Cancer-in-a-dish models should be made as simple as possible, but not simpler—otherwise, they may fail to predict how real cancers will respond to newly developed drugs. So, to improve cancer-in-a-dish models, to help them capture the complexity of real tumors, scientists based at MIT have analyzed the interstitial fluid in which real tumors bathe. This fluid, the scientists discovered, is unlike the culture media that is used in cancer models. It is also unlike plasma. All these fluids differ with respect to nutrient availability.
“It’s kind of an obvious statement that the tumor environment is important, but I think in cancer research the pendulum had swung so far toward genes, people tended to forget that,” said Matthew Vander Heiden, MD, PhD, an associate professor of biology and one of the leaders of the MIT-based team.
Tumors are bathed by interstitial fluid, which carries nutrients that diffuse from blood flowing through the capillaries. The interstitial fluid’s composition is not identical to that of blood, and in tumors, it can be very different because tumors often have poor connections to the blood supply.
In the MIT-led study, researchers chose to focus on particularly nutrient-deprived tumors—pancreatic tumors. Such tumors, the researchers reasoned, could throw the tumor microenvironment and its metabolic consequences into sharper relief.
Details of the researcher’s work appeared April 16 in the journal eLife, in an article titled, “Quantification of microenvironmental metabolites in murine cancers reveals determinants of tumor nutrient availability.” The article describes how the researchers utilized quantitative metabolomics methods to measure the absolute concentrations of >118 metabolites in plasma and tumor interstitial fluid.
“Comparison of nutrient levels in tumor interstitial fluid and plasma revealed that the nutrients available to tumors differ from those present in circulation,” the article’s authors wrote. “Further, by comparing interstitial fluid nutrient levels between autochthonous and transplant models of murine pancreatic and lung adenocarcinoma, we found that tumor type, anatomical location, and animal diet affect local nutrient availability.”
After isolating interstitial fluid from pancreatic tumors in mice, the researchers used mass spectrometry to measure nutrient concentrations. Several of the nutrients that the researchers found to be depleted in tumor interstitial fluid are amino acids that are important for immune cell function, including arginine, tryptophan, and cystine. Not all nutrients were depleted in the interstitial fluid—some were more plentiful, including the amino acids glycine and glutamate, which are known to be produced by some cancer cells.
The researchers also compared tumors growing in the pancreas and the lungs and found that the composition of the interstitial fluid can vary based on tumors’ location in the body and at the site where the tumor originated. They also found slight differences between the fluid surrounding tumors that grew in the same location but had different genetic makeup; however, the genetic factors tested did not have as big an impact as the tumor location.
“That probably says that what determines what nutrients are in the environment is heavily driven by interactions between cancer cells and noncancer cells within the tumor,” suggested Vander Heidens.
Scientists have previously discovered that those noncancer cells, including supportive stromal cells and immune cells, can be recruited by cancer cells to help remake the environment around the tumor to promote cancer survival and spread.
Vander Heiden’s lab and other research groups are now working on developing a culture medium that would more closely mimic the composition of tumor interstitial fluid, so they can explore whether tumor cells grown in this environment could be used to generate more accurate predictions of how cancer drugs will affect cells in the body.