Proinvasive activity of BMP-7 through SMAD4 /src -independent and ERK/ Rac /JNK -dependent signaling pathways in colon cancer cells☆

Grijelmo, Clara; Rodrigue, Christelle M; Svrcek, M.; Bruyneel, Erik; Hendrix, An; Wever, Olivier De; Gespach, Christian

doi:10.1016/j.cellsig.2007.03.008

Cited by 75 publications

(69 citation statements)

References 40 publications

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“…New evidence suggests the importance of BMP7 in the development of an epithelial cancer and in metastatic behaviour. Aberrant BMP7 expression during tumour progression has been reported in a few cancer types, including colorectal cancer, breast cancer, melanoma, and prostate cancer (12,15,18,(21)(22)(23)(24)(25)(26). High levels of BMP7 have been detected in bone metastasis of prostate cancer, and breast carcinoma as they progress to a more aggressive phenotype (3,4,9,15).…”

Section: Discussionmentioning

confidence: 99%

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

et al. 2012

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Abstract. The aim of this study was to investigate the expression of bone morphogenetic protein 7 (BMP7), in human pulmonary cancer tissues/cells and to evaluate the cellular impact of bone morphogenetic proteins on pulmonary cancer cells. BMP7 expression was determined in human lung cancer cell lines. The invasiveness and growth of cells transfected with BMP7, in vitro, were evaluated using the in vitro invasion assay and in vitro tumour models. Cellular migration was analysed using wounding assays. BMP7-positive tumours correlated with the absence of bone metastasis (P=0.040). In this analysis, we identified that 4 of 4 small cell lung cancer (SCLC) tissue specimens had no BMP7 expression, which illustrated that BMP7 may have no role in SCLC. BMP7 expression was not correlated with the overall survival time in lung cancer patients. Downregulation of BMP7 expression significantly inhibited the invasiveness of SPC-A1 cells (P<0.001) and forced-expression of BMP7 dramatically increased the motility of A549 cells. Overexpression of BMP7 in A549 cells and its knockdown in SPC-A1 cells did not significantly alter proliferation compared with the control cells (P>0.5 respectively). In conclusion, we have demonstrated that BMP7 has an important role in controlling lung cancer cell motility and invasiveness, without affecting the growth process, cell proliferation and cell apoptosis. A higher BMP7 expression may be an indicator for bone metastasis. The therapeutic role of BMP7 warrants further investigation. IntroductionLung cancer is one of the most fatal tumours worldwide. Distant metastasis is an important cause for the poor prognosis. Of the factors related to metastasis, bone morphogenetic proteins (BMPs) have been recently shown to regulate the aggressiveness of cancer cells (1-7). BMPs are multifunctional signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily, which play important roles in multiple cellular processes such as cell growth, differentiation, migration and apoptosis in various types of cancer (8-12). The Smad-dependent signaling pathway has been proven to be the canonical pathway for BMP function (13). In lung cancer, expression of the BMP family members has also been reported (1,14). For example, BMP2 protein could stimulate growth, migration and invasion of lung cancer cells, and is overexpressed in virtually all types of lung cancers, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Silencing of BMP3b expression during NSCLC development has been reported and the BMP3b promoter has been found to be methylated. Activation of the BMP4 signaling pathway negatively regulates the growth, and induces senescence of A549 lung adenocarcinoma cells. Thus, there may be a contrasting response to any given BMP, depending on the tumour and cell type. Despite the discordant results defining the specific effects of BMP7 in various types of cancer, published data underscore the important role that BMP7 plays in tumour development and metastasis. The expre...

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Section: Discussionmentioning

confidence: 99%

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

et al. 2012

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“…FAK has been shown to trigger several downstream signaling pathways which mediate different phenotypes including cell spreading, growth, and survival [34,35]. As FAK phosphorylation at Y925 is linked to adhesion turnover [29,36], we analyzed the activation of FAK in endothelial cells. We found that DAB2 knockdown induced Y925 FAK phosphorylation and that in DAB2 silenced HU-VEC the ability to form capillary-like tube structures was restored after pharmacological inhibition of Src by PP2.…”

Section: Discussionmentioning

confidence: 99%

Morphogenesis of human endothelial cells is inhibited by DAB2 via Src

et al. 2008

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Disabled-2 (DAB2) is an adaptor protein implicated in signal transduction pathways and in protein traffic regulation. Here, we show that DAB2 is highly expressed in human endothelial cells. DAB2 silencing in endothelial cells by lentiviral-mediated small hairpin RNA expression affects cell migration and differentiation into capillary-like structures while increasing cell proliferation and viability. DAB2 knockdown causes activation of the Src-FAK signal pathway, extracellular-signal regulated kinase and c-Jun NH 2 -terminal kinase activation, and inhibition of p38 phosphorylation. In DAB2 silenced endothelial cells, pharmacological inhibition of Src with its specific inhibitor PP2 abolishes focal adhesion kinase activation and restores differentiation of endothelial cells. These results suggest that DAB2, via Src and focal adhesion signaling, plays a role in human endothelial cell function.

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“…BMP signaling has also been shown to inhibit tumorigenesis of several tumor types, including brain tumors, basal cell carcinomas of the skin and gastric cancer (Piccirillo et al, 2006;Sneddon et al, 2006;Bleuming et al, 2007). On the other hand, recent evidence has shown that BMPs promote the motility and invasiveness of various cancer cells, including colon cancer, melanoma and prostate cancer cells (Rothhammer et al, 2005;Yang et al, 2005;Bailey et al, 2007;Grijelmo et al, 2007). Furthermore, overexpression of BMP antagonist noggin in tumor cells inhibited osteolytic bone metastasis of lung and prostate cancer in mouse models (Feeley et al, 2006a, b).…”

Section: Introductionmentioning

confidence: 99%

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

et al. 2008

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Transforming growth factor (TGF)-b is known to promote tumor invasion and metastasis. Although bone morphogenetic proteins (BMPs), members of the TGF-b family, are expressed in a variety of human carcinoma cell lines, their roles in tumor progression have not been fully clarified. In this study, we sought to determine the roles of BMPs in the progression of breast cancer bone metastasis using human breast cancer samples and a mouse xenograft model. Immunohistochemical analysis of samples from breast cancer patients as well as a mouse xenograft model of MDA-231-D, highly metastatic human breast cancer cells, revealed phospho-Smad2 and phospho-Smad1/5/8 staining in the nuclei of cancer cells in primary tumor and/ or bone metastasis. Using a functional in vivo bioluminescence imaging system, we showed that TGF-b-and BMPinduced transcriptional pathways are active in bone metastatic lesions in vivo. In addition, both TGF-b3 and BMP-2 promoted the motility and invasiveness of the MDA-231-D cells in vitro. Moreover, expression of dominant-negative receptors for TGF-b and/or BMPs in the MDA-231-D cells inhibited invasiveness in vitro and bone metastasis in the xenograft model. These results suggest that BMPs as well as TGF-b promote invasion and bone metastasis of breast cancer.

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Proinvasive activity of BMP-7 through SMAD4 /src -independent and ERK/ Rac /JNK -dependent signaling pathways in colon cancer cells☆

Cited by 75 publications

References 40 publications

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

Morphogenesis of human endothelial cells is inhibited by DAB2 via Src

Bone morphogenetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathway

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