Cell Metab: the root of cancer cachexia

Many advanced cancer patients die from a state called cachexia which is the result of the interaction between the host and the tumor and mainly displayed by the weight loss in short time, malnutrition et al.

Cachexia is a direct cause of about 20% of cancer deaths. Till now there is no effective therapy for cachexia. A study published in the journal Cell Metabolism indicates a promising strategy that might be used to exercise muscle strength in cancer patients.

The study involved the browning of white fat, which has acquired a considerable attention as a method of combating obesity. White fat provides the largest energy reserve in the body, while the purpose of brown fat is to burn calories in order to generate heat. Thus, the transformation of white fat into brown fat can help people lose weight.

The researchers from Spanish National Cancer Research Center found that in cancer-related cachexia mice and patients, white fat significantly changed into brown fat. This change leads to increased energy consumption and organ failure. Furthermore, the research team also found that in the process of cancer-related cachexia, the inflammation plays an important role in the transformation of white fat into brown fat, which means a potential therapeutic target. In fact, anti-inflammatory treatment, including non-steroidal anti-inflammatory drug sulindac, can improve the severity of cachexia in mice.

The current study in Cell Metabolism suggests that the inhibition of fat transformation is a new hope to improve the quality of the cancer patient cachexia. In addition, identifying the biomarkers of white fat browning biomarkers in the early stages of cancer development might be helpful to predict which patients will develop cachexia.

A research team lead by Nicolas Thomä from Friedrich Michel Institute for Biomedical Research has clarified the molecular mechanism of the different clinical effects caused by thalidomide. Has been published in the journal Nature, the research revealed that the drug can interfere cell processes through two different cellular processes, one is to prevent protein degradation, the other one is to promote protein degradation.

In early 1960s, thalidomide was used as a sedative for treatment of morning sickness. But it was subsequently withdrawn from the market when it was found to cause birth defects. However, in the late 1990s, thalidomide and its derivatives have been proved effective in some types of blood cancer treatment.

The study of Nicolas Thomä revealed how thalidomide interacts with its target protein DDB1-CRBN in vivo. DDB1-CRBN, which is also known as E3 ubiquitin ligase, is a part of the protein degradation system. Interestingly, the scientists found that thalidomide could activate or inhibit DDB1-CRBN depending on the cell type and structure of thalidomide-DDB1-CRBN compound. In the first case, thalidomide promotes the attachment of ubiquitin to Ikaros and Aiolos protein, and this is relevant to the treatment of blood cancer. In the second case, thalidomide blocked the interaction between DDB1-CRBN and MEIS2, a protein involved in all aspects of human development, thereby inhibiting DDB1-CRBN degradation. So, the research provides evidence to explain why the Thalidomide and its derivatives can lead to extremely favorable and unfavorable clinical outcomes.