Researchers at the Spanish National Cancer Research Cente (CNIO) discovered that the FASN enzyme, overexpressed in many types of cancer, is crucial for one of the essential processes by which a normal cell becomes cancerous. Blocking FASN in an animal model of aggressive breast cancer delayed the onset of tumors and extended its survival by 68%.
The body has a fatty acid manufacturing process that is regulated by the FASN enzyme. In normal cells, this process is very little active –except very specifically cells in the liver and adipose tissue– since most of the fatty acids we need for cell maintenance are obtained externally through the diet.
However, it is known that FASN is overexpressed in many types of cancer, such as prostate, breast, thyroid, colorectal, bladder, lung or pancreas. For this reason, and although its relationship with the disease is not yet well known, scientists around the world study it as a potential cancer target.
Now, a team of researchers led by Miguel Ángel Quintela, head of the CNIO Breast Cancer Clinical Research Unit, discovered the connection of FASN with cancer and showed that the therapies that inhibit it are highly effective to prevent the development of tumors in mice and cell cultures, but not to treat it when the tumor has already developed. The results are published in Nature Communications.
One of the main findings of the work is that the importance of FASN for the development of cancer is not related to its ability to generate fatty acids. Until now, it was thought that tumor cells overactivate FASN to generate energy, build their cell membrane, etc. “However, in the work we show that cancer continues to capture these fatty acids externally,” explains Quintela, leader of the study. “Therefore, the FASN function of synthesizing fatty acids is not necessary for cancer.”
What FASN cancer does need is to help it arise. Researchers have discovered that FASN is essential for one of the key processes in the transformation of a normal cell into a cancer cell: anchorage-independent growth, i.e. being able to grow without being subject to a solid surface, a capacity that the normal cell does not have.
“Among other signals –such as the ability to invade, resistance to programmed cell death, etc.– a vital characteristic that defines that a cell is becoming malignant is that it can grow autonomously and separate from the tissue to which it is anchored. As soon as they separate, normal cells enter in a process called anoikis and die, while tumor cells have the ability to continue growing.”
Without FASN, there is no tumor
Working with a transgenic mouse model that develops an aggressive type of breast cancer, the team found that by eliminating FASN the tumors did not appear. Quintela indicates why: “The independent growth of the anchor increases the amount of free radicals produced by the mitochondria, which, having reached a point of accumulation, would suffocate the cancer cells and they would die.”
“They avoid it using FASN, since it regulates a process called reductive carboxylation that eliminates this excess of free radicals. Therefore, when we blocked FASN in our work, free radicals accumulated without braking, which prevented the growth of malignancy,” he explains.
The team confirmed these results in normal mouse cell cultures, in which overexpressed known oncogenes –such as KRAS (related to lung cancer) or PyMT and HER2 (related to breast cancer)– to induce the transformation of normal cells to tumor cells. By eliminating FASN expression, normal cells did not transformed in tumor cells, although oncogenes were overexpressed.
Researchers around the world are studying the potential of FASN to treat certain types of cancer. However, the results of the CNIO team suggest that its effectiveness is preventive, not therapeutic.
“In our mouse model that develops a very penetrating breast cancer, the areas where there is FASN do develop cancer, while in the areas where we block it tumors did not develop and survival increased by 68%,” he says Quintela “But when we tried to inhibit FASN with established tumors, there was a small transient effect that hardly affected the progression.”