The fluid that feeds the tumor cells

Before being tested on animals or humans, most anti-cancer drugs are evaluated in tumor cells grown in a lab box. However, in recent years, it has become increasingly clear that the environment in which these cells are grown does not exactly reproduce the natural environment of a tumor and that this anomaly could produce inaccurate results.

In a new study, MIT biologists analyzed the composition of the interstitial fluid normally surrounding pancreatic tumors and found that its nutrient composition was different from that of the culture medium normally used for cancer cell growth. It also differs from blood, which supplies interstitial fluid and eliminates waste.

The results suggest that growth of cancer cells in a culture medium more similar to this fluid could help researchers better predict the impact of experimental drugs on cancer cells, says Matthew Vander Heiden, associate professor of biology at MIT and member of the Koch Institute for Integrative. Research against cancer.

"It is obvious that the environment of the tumor is important, but I think that in cancer research, the pendulum had up to here flipped to the genes, people tended to find it. "forget," says Vander Heiden, one of the leading authors of the study.

Alex Muir, a former post-doctoral fellow at the Koch Institute and currently an assistant professor at the University of Chicago, is also a senior author of the article that appears in the April 16 issue of the journal. eLife. The main author of the study is Mark Sullivan, a graduate student of MIT.

Environmental issues

Scientists have known for a long time that cancer cells metabolize nutrients differently than most other cells. This alternative strategy helps them generate the building blocks they need to continue to grow and divide, forming new cancer cells. In recent years, scientists have sought to develop drugs that interfere with these metabolic processes. One of these drugs has been approved to treat leukemia in 2017.

An important step in the development of such drugs is to test them on cancer cells grown in a lab box. The growth medium typically used for growth of these cells includes carbon sources (such as glucose), nitrogen, and other nutrients. However, in recent years, Vander Heiden's lab has found that cancer cells grown in this medium respond differently to drugs than wall cancer models.

David Sabatini, a member of the Whitehead Institute and a professor of biology at MIT, also discovered that drugs work differently on cancer cells if they are grown in a medium that resembles the nutritional composition of human plasma, instead of the traditional growth medium. .

"This work, and similar findings from two other groups around the world, suggest that the environment matters a lot," said Vander Heiden. "It was really an awakening for us that to really know how to find the cancer addictions, we have to protect the environment."

To this end, the MIT team decided to study the composition of the interstitial fluid, which bathes the tissue and transports the nutrients that diffuse from the circulating blood into the capillaries. Its composition is not identical to that of blood and, in tumors, it can be very different because tumors often have poor connections with the blood supply.

The researchers chose to focus on pancreatic cancer in part because it is known to be particularly devoid of nutrients. After isolating the interstitial fluid from pancreatic tumors in mice, the researchers used mass spectrometry to measure concentrations of more than 100 different nutrients, and found that the composition of the interstitial fluid was different from that of blood (and that of the culture medium normally). used to grow cells). Many of the nutrients that researchers have found depleted in the interstitial fluid of the tumor are amino acids that play an important role in the function of immune cells, including arginine, tryptophan, and cystine.

Not all nutrients were depleted in the interstitial fluid – some were more abundant, including the amino acids glycine and glutamate, which are known to be produced by some cancer cells.

Location, location, location

The researchers also compared developing tumors in the pancreas and lungs and found that the composition of interstitial fluid could vary depending on the location of the tumor in the body and the site of origin of the tumor. They also found slight differences between the fluid surrounding the tumors that grew in the same place but had a different genetic makeup; However, the genetic factors tested did not have an impact as important as the location of the tumor.

"This probably indicates that the interactions between cancer cells and non-cancer cells within the tumor largely determine the nutrients present in the environment," says Vander Heiden.

Scientists have already discovered that these non-cancerous cells, including support stromal cells and immune cells, can be recruited by cancer cells to replenish the environment around the tumor to promote survival and spread cancer.

Vander Heiden's lab and other research groups are currently working on developing a culture medium that would more closely mimic the interstitial fluid composition of the tumor, in order to explore whether tumor cells developed in this environment could be used to generate more accurate predictions of how anticancer drugs will affect the body's cells.

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