Applying the same solution to different problems is a common mistake, not only among humans but also in our immune system. Flooding a wound with inflammation-causing white blood cells can be helpful for fighting infection, but when the immune system tries to apply this “solution” to a different purpose – fighting cancer – it can end up aiding tumor growth. In a new study a team of researchers, headed by Prof. Ayelet Erez of the Weizmann Institute of Science, has revealed how cancerous tumors use this immune response for their own gain while starving their host’s body – a devastating effect known as wasting syndrome. The scientists propose a method for predicting cancer-caused weight loss, and point the way toward developing possible treatments.

Cancerous tumors have long been known to reprogram metabolic processes within and around themselves so as to obtain a steady supply of essential nutrients. That is why cancer treatments today include metabolic modulators that block this reprogramming. But in recent years, researchers have come to realize that cancer can alter metabolic processes systemically, that is, throughout the patient’s body. Among the grave consequences is wasting syndrome – rapid weight loss that is unconnected to the patient’s diet and cannot be offset by high caloric intake. This syndrome occurs in cancer patients whose body metabolism is thrown far out of whack.

Because the liver is a central metabolic hub that senses metabolic changes and responds to them, the new study – led by Omer Goldman from Erez’s research team in Weizmann’s Molecular Cell Biology Department – explored the liver’s connection to cancer. The researchers aimed to understand whether and how a cancer growing in remote organs affects processes in the liver, and what the payoff for the tumor might be. To this end, Goldman tracked metabolic changes in mouse models of human breast and pancreatic cancers, focusing on the urea cycle, a series of biochemical reactions that take place in the liver. In this cycle, excess nitrogen is transferred to the liver in the form of ammonia and then converted into urea to be excreted from the body in urine.

In a 2018 study of children, Erez’s team, together with colleagues in Israel and abroad, discovered that low urea levels in urine could signal the presence of cancer. This can happen when the cancer is keeping for itself the highly valuable nitrogen – a basic building block of all the body’s amino acids – leaving less nitrogenous waste to be expelled as urea.

In the present research, the scientists first identified the stage at which cancer starts meddling with liver metabolism. “Within a few days of the onset of cancer, we detected a decline in urea cycle activity,” says Goldman. “As a result, amino acids accumulated in the blood of the mice, rather than being broken down in the cycle. The tumor was using these amino acids to assemble its RNA and DNA. As a result of the urea cycle failure, excess ammonia also accumulated, and this impaired the immune cells’ ability to fight cancer.”

Uncovering a Trojan horse in the liver

The next challenge was to reveal exactly how the cancer reprograms metabolic processes in the liver. The scientists discovered that right around the time the metabolic changes appeared, certain types of immune cells started infiltrating the liver. These were white blood cells released into the blood stream as part of the inflammatory response intended to fight the cancer. In particular, as the cancer progressed, the liver was filling up with large numbers of mature, active white blood cells called neutrophils and monocytes.

To understand the connection between white blood cell influx and liver metabolism, the research team sequenced RNA molecules sampled from liver cells at different stages of the disease. Their analysis revealed that as the white blood cell count rose, the liver ceased to produce a protein called HNF4-alpha – known as a master regulator of metabolic processes – and decreased its production of albumin, which is crucial to preventing swelling and leakage from blood vessels. When the levels of these proteins in the liver dropped, the mice started losing weight.

Using gene therapy, the scientists then restored the production of HNF4-alpha in the livers of the mice, and its levels remained high. Consequently, the mice did not lose weight, their tumors shrank and survival rates improved.

These findings provided strong evidence that the wasting syndrome is caused, at least partly, by a decrease in the metabolic master regulator HNF4-alpha, brought on by immune cells infiltrating the liver. The research raises the hope that in the future, it might become possible to prevent or even treat this syndrome, for example, with drugs that would simulate the function of HNF4-alpha or counter the effects of its decrease.

With a view toward these applications, in the present study the scientists focused on identifying at-risk patients. Since metabolic changes in the liver were found to occur long before the symptoms of wasting syndrome appear, the researchers wondered whether a routine liver function test at the time of the cancer diagnosis might help predict the risk of patients developing the syndrome later on. They developed a diagnostic model with a liver function score based on a blood test for albumin and other blood-borne biochemical parameters related to the liver. When they ran this model on large data sets of cancer patients from Clalit Health Services, Sheba Medical Center and Tel Aviv Sourasky Medical Center, they found a correlation between the liver profile measured early on in the disease and the risk of wasting syndrome and even mortality occurring later.

“There is no existing treatment for wasting syndrome, even though it’s obvious that to defeat cancer we ought to keep the patient’s body in good shape,” says Erez. “A deepening understanding of how cancer changes central metabolic processes right from the beginning of the disease, combined with the continuous development of genetic treatments aimed at preventing these changes, might soon translate into new therapies available to patients in the early stages of cancer.”