Whether a tumor flourishes or dies depends, to an extent, on the acidity of the environment in which it lives, and a certain enzyme plays a key role in that balance, according to new research from the University of Florida.
An enzyme known as carbonic anhydrase IX (“carbonic anhydrase nine”) influences tumor biology by working to keep acidity — or pH — at a level at which normal cells perish, but cancer cells thrive.
“We don’t know why cancer cells can tolerate low pH — but they do, and we believe that carbonic anhydrase is a significant player in picking the specific pH at which the cells are happiest,” said biochemist Susan Frost, Ph.D., of the UF Shands Cancer Center, who led the research team.
The enzyme may serve as a new and important target for visualizing, diagnosing and treating cancer. The findings are published in the Journal of Biological Chemistry.
Breast cancers are often characterized by oxygen-deprived regions that clinicians generally use as an indicator of poor prognosis in patients. Such oxygen-deprived — or hypoxic — regions occur when new blood vessels that form to feed a tumor become compressed, cutting off circulation and the supply of oxygen and nutrients. Lack of oxygen leads to metabolic processes that make the cells’ external environment more acidic. Those conditions favor cancer cell survival and resistance to chemotherapy agents.
The enzyme carbonic anhydrase IX is expressed in connection with these oxygen-deprived areas.
In a study of breast cancer cells, the researchers used a novel technique to track how oxygen is exchanged between carbon dioxide and water molecules via a chemical process spurred by the enzyme. That allowed measurement of the enzyme’s activity both inside and outside the cell.
The researchers were able to show, for the first time, a direct link between an increase in both the production and the activity of the enzyme and oxygen deprivation in tumor cell environments. Other researchers previously showed indirect connections between the processes, using pH decrease as a marker for carbonic anhydrase expression. Further, the UF scientists showed directly that the lowering of pH occurred as the activity of the enzyme increased.
“This is clearly a very important result confirming what we already suspected,” said Claudiu Supuran, Ph.D., a chemist who pioneered work on carbonic anhydrase as an antitumor target, and published his findings in the journal Nature Reviews. “This is confirmation that carbonic anhydrase is a very important future target for anticancer drugs.” Supuran was not involved in the current study.
Blocking the enzyme activity could help kill cancer cells by upsetting the pH balance. In addition, it could aid the effectiveness of chemotherapy agents, since many of those drugs depend on the pH gradient across cell membranes, which, if thrown off-balance, hinders proper uptake of the drug by cells.
“It would be a double punch — through inhibition of carbonic anhydrase you can perturb the pH environment, which will be deleterious to the cell, but also you can affect in a positive way how other anticancer drugs interact with cancer cells,” said study co-author David N. Silverman, Ph.D. “My prediction is that this work will have a very strong influence on the way people look at the survival of cancer cells.”
The UF team, including Chingkuang Tu, Ph.D., has already synthesized chemicals that can inhibit the enzyme carbonic anhydrase. They fitted those potential therapeutic compounds with a chemical structure that prevents it from getting inside cells, thus making sure that it targets only the enzyme that works on the outside of the cell to alter acidity levels. Supuran and other researchers were the first to show, through animal studies, that this approach greatly diminished tumor size and metastasis.
The good thing about this anti-enzyme agent is that even when oxygen is re-introduced into the oxygen-deprived environment, it still targets the enzyme, and is therefore a flexible and potentially valuable therapeutic tool.
The researchers envision the nontoxic chemicals could be delivered intravenously, as are other chemotherapy agents, to alter the microenvironment to prevent or reverse tumor growth. They have embarked on a collaboration with colleagues at Moffitt Cancer Center to develop just such a strategy.