BMP-9 – a tumour-suppressive factor in the liver?

Bone morphogenetic protein (BMP)-9, a member of the TGFβ-family, is mainly produced in hepatic stellate cells in the liver and constitutively circulates in the blood of healthy individuals. According to current knowledge, it mainly exerts homeostatic actions, thereby stabilizing the functional, differentiated phenotype of cells but also antagonizing cell proliferation. Due to these functions, BMP-9 could act tumour suppressive.

Our present data show that injection of a low dose of LPS to mice leads to a significant drop of hepatic BMP-9 expression. Furthermore, pre-stages of human liver disease, like steatosis and especially diabetes present with reduced BMP-9 serum levels. HCC cells seem to respond differentially to BMP-9, depending on their expression level of the main BMP-9 receptor, ALK1. In non-ALK1 expressing cells (like healthy hepatocytes), or HCC cells with low ALK1 expression (Hep3B), BMP-9 antagonizes cancer stem cell formation (via ALK2) and stabilizes the differentiated phenotype. In tissue samples from HCC patients, BMP-9 expression negatively correlates with that of stem cell markers like LGR5.

In summary, BMP-9’s tumour-suppressive function on liver cells is executed mainly via acting through other receptors than ALK1, e.g. ALK2. Some HCC cells may rebranch the BMP-9 signal by upregulating ALK1, capturing BMP-9, but without transducing the signal. Thereby ALK1 expressing cancer cells support the tumor's own growth, even in the presence of high BMP-9 levels.

High serum-levels of BMP-9 are related to a generally better health status in humans and a drop in BMP-9 serum levels could serve as an early marker for disease development.

Publication History

Article published online:
20 January 2025