Oxygen-starved tumors have a hard time producing one key amino acid — and researchers hope further denying them this compound could help us fight cancer.
Image credits Laboratory of Metabolic Regulation and Genetics / The Rockefeller University.
Tumors are clumps of rogue cells that don’t do much beyond just growing and gobbling up resources. Still, these freeloaders eventually become deadly, as their rampant growth impact our bodies’ ability to function.
However, new research hopes to turn cancer’s prolific growth against it. As tumors grow and drain resources from the body, they place a strain on oxygen. When this happens, the tumors basically start to suffocate. A new paper published by researchers from the Laboratory of Metabolic Regulation and Genetics (LMRG) at The Rockefeller University suggests that denying tumors aspartate, a key amino acid whose synthesis hinges on oxygen, could help fight the disease.
The bottleneck
The team, led by Kivanç Birsoy, head of the LMRG, suggests that doctors could target oxygen-starved tumors with drugs that impede their ability to synthesize or absorb aspartate in a bid to kill these cells.
The research was built on previous findings that tumors tend to out-grow the host body’s ability to provide them with oxygen and when this happens, they grow more slowly. We didn’t know exactly why this happens, however, as oxygen is a key component in a plethora of cellular reactions — any one of them could have an impact on cells’ ability to grow.
In order to uncover the underlying process, the team mimicked oxygen deprivation in samples of cancer cells harvested from 28 patients. The cells included blood, stomach, breast, colon, and lung cancers — the most often-seen kinds — which were cultured in Petri dishes in the lab after harvesting.
Many of these cells couldn’t properly grow and develop in the low-oxygen-like conditions, the team reports. Others, however, were less sensitive; some didn’t seem to mind at all. So the team set out to compare their metabolites (the chemicals cells generate as part of their normal life cycle) to understand why.
Image credits D.Azani / Wikimedia.
The common denominator between all the cells that did struggle was a lack of aspartate, the researchers found. Aspartate is an amino acid involved in several key processes, from protein production to synthesis of genetic material. While none of the cells could produce aspartate without oxygen, some could get around it — for example, by sucking it up from their environment. Cells that managed even when deprived of oxygen did so by activating a gene called SLC1A3 that drew in aspartate.
Birsoy says he was surprised that so much of the woes these cells have when deprived of oxygen come down to a single compound. When starting out the study, the team expected to find a network of processes or end compounds that hinge on oxygen as the culprit.
To make sure they were on the right track, the team activated SLC1A3 in the cancers that were sensitive to low oxygen; they started growing faster. The modified cancer cells kept their perkiness when transplanted into mice models, further reinforcing the findings’ validity.
It’s excellent news, however — it’s much easy to deny cells a single compound than a range of compounds.
Armed with these findings, researchers can tailor drugs to hit cancer cells at their most vulnerable place — their need for aspartate, the team writes. Any way we can go about this, either by blocking synthesis or absorption from the host, should help. If later trials prove that the approach is effective in treating tumors in humans, anti-aspartate treatments could be used alongside chemotherapy and radiation treatments in fighting tumors.
Even better, tumors in oxygen-starved areas tend to be resistant to both chemotherapy and radiation treatment, the team notes — so the anti-aspartate treatment could help us fight a problematic type of tumors. Birsoy hopes his findings will lead to a two-pronged approach to cancer: one part of the treatment to deal with tumors that have oxygen aplenty, and the aspartate blocker to mop up the rest.
Still, such a combined treatment won’t be available anytime soon. For starters, we don’t even know what drugs we could employ to deny these cancer cells their aspartate. Birsoy says his team will focus on finding such compounds next.
The paper “Aspartate is a limiting metabolite for cancer cell proliferation under hypoxia and in tumours” has been published in the journal Nature Cell Biology.
