Increasingly better treatments have increased the chances of surviving breast cancer, but certain types of tumours are difficult to treat. Research suggests that fat tissue increases the growth of tumours, but how this happens is uncertain. Now researcher have shown that adipose tissue can enhance the conversion of glucose to fat in cancer cells, a metabolic process associated with increased tumour growth. Thus, inhibiting this process holds promise as an anti-cancer treatment. However, the researchers say that such therapy should be rather aggressive and given in combination with conventional treatments to avoid cancer cells adapting and becoming resistant to treatment.
One in seven women with breast cancer have an especially aggressive triple-negative variant that responds poorly to normal treatment. These women survive for only 12–15 months on average after diagnosis. Intensive research therefore seeks to find new forms of treatment, and in recent years there has been some focus on the fat tissue in the breasts in which the tumours grow. Researchers now believe that they have discovered both the reason why the tumours grow especially well in the fat tissue and a possible way to slow their growth.
“We investigated the metabolic interactions between breast cancer cells and fat tissue and showed that the faster growth of cancer cells in fat is linked to increased lipogenesis in the cancer cells, and our data suggest that the large amount of lactate produced by the fat cells can trigger this metabolic change in the cancer cells. Fat and tumours are therefore symbiotic, and this symbiosis represents a possible target for new types of therapy. However, our first attempt to slow the growth of cancer in this way shows that we need to use aggressive treatment to prevent the cancer from adapting,” explains Ingrid Wernstedt Asterholm, Associate Professor, Institute of Neuroscience and Physiology, University of Gothenburg, Sweden.
One of two theories fits
The close link between breast cancer and fat is well known. Breast cancer grows close to mammary fat tissue, implying that such lipid-related metabolic symbiosis may be especially important for this type of cancer. One study also shows that increased tumour aggressiveness is also associated with increased fatty acid oxidation.
“Metabolising fatty acids provides cancer cells the necessary energy to divide rapidly. In addition, fatty acids can serve as building blocks for building cell membranes and act as signalling molecules. A cancer cell can meet the increasing need for fatty acids in two ways: either increasing fatty acid uptake or de novo lipogenesis: increasing its own production of fatty acids. In our research, we tried to determine which method an aggressive breast cancer type uses,” says Ingrid Wernstedt Asterholm.
To find the answer, the researchers examined two groups of mice. One group had tumours growing within fat tissue, and the tumours of the other group grew without contact with adipose tissue, and the presence of fat tissue substantially affected the growth rate of the tumours. The researchers then investigated what substances the fat cells could provide for the cancer cells.
“We observed that these cancer cells certainly can take up fatty acids, but the faster growth of tumours within fat was clearly linked to increased conversion of glucose to lipids. And we could also mimic this metabolic effect of adipose tissue in cultured cancer cells as well as by lactate treatment,” explains Ingrid Wernstedt Asterholm.
Use with caution
Lipogenesis is already recognized as one of the hallmarks of cancer cells’ metabolism and is associated with poor prognosis and resistance to chemotherapy. Several de novo lipogenesis inhibitors have therefore been developed as potential anti-cancer therapies. The researchers tested the effect of one to see what happened.
“When we tried to inhibit fatty acid synthesis in petri dishes in the laboratory, we could inhibit the tumours at high concentrations. However, if the treatment was given intermittently at lower concentrations, it actually increased the growth. We saw similar effects in the live mice, even though they all got the same concentration of the inhibitor,” says Ingrid Wernstedt Asterholm.
The fatty acid inhibitors were effective in only half the cases and led to further acceleration of tumour growth in the remaining ones. The researchers interpret this as indicating that inhibiting fatty acid synthesis can stop the tumours – but only if given at sufficient concentration.
“The cancer cells that escape appear to become resistant and actually upregulate their growth. So insufficient or narrow targeting of fatty acid synthesis alone could be harmful,” she explains.
The exact reason for this requires more research. The researchers agree that fatty acid inhibitors can potentially treat people with breast cancer that responds poorly to currently available treatments, but they should be used with caution.
“Circumventing the tumour’s ability to adapt to treatment requires applying aggressive treatment, preferably targeting several metabolic pathways simultaneously, together with conventional therapy,” concludes Ingrid Wernstedt Asterholm.