BMP4 Administration Induces Differentiation of CD133+ Hepatic Cancer Stem Cells, Blocking Their Contributions to Hepatocellular Carcinoma

Abstract

CD133þ cancer stem cells (CSC) contribute to hepatocellular carcinoma (HCC) progression and resistance to therapy. Bone morphogenetic protein BMP4 plays an important role in hepatogenesis and hepatic stem cell differentiation, but little is known about its function in hepatic CSCs. In this study, we showed that high-dose exogenous BMP4 promotes CD133 þ HCC CSC differentiation and inhibits the self-renewal, chemotherapeutic resistance, and tumorigenic capacity of these cells. Interestingly, we found that low-dose exogenous BMP4 upregulated CD133 protein expression in vitro, and endogenous BMP4 was preferentially expressed in CD133 þ HCC CSCs, suggesting that low doses of BMP4 may facilitate CSC maintenance. A reduction in endogenous BMP4 levels decreased CD133 protein expression in vitro. In HCC tissues, expression of the BMP4 signaling target gene SMAD6 was positively correlated with CD133 expression. Activation of the Erk1/2 signaling pathway led to BMP4-mediated reduction in CD133 expression, which was reversed by treatment with MEK inhibitors. Taken together, our findings indicated that BMP4 might be a potent therapeutic agent in HCC that targets CSCs. Cancer Res; 72(16); 4276-85. Ó2012 AACR.

Bone Morphogenetic Proteins

“…Although autocrine TGF-b signals play important roles in maintaining the stem-cell-like properties and tumorigenic activity of glioma-initiating cells (GICs), BMP signals induce the differentiation of these cells (Piccirillo et al 2006;Lee et al 2008). BMPs also regulate the differentiation of other types of cancer stem cells, including colorectal and breast cancers (Lombardo et al 2011;Buijs et al 2012;Gao et al 2012;Zhang et al 2012). Taken together with their inhibitory effects on proliferation of various types of cancer cells, activation of BMP signals is expected to serve as a therapeutic strategy for cancer.…”

Cancer stem cells in the development of liver cancer

“…Wnt and TGF-β signaling pathways may collaborate in the development of HCC or HCC-CCA with poor prognosis (64,65). Signaling of OSM and BMP4 appears to induce hepatocytic differentiation of liver CSCs (66,67), while TGF-β signaling is implicated in the biliary differentiation of hepatoblasts; loss of TGF-β signaling by β2-spectrin knockout resulted in the expansion of progenitor cells in mice (68,69). TGF-β signaling may also regulate the development and maintenance of HCC and liver CSCs, but its role seems paradoxical and is often referred to as a double-edged sword (70)(71)(72)(73).…”

T3/TRs axis in hepatocellular carcinoma: new concepts for an old pair

“…The same work also showed that increasing intracellular levels of T 3 results in reduced 23:8 clonogenic and tumourigenic potential and establishes a higher sensitivity of CR-CSCs to chemotherapy, supporting the hypothesis that T 3 may inhibit tumour development by activating a differentiation program. Since high doses of exogenous BMP4 promote CD133-positive HCC-CSC differentiation and inhibit the self-renewal and tumourigenic capacity of these cells (Zhang et al 2012), one can speculate that treatment with T 3 may also induce differentiation of highly aggressive HCC-CSC and reduce their tumourigenic capacity by inducing BMP4 levels.…”