Rapidly growing cancer cells make their microenvironment highly acidic. When the cancer cells adapt to this, they become more aggressive, and the acidic tumour microenvironment also makes it hard for the immune system to eliminate cancer cells. Researchers now say that changing the acidic microenvironment or how it affects the cancer cells may enable cancer cells to be killed more easily or enable the immune system to do this.
When cancer cells grow and divide at a hectic pace, they secrete acid. Because the blood vessels in a tumour rarely function very well, the acid accumulates in the tumour, making the tumour environment highly acidic.
Researchers have studied cancer cells for more than a century, but the importance of cancer cells both creating and adapting to an acidic microenvironment and acquiring aggressive properties has only recently come into focus.
The research provides insight into how cancer cells use an acidic microenvironment to metastasise and inhibit the cancer-specific immune cells so that the immune system cannot overcome the cancer.
According to a researcher who has studied the importance of the acidic microenvironment for cancer cells, the insight can lead to the development of new types of therapy that can both prevent cancer from metastasising and make eliminating the cancer cells easier for the immune system.
“For many years, researchers have tried to understand why tumours have a very low oxygen concentration, but there has been less focus on understanding the significance of the acidic microenvironment. We have been researching this for many years, and although this field is still insufficiently studied, the research community is now beginning to realise that acidosis is a key part of the tumour environment and that understanding its importance is required to understand cancer – and how to optimally fight it,” explains Stine Falsig Pedersen, Professor, Department of Biology, University of Copenhagen.
Stine Falsig Pedersen and colleagues from Aarhus University and the University of Oxford recently published a review in Nature Reviews Cancer on how an acidic microenvironment leads to aggressive cancer.
Releasing acid into the microenvironment
Cancer cells divide at a hectic pace. They therefore use considerable energy and lots of molecular building blocks to build the new cells. Both the energy and the building blocks come from the breakdown of glucose and lipids, and this process releases protons and CO2.
Both protons and CO2 increase the acidity of the microenvironment to pH 6.0–6.5 versus the normal pH of 7.4. For cells, pH 6.5 is really acidic.
In addition, the blood vessel system in tumours does not usually work optimally, and the body therefore cannot expel the acid.
“This means that inside the tumours, the cancer cells have to adapt to living in an acidic microenvironment to survive. Our research has shown that as the cancer cells adapt, they become more aggressive, invasive and even resistant to chemotherapy. For these cells, what does not kill them makes them stronger,” says Stine Falsig Pedersen.
Cells alter their metabolism to thrive in an acidic microenvironment
Stine Falsig Pedersen and colleagues have spent many years studying how the cancer cells inside an acidic tumour adapt to this otherwise hostile microenvironment.
The cancer cells upregulate the production of specific transport proteins in the plasma membrane with the aim of expelling acid from the cells.
This means that even if the microenvironment is acidic, the cellular processes inside the cancer cells can still proceed normally.
In addition, the cancer cells switch their metabolism to pathways with less acid production.
The reason is that the normal metabolic pathways do not work very well at high acidity and are thereby blocked. The surviving cancer cells are the ones that find new ways to survive.
“This is very advantageous for the cancer cells when they have to spread and metastasise. They are better adapted to surviving and dividing in different microenvironments, including the acidic microenvironments that they help to create, and this gives them an advantage over other types of cells,” explains Stine Falsig Pedersen.
Cancer cells use acidity in different ways
One way cancer cells adapt to a more acidic microenvironment is by mutating.
p53 is a well-known tumour suppressor gene. Some of the most important mutations in p53 make its function so sensitive to pH that the protein functions poorly in cancer cells which have become very good at regulating their pH.
Once the cancer cells have created an acidic microenvironment and have adapted to it, this can increase the aggressiveness of the disease.
The extremely acidic environment in the layer just outside the cells helps to break down the extracellular matrix – the structural proteins surrounding the cells. This facilitates the spread of the cancer by enabling the cells to leave the tumour and invade the surrounding tissues.
The acidic microenvironment also limits the ability of many chemotherapeutic drugs to enter the cancer cells and therefore can make the cells chemotherapy resistant. Finally, the acidic microenvironment created by the cancer cells also affects the immune system. The CD8+ T cells, the immune cells that can kill cancer cells, are especially inhibited by low pH, and this reduces the cancer-specific immune response. In addition, the acidic microenvironment causes the immune system’s macrophages to behave in a way that favours the cancer cells.
May lead to new treatments
According to Stine Falsig Pedersen, improved understanding of the importance of secretion of acid for cancer cell growth, metastasis and anticancer immune defence provides a window into potential new types of treatment.
Limiting the acidity in and around cancer cells can help the part of the immune system that fights the cancer cells and thus help to increase the effectiveness of immunotherapy.
One way to lower the degree of acidity in and around cancer cells is using drugs to inhibit the proteins that transport acid out of the cancer cells or to inhibit the mechanisms by which the cancer cells sense the acidity in the environment, thereby preventing them from adapting to this condition.
New studies in mice have shown that such treatments can increase the effectiveness of immunotherapy in pancreatic cancer and glioma, an aggressive type of cancer in the brain.
Such treatments have not been tested yet in humans, but this is one of the perspectives in understanding how cancer cells create and survive in an acidic microenvironment.
“Another option that is being developed is treatments that are only activated in an acidic microenvironment. This means that the cell-killing substances only become active or released when there is acid around them, which means around cancer cells. Direct or indirect measurements of the acidity of tumours are also being explored as diagnostic tools. There are many opportunities to better understand and treat cancer by learning more about how the acidosis, together with other traits of the tumour microenvironment, affect the development of cancer,” concludes Stine Falsig Pedersen.
