a new study from the Wistar Institute, the University of Nebraska-Lincoln and others.
Posted on April 17 in Review Nature, the study found high levels of fatty acid transport protein 2, or FATP2, in a cell type known to attenuate immune responses and hinder cancer treatments. After isolating tumor cells in humans and mice, the researchers also discovered a significantly higher number of energy-giving lipids that FATP2 helps to produce and introduce into cells.
Collectively, the results of the study involve FATP2 in the malicious rewiring of the body's white blood cells, which would otherwise act as first responders in the fight against infections.
When the researchers destroyed a gene linked to FATP2, they found that tumors of several cancers – lymphoma, lung carcinoma, colon carcinoma and pancreatic cancer – developed significantly more slowly in mice. The administration of the FATP2 inhibitor compound, Lipofermata – identified by Concetta DiRusso in Nebraska in the mid-2000s – also slows down and even rejects tumors when it was badociated with a drug that disrupts replication cellular.
The study suggests that targeting FATP2 in immunosuppressive cells could block the resulting accumulation of lipids and attenuate tumor progression without significant side effects, the team said.
"I think that what's unique, and why it will spark some excitement, is that it's not specific to cancer," said DiRusso, co-author of the study and professor of biochemistry at George Holmes University. "Being able to target some of the cells common to different cancers is something that is highly desired.
"Tumors do not disappear totally, but it's a part of the picture." We are now more interested in combination therapy.This is not a target but rather a target in many ways because cancer is smart, a way to get around our best medicines, that's why these drug combinations are so powerful and, we expect, more effective. "
Dmitry Gabrilovich of the Wistar Institute and her colleagues first noticed an increase in FATP2 in solid tumors several years ago. Their observation prompted Gabrilovich to contact Nebraska biochemist Paul Black, who has studied the fundamentals of how fat molecules cross cell membranes.
Black Lab's early research on yeast has identified a gene segment and badociated protein that activate and transport fatty acids into cells, where they are metabolized into energy or integrated into membranes. This protein? FATP2.
"If you have a portal sitting on the membrane that controls the amount of fat that comes in, and you start messing around with this portal, it's going to impact downstream things," said Black, Professor Charles Bessey and President. biochemistry board. "And if a cancer cell needs a lipid diet to be able to undergo metastasis and become a real disease, it has to up-regulate that protein, so this gate plays a vital role in all these metabolic systems."
Black's previous research had also determined the existence of two genetic variants of FATP2: one to prime fatty acid metabolism, the other to actually transport it across cell membranes. This important distinction has inspired the efforts of the DiRusso laboratory, which has examined more than 100,000 anti-FATP2 compound candidates, which could help fight obesity and type 2 diabetes.
Lipofermata, blue ribbon candidate, essentially eliminates fat accumulation in tissue cultures and reduces by more than 60% the lipid absorption in mice, which has led DiRusso to patent its use in the treatment of metabolic diseases. Thus, when Gabrilovich contacts Black, he quickly contacts DiRusso. The duo finally provided Gabrilovich with the biochemical knowledge, samples and Lipofermata needed to carry out his team's experiments.
"Whether it's cancer biology, diabetes or whatever you want in this biomedical world, you can not do it yourself anymore," said Black. "The time is past when we can just sit down and make a small silo somewhere to do our own things, some of our early mechanistic work was done that way, but the work (now) is far too complicated. d & # 39; information.
"We do not yet know the whole story, but the data that reaches us will really move these things forward very, very quickly."
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Researchers from the Wistar Institute and Nebraska wrote the Nature study with colleagues at the University of Pittsburgh, Duke University School of Medicine, the University of Pennsylvania School of Medicine, the Helen F. Graham Cancer Center, and the Medical University of Moscow.
The team received support from the National Institutes of Health for grants CA R01CA165065 and AI110485.
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