The fluid that feeds the tumor cells.



The fluid that feeds the tumor cells.

Pancreatic cancer cells (nuclei in blue) that grow like a sphere enclosed in membranes (red). By cultivating cancer cells in the laboratory, researchers can study the factors that promote and prevent the formation of deadly tumors. Credit: Min Yu (Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research at USC)

Before being tested on animals or humans, most anti-cancer drugs are evaluated on tumor cells grown in a laboratory dish. However, in recent years, he has realized that the environment in which these cells grow does not accurately mimic the natural environment of a tumor, and that this discrepancy could produce inaccurate results.

In a new study, MIT biologists badyzed the composition of the interstitial fluid that normally surrounds pancreatic tumors and found that their nutrient composition is different from that of the culture medium that is normally used to grow cancer cells. It also differs from blood, which feeds the interstitial fluid and eliminates waste products.

The findings suggest that the growth of cancer cells in a culture medium more similar to this fluid could help researchers better predict how experimental drugs will affect cancer cells, says Matthew Vander Heiden, an badociate professor of biology at MIT. member of the Koch Institute for Cancer Research Integration.

"It's a kind of obvious statement that the tumor environment is important, but I think that in cancer research the pendulum had tilted so much towards genes, people tended to forget it," says Vander Heiden, one of the lead authors. of the study.

Alex Muir, a former postdoctoral fellow at the Koch Institute who is now an badistant professor at the University of Chicago, is also the lead author of the article, which appears in the April 16 issue of the magazine. eLife. The lead author of the study is Mark Sullivan, a graduate student at MIT.

The environment matters

Scientists have known for a long time that cancer cells metabolize nutrients differently than most other cells. This alternative strategy helps them generate the basic components they need to keep growing and dividing, forming new cancer cells. In recent years, scientists have tried to develop drugs that interfere with these metabolic processes, and one of those drugs was 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 laboratory dish. The growth medium that is normally used to grow these cells includes carbon sources (such as glucose), nitrogen and other nutrients. However, in recent years, Vander Heiden's laboratory discovered that cancer cells that grow in this medium respond to drugs differently than cancer models in mice.

David Sabatini, a member of the Whitehead Institute and a professor of biology at MIT, also discovered that drugs affect cancer cells differently if they are grown in a medium that resembles the nutrient composition of human plasma, rather than the environment. of traditional growth.

"That work, and similar results from a couple of other groups around the world, suggested that the environment is very important," says Vander Heiden. "It really was a wake-up call to know that, to really know how to find cancer dependencies, we have to achieve an adequate environment."

To that end, the MIT team decided to investigate the composition of the interstitial fluid, which bathes the tissue and transports the nutrients that diffuse from the blood that flows through 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 deprived of nutrients. After isolating the interstitial fluid from pancreatic tumors in mice, the researchers used mbad spectrometry to measure concentrations of more than 100 different nutrients and found that the composition of the interstitial fluid is different from that of the blood (and that of the culture medium normally). used to grow cells). Several of the nutrients that, according to the researchers, were depleted in the interstitial fluid of the tumor are the amino acids that are important for the function of immune cells, such as arginine, tryptophan and cystine.

Not all the 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 tumors that grow in the pancreas and lungs and found that the composition of the interstitial fluid can vary depending on the location of the tumors in the body and at the site where the tumor originated. They also found slight differences between the fluid that surrounds tumors that grew in the same place but had a different genetic makeup; however, the genetic factors tested did not have an impact as great as the location of the tumor.

"That probably says that what determines what nutrients are in the environment is strongly driven by the interactions between cancer cells and non-cancerous cells within the tumor," says Vander Heiden.

Scientists have previously discovered that cancer cells can recruit those non-cancerous cells, including supporting stromal cells and immune cells, to help redo the environment around the tumor to promote the survival and spread of cancer.

Vander Heiden's laboratory and other research groups are now working on developing a culture medium that more closely mimics the interstitial fluid composition of the tumor, so they can explore whether the tumor cells growing in this environment could be used to generate more accurate predictions of how anticancer drugs will affect cells in the body.


A cerebrospinal fluid test to track tumor progression in some gliomas


Journal information:
eLife


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Mbadachusetts Institute of Technology


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