By probing what happens to cells in acid regions of tumors, scientists have uncovered new information about cancer’s invasiveness and spread. The discovery could lead to better treatments for aggressive tumors.
Researchers at the Massachusetts Institute of Technology (MIT) in Cambridge found that acidic, or low-pH, tumor regions alter gene expression in cancer cells in ways that make them more aggressive.
In a paper that appears in the journal Cancer Research, they describe how, by reducing tumor acidity, they were able to reverse the process in mice.
“Tumor acidosis,” says first study author Nazanin Rohani Ph.D., who was a postdoctoral researcher in the Koch Institute for Integrative Cancer Research at MIT when she completed the work, “gives rise to the expression of molecules involved in cell invasion and migration.
“This reprogramming, which is an intracellular response to a drop in extracellular pH, gives the cancer cells the ability to survive under low-pH conditions and proliferate.”
Metastasis is the complex process through which cancer cells become mobile, detach themselves from primary tumors, invade nearby tissue, migrate, and then set up secondary tumors in other parts of the body.
Around 9 in 10 of all deaths to cancer “are related to metastasis.” Without metastasis, cancer would be a much more manageable and less severe disease.
There was a time when scientists believed that the potential for tumors to metastasize depended only on alterations to cancerous cells.
Since then, however, researchers have learned that the “malignant progression of cancer” also depends on cancerous cells participating in an “intricate network of interactions” with other parts of the tissue that surrounds them, or the tumor microenvironment.
There is now a good understanding among scientists that tumors are not simply collections of multiplying cancerous cells, but “living entities,” comprising many different types of cell. In fact, the complexity of tumor tissue “may even exceed” the complexity of healthy tissues.
The study that Dr. Rohani and her colleagues undertook adds to the growing body of knowledge about tumor microenvironments and their contribution to metastasis.
Previous research had already established that acidity in the tumor microenvironment had a powerful effect on cancer invasiveness. However, what was not clear was how acidity varied in a tumor, and how it might alter genes to make tumor cells more invasive.
Before the recent study, the prevailing view was that high acidity in tumors occurred mainly in oxygen-starved areas with a poor blood supply.
For their investigation, the MIT researchers used a “pH-probe” to map acidity in breast cancer tumors in mice.
When the pH-probe detects a cell in an acidic environment, it inserts a small protein molecule into the cell’s membrane. In this way, the researchers can tag and identify cells in acidic regions of the tumors.
To its surprise, the team found that acid regions were not only present in hypoxic, or oxygen-starved, pockets inside tumors. The surfaces of tumors — where they connect to the stroma, or “structural tissue” that surrounds them — also contained acidic regions.
This discovery suggested that oxygen-starvation was not the main reason for acidity in tumors. On closer investigation, the scientists found a different cause of microenvironment acidity at the tumor surface.
It appeared that the metabolism of many of the cells on the surface of the breast tumors had changed to aerobic glycolysis. This type of metabolism produces lactic acid, which made the tumor microenvironment more acidic.
In these acidic tumor surface regions, the cells had altered their genes to switch on processes that favor invasion and metastasis.
The activated genes included one that is involved in embryo development and produces a protein that aids cell migration via the bloodstream. Another was one that makes tumor cells more able to penetrate their surrounding tissue.
In another set of experiments, the team found that reducing the acidity of the tumor microenvironment returned the gene expressions almost back to normal.
The researchers reduced tumor acidity in the mice by adding sodium bicarbonate to their drinking water. Other studies have also found that this reduces metastasis in mice.
Senior study author Frank B. Gertler, who is a professor of biology at MIT, says that humans do not tolerate sodium bicarbonate, and so it would not be a suitable potential treatment for them.
“Other methods that would more focally target acidification could be of great value.”
Prof. Frank B. Gertler