BMP activated Smad signaling strongly promotes migration and invasion of hepatocellular carcinoma cells

Maegdefrau, Ulrike; Bosserhoff, Anja‐Katrin

doi:10.1016/j.yexmp.2011.10.004

Cited by 54 publications

(54 citation statements)

References 45 publications

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“…The mechanism of action of BMPs may be different at the molecular level in different cancerous environments (31). In hepatocellular carcinoma, Maegdefrau and colleagues reported that BMP4 expression increased in HCC samples and BMP4 suppression resulted in a strong reduction of migratory and invasive potential (32,33). Chiu and colleagues reported that BMP4 and its receptor, BMPRIa are overexpressed in HCC, and it promotes the growth and migration (23).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2012

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“…We found enhanced levels of several BMPs (BMP4, 6, 7, 8, 9, 10, 11, 13 and 15) in hepatocellular carcinoma (HCC) compared with normal liver tissues3 and demonstrated that general BMP inhibition decreased the invasive phenotype of HCC cells in vitro. In line with this, we confirmed enhanced BMP4 expression and its correlation with aggressive tumour growth in human HCC tissues 4.…”

Section: Introductionmentioning

confidence: 92%

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Arndt

Wacker

Dorn

et al. 2014

Gut

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“…Both pathways, ERK and SMAD, are known to be responsible for BMP signal transduction [33,34]. Interestingly, Maegdefrau et al revealed that blocking of the SMAD pathway lead to a significantly decreased migration and invasion upon BMP stimulation [35]. Taking these findings into account, the impairment of migration and invasion found in hMSC from osteoporotic patients may be due to a downregulation of integrin a2 and reduced phosphorylation of ERK.…”

Section: Discussionmentioning

confidence: 99%

Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7

Haasters

Docheva

Gassner

et al. 2014

Biochemical and Biophysical Research Communications

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Fractures to the osteoporotic bone feature a delay in callus formation and reduced enchondral ossification. Human mesenchymal stem cells (hMSC), the cellular source of fracture healing, are recruited to the fracture site by cytokines, such as BMP-2 and BMP-7. Aim of the study was to scrutinize hMSC for osteoporosis associated alterations in BMP mediated migration and invasion as well as in extracellular matrix (ECM) binding integrin expression. HMSC were isolated from 18 healthy or osteoporotic donors. Migration was assessed using a collagen IV coated micro-slide linear gradient chamber and time-lapse microscopy. Invasion was analyzed utilizing an ECM coated transmembrane invasion assay. Quantitative real-time RT PCR was performed for the ECM binding integrins α1, α2, α3, α4, α5, α11, αv and β1. HMSC from osteoporotic patients showed a significant increase of migration upon BMP-2 or FCS stimulation, as well as a significant increase of invasion upon BMP-2, BMP-7 or FCS stimulation. Nevertheless, the migration and invasion capacity was significantly decreased compared to healthy controls. Out of all integrins analyzed, collagen binding integrin α2 was significantly downregulated in hMSC from osteoporotic patients. In conclusion, we here demonstrate for the first time osteoporosis associated alterations in BMP mediated hMSC recruitment. These findings may underlie the reduced healing of osteoporotic fractures. Nevertheless, the maintained migration and invasion response upon BMP stimulation illustrates the therapeutic potential of these clinically approved substances in the treatment of osteoporotic fractures. Another therapeutic target may be the downregulation of the collagen binding integrin α2 in hMSC from osteoporotic patients.

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BMP activated Smad signaling strongly promotes migration and invasion of hepatocellular carcinoma cells

Cited by 54 publications

References 45 publications

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

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

Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease

Mesenchymal stem cells from osteoporotic patients reveal reduced migration and invasion upon stimulation with BMP-2 or BMP-7

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