While cancer cells have been known to compete with each other for resources, it seems that they have also found a way to work together to gather nutrients. When exposed to amino acids, cells can compete to absorb them, but researchers found that when cancer cells were deprived of certain amino acids, like glutamine, they began to work cooperatively to find the necessary nutrients. The findings have been reported in Nature.
This work revealed certain cooperative interactions that cancer cells use which helps them grow, said senior study author Carlos Carmona-Fontaine, an associate professor of biology at New York University.
In this work, the researchers used microscopy and robotics to monitor cell growth as tumors formed. Millions of cells were tracked under various conditions, and different cell densities were observed along with variable nutrient levels. This showed that a lack of an amino acid would trigger a cooperative effort to acquire crucial nutrients.
"Surprisingly, we observed that limiting amino acids benefited larger cell populations, but not sparse ones, suggesting that this is a cooperative process that depends on population density," noted Carmona-Fontaine. "It became really clear that there was true cooperation among tumor cells."
The study also revealed that bits of proteins that are composed of short chains of amino acids known as oligopeptides act as an important nutrient source for cancer cells. But rather than take up these oligopeptides, tumor cells can release an enzyme called CNDP2 that breaks the oligopeptides down into individual amino acids, explained Carmona-Fontaine. This occurs outside of the cells, and contributes to a pool of amino acids that all of the cells can share.
The investigators also determined that a drug called bestatin can disrupt the function of CNDP2. When cancer cells were exposed to this drug, they could not use oligopeptides as a nutrient sources, and were killed.
The scientists also used the CRISPR gene editing technology to take out the gene that encodes for CNDP2 in tumor cells. In a mouse model, the tumors lacking CNDP2 did not grow as much as unaltered tumors. When the removal of CNDP2 from tumor cells was combined with an approach to lower certain amino acid levels with a specific diet, tumor growth was reduced further. The amino acid restriction alone also helped reduce tumor growth.
"Because we've removed their ability to secrete the enzyme and to use the oligopeptides in their environment, cells without CNDP2 can no longer cooperate, which prevents tumor growth," said Carmona-Fontaine. "Competition is still critical for tumor evolution and cancer progression, but our study suggests that cooperative interactions within tumors are also important."
While bestatin has only demonstrated a limited effectiveness by itself, the researchers are hopeful that these findings could help cancer patients.
"We hope that a clearer understanding of this mechanism can help us make drugs more targeted and more effective," said Carmona-Fontaine.
Sources: New York University, Nature