When medical professionals are targeting a patient’s cancer, the goal is first to eliminate the cancer and if that isn't possible get the cancer to stop growing. The spread of cancer cells from one area of the body to another, a process called metastasis, is what increases the risk of death in cancer patients. While each form of cancer is different in how it spreads and each patient is different, researchers around the globe are furiously trying to figure out what causes some cancers to grow out of control, and what, if anything, can shut down that growth.
One of the factors in the growth of cancer is a bit of a double-edged sword. The amino acid glutamine is is somewhat of a conundrum. Having adequate amounts of it is beneficial to nitrogen balance, the gut microbiome and our immune system. It’s a positive in many ways for staying healthy. Conversely, it’s also known that cancer cells live for glutamine. It’s known to be a strong catalyst in the grown of tumors. Bascially, there is no part of cancer growth and metabolism that isn’t spurred on by glutamine. It provides fuel in the form of nitrogen so cancer cells can replicate. It enhances protein and nucleotide synthesis and it can thwart the body’s own immune defense systems, resulting in a target rich environment in which cancer can flourish.
So, the simple answer would seem to find a way to starve the cancer cells of glutamine and stop their growth. As it turns out, that isn’t so simple. Researchers at the Centenary Institute in Sydney Australia have been working on the problem and may have a breakthrough on the way. Professor Jeff Holst is stated recently that his lab has made some significant strides in finding a way to mediate the glutamine factor in cancer metastasis. He explained, “We have known for 100 years that cancer cells take up nutrients and use them differently to normal cells but we haven’t been able to target that. Cancer cells have found ways to use glutamine to fuel their growth and they become addicted to it, they are so dependent on it, that if you take it away from the cells they die” In the course of this research, they have found new drugs that could potentially shut down the glutamine fueling of tumors, and leave healthy cells intact.
Holst, who is the Head of the Origins of Cancer Program at the Institute collaborated with colleagues at Sydney University and discovered an important role for a protein involved in the metabolism of certain cancer cells that is crucial for spurring the grown of cancer cells. In a press release about the a new drug that his team is working on Holst stated, “If we are able to specifically block the supply of nutrients to cancer cells by inhibiting the function of this protein, we can essentially ‘starve’ the cells and stop them from growing.” The team has also
been able to identify molecules that can stop this protein in its tracks and this information is now being developed to create new drugs.
The Institute and the researchers at the University of Sydney will be working with a privately held biotechnology company called MetabloQ Pty Ltd which is focused on translating the results of Associate Professor Holst’s research into drugs for testing in clinical trials. The video below talks more about the important work being done on the cancer-glutamine connection, check it out.
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Cancer cells usually live in an environment with limited supplies of the nutrients they need to proliferate — most notably, oxygen and glucose. However, they are still able to divide uncontrollably, producing new cancer cells.
A new study from researchers at MIT and the Massachusetts General Hospital (MGH) Cancer Center helps to explain how this is possible. The researchers found that when deprived of oxygen, cancer cells (and many other mammalian cells) can engage an alternate metabolic pathway that allows them to use glutamine, a plentiful amino acid, as the starting material for synthesizing fatty molecules known as lipids. These lipids are essential components of many cell structures, including cell membranes.
The finding, reported in the Nov. 20 online edition of Nature, challenges the long-held belief that cells synthesize most of their lipids from glucose, and raises the possibility of developing drugs that starve tumor cells by cutting off this alternate pathway.
Lead author of the paper is Christian Metallo, a former postdoc in the lab of Gregory Stephanopoulos, the William Henry Dow Professor of Chemical Engineering and Biotechnology at MIT and a corresponding author of the paper. Othon Iliopoulos, an assistant professor of medicine at Harvard Medical School and MGH, is the paper’s other corresponding author.
Much of the body’s supply of oxygen and glucose is carried in the bloodstream, but blood vessels often do not penetrate far into the body of tumors, so most cancer cells are deficient in those nutrients. This means they can’t produce fatty acids using the normal lipid-synthesis pathway that depends mostly on glucose.
In prior work, Stephanopoulos’ lab identified a metabolic pathway that uses glutamine instead of glucose to produce lipids; the new paper shows that this alternate pathway is much more commonly used than originally thought. The researchers found that in both normal and cancerous cells, lack of oxygen — a state known as hypoxia — provokes a switch to the alternate pathway.
In a normal oxygen environment, 80 percent of a cell’s new lipids come from glucose, and 20 percent from glutamine. That ratio is reversed in a hypoxic environment, Stephanopoulos says.
“We saw, for the first time, cancer cells using substrates other than glucose to produce lipids, which they need very much for their rapid growth,” Iliopoulos explains. “This is the first step to answering the question of how new cell mass is synthesized during hypoxia, which is a hallmark of human malignancies.”
The glutamine may come from within the cell or from neighboring cells, or the extracellular fluid that surrounds cells.
“There’s protein everywhere,” says Matthew Vander Heiden, the Howard S. and Linda B. Stern Career Development Assistant Professor of Biology at MIT and a co-author of the Nature paper. “The new pathway allows cells to conserve what glucose they do have, perhaps to make RNA and DNA, and then co-opt the new pathway to make lipids so they can grow under low oxygen.”
The switch from glucose to glutamine is triggered by low oxygen and allows cancer cells to thrive and proliferate in an environment with minimal glucose, though it is not clear how this is done. “Elucidating the molecular mechanism regulating this switch would be important in understanding regulation of cancer metabolism,” Stephanopoulos says. “This could be important not only for cancer cells but also other cells growing in hypoxic environments, such as stem cells, placenta and during embryonic development.”
New insights into old models
The researchers are now looking into what other unexpected sources might be diverted into lipid-synthesis pathways under low oxygen. “We had to revise models of metabolism that had been established over the past 50 years. This opens up the possibility for more exciting discoveries in this field that may impact strategies of therapy,” Metallo says.
A better understanding of metabolic pathways and their regulation raises the possibility of developing new drugs that could selectively disrupt key metabolic pathways for cancer cell survival and growth. One possible target is the enzyme isocitrate dehydrogenase, which performs a critical step in the transformation of glutamine to acetyl CoA, a lipid precursor.
“While this target is not new, our findings point to a new function and, hence, generate new ideas for drug development,” Iliopoulos says. “The better we understand the molecular basis of these phenomena, the more optimistic we can be about efforts to translate these basic results into effective treatments of cancer.”
“We’ve been looking, as a field, for almost 90 years for a metabolic pathway that could truly be used to differentiate malignant tumors from normal tissues,” says Ralph DeBerardinis, an assistant professor of pediatrics and genetics at the University of Texas Southwestern Medical Center, who was not involved in this research. He adds that more study is needed, but “if this could be exploited, that could have significant therapeutic potential.”