Publications
- Cancer is often detected at an advanced stage, making successful treatment very challenging.
- Treatment options are, however, increasing with advances in cancer research, increasing survival.
- Focusing on the role of the mitochondria aims to improve cancer treatment for many patients.
Cancer remains one of the most feared diseases across the globe. According to the World Health Organization (WHO), approximately 19 million new cancer cases and 10 million cancer-related deaths were reported worldwide in 2020. Cancer cases are also expected to increase due to population growth and increasing lifespan.
Cancer is a significant dilemma in low-to middle-income countries, such as South Africa, due to a lack of awareness and screening programmes. Consequently, it is often detected at an advanced stage, making successful treatment very challenging.
As we observe World Cancer Day on 4 February, it’s good to know that treatment options are increasing with advances in cancer research. Surgery, radiation, chemotherapy, immunotherapy, targeted therapy, and hormone therapy can significantly improve survival.
However, many therapies face the same problem in advanced cancers: the adaptation of cancer cells to become resistant to treatment. If cancer cells are advanced enough to resist treatment, there is a high risk that the tumour will come back more strongly when treated, making further treatment far more difficult.
Powerhouses of the cells: mitochondria’s role in treatment resistance
It has recently been discovered that the mitochondria of cancer cells are major role players in treatment resistance. Anyone with high school biology has probably heard the following: "The mitochondria are the powerhouse of the cell."
Scientists have since discovered that mitochondria are involved in so much more than energy generation for the cell. These organelles also regulate important cell fate decisions such as cell signalling, cell death, energy regulation, cell growth, and cancer treatment resistance.
Mitochondria are tiny organelles present in all body cells (except for a few cells such as red blood cells). They convert metabolites from the food we consume to a molecule known as ATP (adenosine triphosphate), which is the energy currency of our cells. Scientists suspect that mitochondria were once free-living bacterial organisms that were very efficient at producing energy (ATP) through a process known as aerobic respiration – the process by which cells use oxygen to make energy from sugars/carbohydrates.
It is thought that, during evolution, mitochondria were engulfed by larger cells and became part of the cells. This is known as the endosymbiotic theory. The process of engulfing is believed to be mutually beneficial as mitochondria benefit by safely hiding inside bigger cells. The cells, in turn, make use of the mitochondria for more efficient energy production.
German biochemist Otto Warburg, a Nobel Laureate in the 1930s, first discovered that cancer cells use their mitochondria differently compared to normal healthy cells. We know that our cells get energy from glucose, and the mitochondria are the powerhouse that drives this process.
Warburg showed us that cancer cells use a different energetic process called aerobic glycolysis (the process where glucose is broken down to produce energy, even in the presence of oxygen) rather than oxidative phosphorylation (a mitochondrial metabolic pathway by which enzymes break down nutrients to produce energy ). Scientists initially thought the mitochondria in cancer cells were defective, or "broken", but we now know they are actually perfectly functional and specifically reprogrammed to help cancer cells survive and resist treatment.
Reprogramming mitochondria: DNA mutations and treatment resistance
DNA is the information stored in our cells that tells the cells to make all the molecules they need to function. Inside the mitochondria there are molecules called enzymes that are constantly converting nutrients, or metabolites from one form to another and regulating the speed at which these conversions are happening. The end goal of these conversions is the production of energy (ATP).
If any of these enzymes are disrupted, and work faster or slower than they should, all sorts of downstream processes are interrupted, and molecules called metabolites start accumulating where they shouldn’t. These accumulations and imbalances can make cancer cells resistant to treatment. Because we know this, we can target these disruptions as a point of hope for medical intervention.
There are common DNA mutations in cancer cells that disrupt the proper functioning of certain mitochondrial enzymes. Consequently, nutrients are not converted from one form to another, and we often end up with too much fumarate or 2-hydroxyglutarate (2-HG) in the cancer cells.
The accumulation of these two molecules can help the cancer cells to survive and resist therapy. With too much fumarate, the cells can resist treatment by detoxifying themselves from cancer drugs. Furthermore, 2-HG can inactivate our immune cells, which naturally fight the cancer cells, making immune therapy (therapies designed to "train" our immune cells to recognise cancer cells) more challenging. In both cases, essentially, the cancer cells have hijacked our DNA to fight back against the treatment therapies as shown in Figure 1.
Healthy mitochondria are critical for the cell's overall health. This is why many cancer therapies damage the mitochondria to kill the cancer cells. Interestingly, recent evidence shows that cancer cells can even navigate this kind of treatment by forming links with normal healthy cells.
The healthy cell then transfers its mitochondria through these links and donates it to the cancer cells to help them survive and resist treatment, as illustrated in Figure 1.
Figure 1: DNA mutations in cancer cells can disrupt the functioning of mitochondrial enzymes that usually assist with critical chemical reactions in the mitochondria. Subsequently, too much fumarate and 2-HG are produced.
These two chemicals help cancer cells resist treatment by detoxifying themselves from cancer therapy or suppressing the immune system. Additionally, cancer cells can steal mitochondria from healthy cells to replace damaged mitochondria and maintain cell health.
Targeting mitochondria for cancer treatment
In a nutshell, scientists found that: 1) the mitochondria of cancer cells function slightly differently compared to normal healthy cells, 2) these mitochondrial differences help cancer cells to survive and resist treatment, and 3) if therapy damages cancer cells’ mitochondria, the cancer cells can "steal" the mitochondria from healthy cells to survive.
Although these findings sound dire and pessimistic, they are actually very important puzzle pieces that will help us to treat cancer more efficiently in the future. For example, if we know that an individual has a mutation that results in the overproduction of fumarate and enhanced detoxification processes, we can inhibit the detoxification pathway to improve treatment outcomes.
Likewise, if an individual has a mutation that results in too much 2-HG, and decreased immune system activation, we can target that specific mutation to enhance the outcome of immunotherapy. We can even learn from the cancer cells that are stealing healthy cells’ mitochondria, by inhibiting the formation of the links that can transfer mitochondria from healthy cells to cancer cells, thus preventing drug resistance in cancer cells.
This type of approach that understands the unique, ongoing adaptive response of cancer cells in each individual is referred to as personalised medicine. It harnesses specific information about each person's individual cancer to help make a diagnosis and choose a treatment. Personalised medicine is expected to grow in the future and further improve treatment outcomes.
Ongoing research and clinical trials exploring personalised medicine are critical to keeping our treatment strategies and targeted therapies flexible enough to match the flexibility of the cancer cells that are constantly adapting to our treatments. An improved understanding the role of the mitochondria in mediating treatment resistance is a big step forward regarding improved cancer treatment for patients with these specific genetic mutations.
*Prof Anna-Mart Engelbrecht leads the Cancer Research Group in the Department of Physiological Sciences at Stellenbosch University (SU). Michelle van der Merwe is her MSc student. Prof Engelbrecht is also co-director of the SU Spin-Out Company, BIOCODE Technologies, which develops biomarker and biosignal screening solutions for inflammatory disease and cancer risk identification.
