When people have cancer, one of the most visible and distressing symptoms is weight loss, known as cachexia. With some types of cancer, as many as four in five patients are affected when the illness reaches an advanced stage.
Also seen in medical conditions ranging from chronic pancreatitis to heart disease, cachexia is said to affect as many as nine million people across the globe.
Involving a loss of muscle and, to a lesser extent, fat, cachexia can make it harder for cancer patients to cope with treatments such as radiotherapy or chemotherapy, and also puts patients at a higher risk of mortality after surgery. For a significant proportion of them, it is the actual cause of death.
Despite its prevalence and the severity of its effects, cachexia caused by cancer remains poorly understood in terms of the biochemical and genetic factors behind it.
A study by UAE-based researchers funded by the Al Jalila Foundation has now taken science a step closer to uncovering these causes.
“This was a topic we’ve been interested in for a long time now. Patients with cancer cachexia have such a hard time. It makes the disease difficult to treat, it’s the cause of death in about one third of people and contributes to the demise of much larger numbers,” says the principal investigator of the study, Professor Thomas E Adrian, of the College of Medicine and Health Sciences at UAE University in Al Ain.
Carrying out much of the research was Dr Amal Al Haddad, a UAE-born Palestinian oncology nurse manager at the Al Noor Hospitals Group who undertook the work for her PhD.
“I like to look at things that are other than what people look at normally. I [wanted] to think about things that decrease the quality of life of patients,” says Dr Al Haddad.
There has been much previous research on cachexia but Prof Adrian said a significant amount of this has involved animal models, and these studies “don’t really reflect the human cachexia syndrome”.
So, to help reveal more about cachexia in people, a dozen cancer patients at Tawam Hospital in Al Ain were selected to take part in the research.
Half of these patients had experienced a limited amount of weight loss – 5 to 10 per cent of their body weight - while the other half had not lost any weight. The patients in the two groups were approximately matched for age and gender.
“We were interested in trying to unravel the mechanism of cachexia by studying patients with early disease, rather than the result of someone losing a large amount of body weight just before they died,” says Prof Adrian, who is originally from the UK but who spent much of his career working in the United States before moving to the UAE a decade ago.
Dr Al Haddad says: “We tried our best to apply the most stringent inclusion criteria to ensure that our samples are representative for the early disease.”
Samples of muscle and adipose (fat) tissue were taken from the abdomen of the 12 patients and cutting-edge genetic analysis highlighted the presence of more than 20,000 transcripts, which are stretches of ribonucleic acid, or RNA. These are produced when genes, which are made from deoxyribonucleic acid, or DNA, are active. These fragments of genetic material were sequenced and computer analysis put the various pieces together. The researchers were interested in whether particular genes were more active or less active when individuals had cachexia, and the analysis was able to show the relative level of activity in the two groups of patients of the various genes identified. Prof Adrian says the work “could not have been completed” without the collaboration of Dr Joel Malek, an assistant professor of genetic medicine at Weill Cornell Medical College in Qatar, and his team.
Genes more active than normal – described as upregulated – showed up on a genetic “map” as red, while those less active, or downregulated, were coloured blue.
The vast majority of genes – more than 95 per cent – were “housekeeping genes” that showed no difference in expression between the samples from the two groups.
However, Prof Adrian says it was “very clear” that there were “substantial differences” in the activity of particular genes.
“We’re looking at a relatively small number of genes that seem to be involved in the early stage of the cachexia process,” he says.
Genes that were downregulated in muscle were involved in processes such as the control of calcium signalling between and within cells. Some genes involved in the structure of the muscle were also downregulated, as were those linked to the synthesis and breakdown of glycogen, a substance made up of many glucose molecules joined together that acts as an energy store.
Muscle cells tend to show an increase in the amount of glucose breakdown that takes place without the use of oxygen, known as anaerobic glycolysis. This generates less energy per glucose molecule than the normal aerobic metabolism.
“These changes can explain why these patients have severe muscle weakness and fatigability,” says Prof Adrian.
One area of interest is a protein called myostatin, which inhibits the growth and development of muscle cells. Studies have indicated that tumours produce myostatin, and there are clinical trials under way aimed at blocking the action of myostatin in cachexia patients. This latest study indicates, however, that synthesis of its receptor molecule is downregulated in patients with cachexia, something that suggests that blocking the effects of myostatin in cancer patients is unlikely to alleviate their cachexia.
Given its complexity, it is no surprise that Prof Adrian describes cachexia as a “multifactorial syndrome” that involves multiple biochemical pathways. Preventing it will not be easy, and any implications for patients of the recent work are many years away.
“There’s not going to be a simple fix: it is not that there’s a single gene involved and if we changed the expression of that and the whole thing will be put right,” said Prof Adrian.
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