Tumour-suppressive BMP-9 signalling in HCC

Bone Morphogenetic Protein (BMP)-9, a member of the TGF-β family of cytokines that is constitutively produced by hepatic stellate cells of the liver, is a high-affinity ligand of the type I receptor activin receptor-like kinase1 (ALK1). BMP-9 is a strong enhancer of bone formation, plays an important role in vascular and hepatic homeostasis and it affects glucose metabolism and insulin resistance. In addition, we recently found that BMP-9 enhances pro-inflammatory responses of macrophages.

Regarding its role in tumorigenesis and liver fibrosis, the results have been controversial. It seems that BMP-9 can be both, a pro- as well as anti-fibrogenic factor and it can act pro- or anti-proliferative on cancer cells.

We found that in human liver ALK1 is highly expressed on sinusoidal endothelial cells and Kupffer cells/macrophages but not hepatocytes (HC). In healthy HC BMP-9 therefore signals via alternative type I receptors, like ALK2, and mediates maintenance of a differentiated, non-proliferative cellular phenotype via activation of the Smad-1 pathway. In many HCC patient samples, in contrast, ALK1 expression is upregulated and correlates with tumour-promoting expression signatures. We found that in highly malignant HC BMP-9 does not efficiently activate the Smad-1 pathway anymore and ID1 induction is strongly dampened. Obviously, in such cancer cells ALK1 acts like a ligand trap, preventing the anti-cancerous BMP-9 signalling via ALK2.

In conclusion, BMP-9 targeted therapy acting via specific blockage of the BMP-9/ALK1 interaction on HC but leaving BMP-9/ALK2 signalling intact, could be a promising new approach to treat HCC patients.

Publikationsverlauf

Artikel online veröffentlicht:
26. Januar 2022