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 and tumor environment
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.
Mapping tumor acidity
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
cancertumors 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.
Reducing tumor acidity
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."
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