Tumor protein drives cancer wasting in mice

When cancer patients lose weight, the tumor may be doing more than suppressing appetite. A team in Germany has identified ADAMTSL4, a protein secreted by tumor cells, as a factor that can drive the loss of muscle and fat in cancer cachexia, a wasting process that weakens patients and can complicate treatment.

The researchers from Helmholtz Munich, Heidelberg University’s Faculty of Medicine, the German Center for Diabetes Research and the Technical University of Munich studied the protein in several mouse models. When they switched off ADAMTSL4 production in tumor cells that normally cause cachexia, the animals lost significantly less muscle and fat mass. When they increased production in tumor cells that did not usually cause cachexia, those cells formed tumors that induced the wasting process.

The mechanism links the tumor to tissue breakdown through TGF-β1, a signaling molecule involved in cell and tissue remodeling. TGF-β1 sits on muscle cells in an inactive complex. ADAMTSL4 binds to part of that complex and releases active TGF-β1, which then triggers signals that promote protein breakdown in muscle and fat breakdown in adipocytes, the cells that store fat.

The same protein was found at elevated levels in the blood of cachectic patients with colorectal and lung cancer. Higher ADAMTSL4 levels were associated with greater weight loss and more pronounced cachexia. That human finding is an association, however; the cause-and-effect tests came from mouse tumor models.

So what changes, concretely? The work suggests a narrower therapeutic route than blocking TGF-β throughout the body. Because TGF-β has many important functions, broad inhibition could cause substantial side effects; targeting the tumor-derived ADAMTSL4 signal might act more locally. No approved drug for cancer cachexia exists, and the researchers still need to determine whether inhibiting ADAMTSL4 can slow muscle and fat loss in patients. They also expect the approach to help only some patients, since cachexia involves appetite, inflammation and other tumor factors.