An early symptom of pancreatic cancer is a profound loss in weight that can precede disease diagnosis by months1. Weight loss also occurs in other types of cancer, and is often associated with severe illness and a reduced quality of life. In a paper in Nature, Danai et al.2 report an analysis of pancreatic cancer, using mouse models and clinical data, that illuminates the consequences of weight loss for cancer outcomes.
Cachexia, the term used to describe the cancer-linked symptom of severe weight loss, has been recognized since at least the time of the ancient Greek physician Hippocrates. It is often a hallmark of cancers originating in the gut system3, and might manifest in changes such as loss of fat (adipose) tissue or skeletal-muscle wasting, which could arise if the body is using up the nutrient stores in such tissues. Cachexia is particularly common in people who have a type of cancer called pancreatic ductal adenocarcinoma. The mechanisms driving cachexia are not the same in all tumours4, but whether there are different types of cachexia depending on the tumour type or the stage of the cancer at which weight loss occurs remains to be determined.
Two key mechanisms4 thought to drive cachexia are the breakdown of molecules in a process called catabolism, and inflammation, which is controlled by the body’s immune system. The pancreas secretes digestive enzymes that break down complex, calorie-rich food to provide the components needed for tissue growth and maintenance5; this catabolism-supporting function is known as its exocrine role. Exocrine-system impairment causes malnutrition that can lead to life-threatening tissue wasting. However, the degree to which pancreatic exocrine-system abnormalities contribute to human cachexia was unknown.
Human pancreatic cancer often occurs in a region of the organ that can obstruct the main pancreatic duct, hampering enzyme release. This can lead to a situation termed pancreatic exocrine insufficiency, which results in nutrient-absorption deficiencies and weight loss6. Cachexia in humans can be exacerbated if deficiencies occur in essential nutrients7,8, for example long-chain fatty acids and vitamin D, whose uptake is facilitated by pancreatic enzymes such as lipase. The administration of fatty acids increases skeletal-muscle mass in people with pancreatic cancer, particularly when this supplementation is combined with pancreatic enzymes9.
The research group that conducted the current study had previously10 observed that tissue breakdown occurs before pancreatic-cancer diagnosis in humans and before the development of early-stage pancreatic cancer in mice. To continue their investigation, Danai and colleagues studied pancreatic cancer using genetically engineered mouse models of the condition11,12, and they used transplantation experiments to test whether tumour location affects wasting. They found that if pancreatic-tumour cells were transplanted into mice beneath the skin surface, adipose-tissue wasting did not occur, whereas wasting did occur if the cells were transplanted into the pancreas. This finding indicates that some aspect of the pancreatic environment has a key role in this phenomenon, and is consistent with the results of a previous study11. However, that study also found that tissue wasting was promoted when tumour cells were introduced into the body cavity, suggesting that tumour presence at a non-pancreatic site can also trigger this phenomenon.
Danai and colleagues’ metabolic investigations revealed that mice with pancreatic tumours used less oxygen and produced less carbon dioxide than did control mice lacking tumours. This suggested that the presence of the cancer might be linked to a decrease in the processes involved in food breakdown and nutrient adsorption. To investigate how the pancreatic-tumour environment might cause this early metabolic change and weight loss, the authors tested whether pancreatic exocrine insufficiency was responsible, given that this can occur in human pancreatic cancer6. When Danai and colleagues gave the mice pancreatic enzymes, the level of adipose-tissue wasting decreased, suggesting that pancreatic exocrine insufficiency has a causal role in cachexia (Fig. 1).
Danai and colleagues found that, although pancreatic-enzyme supplementation could limit the tissue wasting, the animals’ survival rate did not improve. This striking result indicates that cachexia does not drive cancer-associated mortality. The result is also consistent with previous clinical evidence6 that pancreatic-enzyme supplements do not improve survival in pancreatic cancer. More-over, when Danai et al. analysed clinical data to assess adipose-tissue wasting in 782 people with pancreatic cancer, they found that wasting did not correlate with poorer survival rates. However, it was previously reported13 that the loss of skeletal muscle and adipose tissue is linked to worse cancer survival rates, so Danai and colleagues’ results call into question the idea that cachexia affects survival.
As well as regulating exocrine function, the pancreas has endocrine functions — it produces hormones that regulate metabolism. A key component of the endocrine system produced by the pancreas is the hormone insulin. Insulin facilitates glucose uptake into cells, and its absence can cause diabetes. Diabetes can sometimes precede pancreatic-cancer diagnosis by a year or two, and might be a red flag of trouble ahead14. Moreover, abnormal glucose metabolism might contribute to adipose- and skeletal-tissue wasting15, and diabetes can cause exocrine insufficiency16.
Danai and colleagues observed lower insulin and glucose levels in the blood of their model mice compared with the levels in control mice, and this decrease in insulin and glucose might lead to increased breakdown of stored fats, which could, in turn, increase the level of tissue wasting. This potential connection between the endocrine and exocrine systems and weight loss is supported by studies in the fruit fly Drosophila melanogaster17.
Much remains to be understood about the role of the exocrine and endocrine systems in pancreatic cancer. One way to address this might be to perform detailed gene- and protein-expression analyses to determine the signalling crosstalk between transplanted cancer cells and the surrounding healthy pancreas in the mouse model used by the authors. Another potential avenue of research would be to investigate pancreatic exocrine insufficiency at the time of cancer diagnosis, especially in people whose tumours do not block the main pancreatic duct.
The authors did not investigate the role of inflammation in cancer-associated weight loss, but this is tricky to investigate because pancreatic tumours are associated with immuno-suppression caused by factors such as the protein TGF-β. Inhibiting TGF-β reduced cachexia in a mouse model of pancreatic cancer18, and there is circumstantial evidence that low-level inflammation contributes to pancreatic-exocrine insufficiency19. These observations provide tantalizing hints that inflammation warrants further investigation in this context.
It is worth considering whether other mechanisms might contribute to cachexia. For example, appetite loss might in turn reduce enzyme output, so dietary intake could be another key factor. As work such as that of Danai and colleagues improves our understanding of cachexia, the condition comes into focus as a distinct entity, rather than merely an early symptom of cancer. A goal for future research should be to delineate the interactions between exocrine and endocrine function and inflammation in cachexia. Although Danai and colleagues’ results cast doubt on whether cachexia affects survival in cancer, if progress could be made to stop tissue wasting, it would substantially alleviate the disease burden for patients.
Nature 558, 526-528 (2018)
J.M.L does consulting for Abbott/Mylan. The author also declares non-financial competing interests: he is a steering group member of pancreaticcancereurope.org