Oxidative stress is a phenomenon that occurs at a cellular level, and which can drive previously healthy cells to deteriorate and eventually die. Cancer often uses oxidative stress to its own benefit, but could this phenomenon be turned against it?
Reactive oxygen species (ROS) are substances that are produced naturally following the process of oxygen metabolism.
They usually play an important role in regulating biological functioning (homeostasis), as well as in cell signaling.
But when ROS reach abnormal levels, this can produce oxidative stress, a phenomenon that leads to cellular aging and deterioration.
Recently, researchers from the Georgia Cancer Center in Augusta and the Department of Medicine at the Medical College of Georgia at Augusta University decided to test an intriguing strategy in cancer therapy: increasing ROS production to a point where it would cause cancer cell death.
The research has now been published in the journal Cell Metabolism.
When ROS become fatal to cancer
Dr. Gang Zhou and colleagues used a type of therapy called adoptive T cell therapy to lead to an increase of ROS in cancer tumors, pushing the overloaded cells to self-destruct.
Adoptive T cell therapy is a type of immunotherapy in which specialized immune cells, or T cells, are used to target and destroy cancer tumors.
In the new study, the scientists worked with a mouse model of colorectal cancer. After giving the mice a type of chemotherapy that is known to support the action of the T cells, the animals were exposed to the immunotherapy.
After delivering this treatment, the team saw that the production of glutathione — a natural antioxidant produced at cell level, which helps to counterbalance ROS — was disrupted. Consequently, ROS overaccumulated and reached too high levels in cancer cells.
The T cells also stimulated the production of a series of specialized proteins known as cytokines with a proinflammatory effect. These cytokines included tumor necrosis factor alpha, which is known to play a role in cell death as well as in tumor progression.
"We started," notes Dr. Zhou, "by asking questions about how immunotherapy can change the metabolism of tumor cells."
"Our studies show," the researcher adds, "tumor necrosis factor alpha can act directly on tumor cells and induce ROS inside them."
Thanks to the metabolic changes induced by adoptive T cell therapy, the scientists witnessed complete tumor regression in almost all of the mice that received this treatment.
A promising approach
Also, the researchers noticed that an increased production of tumor necrosis factor alpha — due to immunotherapy — in conjunction with chemotherapy increased oxidative stress even more, destroying cancer cells.
Another finding was that administering pro-oxidants afforded similar effects to the adoptive T cell therapy, since these drugs also increased ROS levels.
"Their baseline is already high and if you further disrupt their ability to deal with these free radicals [the ROS], they will go toward apoptosis [cell death]," says Dr. Zhou.
While excessive ROS — leading to oxidative stress — seemed crucial to destroying the cancer cells, the researchers note that it is, nonetheless, possible that cancer cell death might occur because of tumor necrosis factor alpha's action, as this cytokine is known to cut off tumors' blood supply, thus stunting their growth.
Researchers have noted that cancer cells and T cells might compete for energy resources, so they have a detrimental effect on one another. And often, T cells end up starved of the nutrients they require, leaving cancer cells at an advantage, they explain.
And, Dr. Zhou and team claim, not enough is yet known about how T cells impact cancer tumors. Adoptive T cell therapy is, in itself, a new kind of approach that is still being developed for the treatment of certain types of cancer, such as colorectal cancer.
So, the authors suggest, more effort should be focused on better understanding the action of T cells and improving immunotherapy's potential in destroying cancer.