ADAMTSL4 switches on dormant TGF-β1 in mouse muscle and fat and advances cachexia
Helmholtz Munich researchers, with Heidelberg University and the Technical University of Munich, report that ADAMTSL4 binds the latent TGF-β1 complex and releases the active signal in muscle and fat. In mouse models of cancer cachexia ADAMTSL4 was elevated in the blood; switching it off in cachexia-inducing tumour cells left mice losing less muscle and fat, while raising it in other tumour cells turned them into cachexia-inducing tumours. In colorectal and lung cancer patients, higher ADAMTSL4 went with greater weight loss. The study appears in Cancer Discovery.
Science··Midday
ADAMTSL4 switches on dormant TGF-β1 locally in muscle and fat
Helmholtz Munich researchers, with Heidelberg University and the Technical University of Munich, report that the tumour-secreted protein ADAMTSL4 binds a component of the latent TGF-β1 complex and releases the active signalling molecule locally in muscle and fat. In the account carried by News-Medical, TGF-β1 sits first in an inactive form on the muscle-cell surface; ADAMTSL4 binds this dormant complex and releases active TGF-β1. That switches on signalling pathways that promote protein breakdown in muscle cells and fat breakdown in adipocytes. The study appears in Cancer Discovery.[1], [2]
The Helmholtz team switched ADAMTSL4 off and on in mouse tumours
The Helmholtz team found elevated ADAMTSL4 in the blood in several mouse models of cancer cachexia. Switching off its production in cachexia-inducing tumour cells left the animals losing significantly less muscle and fat, while raising it in tumour cells that do not normally induce cachexia turned them into cachexia-inducing tumours. Juliano Machado said this showed ADAMTSL4 is not merely associated with cachexia, but can actively advance the process. Mauricio Berriel Diaz said the team wanted to understand which signals from the tumour start the breakdown of muscle and fat tissue.[1], [2]
In colorectal and lung cancer, ADAMTSL4 rises alongside greater weight loss
In patients with colorectal and lung cancer, higher ADAMTSL4 levels went with greater weight loss, an association the mouse experiments cannot confirm as causal in humans. Stephan Herzig notes that ADAMTSL4 activates TGF-β1 locally rather than throughout the body, and points to a route around the side effects that have limited systemic TGF-β inhibitors. The authors caution that cachexia involves several mechanisms, that ADAMTSL4 elevation varies between patients, and that appetite and inflammation also contribute. News-Medical also notes that there is currently no approved pharmacological therapy for cancer cachexia.[1], [2]
