Cancer cachexia—when proteasomal inhibition is not enough

Cachexia is a life threatening syndrome associated with several diseases, such as end-stage heart failure, end-stage renal disease, chronic obstructive pulmonary disease, chronic inflammation (i.e. rheumatoid arthritis), acquired immune deficiency syndrome, and cancer. Cachexia is found in 31–87% of cancer patients especially in advanced disease stages. It is characterized by progressive weight loss, metabolic alterations, fatigue, and persistent reduction of body cell mass in response to a malignant tumour. The incidence of cachexia in cancer patients is dependent on the type and site of the tumour. While patients with non-Hodgkin’s lymphoma, breast cancer, and sarcomas show low incidences, rates up to 83% in pancreatic cancer patients, and over 85% in patients with gastric cancer have been found. Additionally, around 60% of small-cell and non-small-cell lung cancer patients develop cachexia. Cancer cachexia affects the function of several organs such as muscle, adipose tissue, liver, brain, immune system, and heart, collectively decreasing patients’ quality of life and worsening their prognosis. Therefore, cachexia must be considered as a true multi-organ syndrome. Because cancer cachexia leads to a decrease in physical performance and quality of life, and is associated with poor survival (accounting for more than 20% of cancer deaths,) it is of major clinical relevance. Even more so since cachectic patients show lower response rates to chemotherapy and a reduced tolerance to anticancer treatment. Despite its importance, weight loss in cancer patients is rarely recognized, assessed, or treated actively. Thus, cancer cachexia represents an important underappreciated clinical syndrome. Muscle wasting is a major constituent of cancer cachexia