High expression of BMP-9 in colorectal cancer (CRC) is associated with a better patients’ prognosis

BMP-9 is a secreted cytokine belonging to the TGF-β superfamily and circulating with the blood stream of healthy individuals in a constitutive fashion. We previously showed that in addition to the liver, BMP-9 is also locally expressed in the small intestine and by upregulating ID1 expression, it seems to have protective functions in the setting of colorectal cancer (CRC).

We therefore further analysed the mechanism(s) of such potentially protective effects of BMP-9.

By in silico data analyses (TNMplot) we found that in colon cancer tissue BMP-9 expression is often reduced compared to the surrounding normal mucosa. Furthermore, low BMP-9 expression in CRC patient samples was associated with reduced survival times, indicating again that BMP-9 might have protective effects.

In mice low but clearly detectable expression of BMP-9 was found in all segments of the intestinal tract (stomach, duodenum, jejunum, ileum, colon) at comparable levels. ALK1, the high affinity BMP-9 receptor, was higher expressed at both “ends” (stomach/duodenum and colon) and this was even more prominent for the LPS receptor TLR4. We previously showed that LPS can down-regulate BMP-9 expression in vitro and this might explain why cancers in stomach or colon develop more often than in the small intestine (jejunum and ileum): LPS would down-regulate local BMP-9 via TLR4 signalling leading to a more vulnerable mucosa with low ID1 expression.

In the high fat diet (HFD) feeding model in mice the liver-to-body weight ratio gets significantly increased. Using this model, we found that this is accompanied by enhanced hepatic BMP-9 expression and elevated BMP-9 serum levels. In parallel HFD feeding led to an increase in serum cholesterol. This prompted us to measure BMP-9 and cholesterol in a set of human serum samples and we found that both are significantly positively correlated. Furthermore, in human colon organoids BMP-9 stimulation upregulated the expression of the cholesterol/LDL binding receptor LDLR. These data imply that BMP-9, by upregulating LDLR might further act protective in the intestinal tract by promoting clearance of diet-induced cholesterol from the circulation.

We conclude that BMP-9 acts protective against intestinal cancer development via (at least) two mechanisms: up-regulation of ID1 (which was shown to be associated with better survival times) and dampening the damaging effects of diet-induced cholesterol accumulation by mediating its uptake into the cells.

Publikationsverlauf

Artikel online veröffentlicht:
04. September 2025