The role of bone morphogenetic proteins and their signalling in human cancers

Both endogenous and exogenous GDF-9 led to a promotion in prostate cancer cell adhesion, invasion, motility, and growth. GDF-9 mediated growth promotion was shown to correlate with an increase in cell cycle progression via up-regulation of Cyclin D1, and protection from apoptosis in a Smad-independent manner. Furthermore, GDF-9 associated cell adhesion, motility, and invasion was shown to involve FAK, paxillin, and Rho-ROCK signalling, as well as EMT and its associated inducers. These effects promote the aggressiveness of PC-3 cells, aiding in their progression and possibly metastasis. These results suggest that GDF-9 is involved in prostate cancer progression by activation of a complex network of signalling pathways and molecules. This provides further proof of the importance of BMP signalling, and suggests that perhaps novel treatments for prostate cancer based on BMPs should be investigated. In addition, it sheds some light on the use of BMPs as prognostic indicators of disease, aiding in diagnosis, and perhaps future forms of treatment.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

The role of bone morphogenetic proteins and their signalling in human cancers

Both endogenous and exogenous GDF-9 led to a promotion in prostate cancer cell adhesion, invasion, motility, and growth. GDF-9 mediated growth promotion was shown to correlate with an increase in cell cycle progression via up-regulation of Cyclin D1, and protection from apoptosis in a Smad-independent manner. Furthermore, GDF-9 associated cell adhesion, motility, and invasion was shown to involve FAK, paxillin, and Rho-ROCK signalling, as well as EMT and its associated inducers. These effects promote the aggressiveness of PC-3 cells, aiding in their progression and possibly metastasis. These results suggest that GDF-9 is involved in prostate cancer progression by activation of a complex network of signalling pathways and molecules. This provides further proof of the importance of BMP signalling, and suggests that perhaps novel treatments for prostate cancer based on BMPs should be investigated. In addition, it sheds some light on the use of BMPs as prognostic indicators of disease, aiding in diagnosis, and perhaps future forms of treatmen

Bone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (review)

Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily, which plays important roles in foetal and postnatal development and also maintains the homeostasis of various tissues and organs. Due to the critical role played by BMPs in bone formation and bone turnover, the implication of these molecules in bone metastasis has been intensively studied over the past decade. BMPs have been implicated in the development and progression of solid tumours, particularly the disease-specific bone metastasis. In breast cancer, a tumour type which most commonly metastasizes to bones, aberrations of both BMP expression and their signalling have been recently demonstrated. These aberrations have certain correlations with the development and progression of the disease. Recent in vitro studies have also demonstrated that BMPs can regulate a range of biological functions of breast cancer cells. Targeting BMPs or BMP signalling may provide novel therapeutic approaches for breast cancer. In the current review, we discuss the present knowledge on BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease-specific bone metastasis

Growth and differentiation factor-9 promotes adhesive and motile capacity of prostate cancer cells by up-regulating FAK and Paxillin via Smad dependent pathway

The majority of advanced prostate cancers metastasise to the bone. Mediators of bone remodelling, the bone morphogenetic proteins have extensively been implicated in the progression and metastasis of prostate cancer. The present study investigated the function of BMP member GDF-9, in prostate cancer. We overexpressed GDF9 in PC-3 cells using a mammalian expression construct, and knocked-down with the use of ribozyme transgenes. These cells were further used in in vitro adhesion and motility assays, in order to determine the effect of GDF-9 on these properties. Recombinant GDF-9 was generated to treat PC-3 WT cells before further analysing the effect on adhesion. The GDF-9 overexpressing PC-3 cells demonstrated a significantly enhanced adhesive and motile capacity compared to their controls. The opposite effect was seen in the GDF-9 knock-down cells. In addition, treating PC-3 cells with rh-GDF-9 resulted in them becoming more adhesive. Both endogenous and exogenous GDF-9 was demonstrated to up-regulate focal adhesion associated proteins FAK and paxillin which contribute to promoted cell adhesion and motility. With the use of a Smad3 inhibitor, this effect was inhibited suggesting that GDF-9 signals via Smad3 to up-regulate expression of these proteins. This study shows that GDF-9 can promote the motile and adhesive capacity of PC-3 prostate cancer cells by up-regulating expression of FAK and paxillin in a Smad dependent manner, suggesting a pro-tumourigenic role for GDF-9 in prostate cancer

Phenotypic consequences of somatic mutations in the ataxia-telangiectasia mutated gene in non-small cell lung cancer

Mutations in the Ataxia-telangiectasia mutated (ATM) gene are frequently found in human cancers, including non-small cell lung cancer (NSCLC). Loss of ATM function confers sensitivity to ionising radiation (IR) and topoisomerase inhibitors and may thus define a subset of cancer patients that could get increased benefit from these therapies. In this study, we evaluated the phenotypic consequences of ATM missense changes reported in seven NSCLC cell lines with regard to radiosensitivity and functionality of ATM signalling. Our data demonstrate that only 2/7 NSCLC cell lines (H1395 and H23) harbouring ATM missense mutations show a functional impairment of ATM signalling following IR-exposure. In these two cell lines, the missense mutations caused a significant reduction in ATM protein levels, impairment of ATM signalling and marked radiosensitivity. Of note, only cell lines with homozygous mutations in the ATM gene showed significant impairment of ATM function. Based on these observations, we developed an immunohistochemistry-based assay to identify patients with loss or reduction of ATM protein expression in a clinical setting. In a set of 137 NSCLC and 154 colorectal cancer specimens we identified tumoral loss of ATM protein expression in 9.5% and 3.9% of cases, respectively, demonstrating the potential utility of this method

When BMP signalling goes wrong: the intracellular and molecular mechanisms of BMP sgnalling in cancer

Bone Morphogenetic Proteins (BMPs), members of the TGF-β superfamily, are pleiotropic growth factors, known for their role in embryogenesis and bone induction. BMPs signal via two types of serine/threonine kinase BMP receptors (BMPRs), type I, and type II receptors. Ligand binding induces activation of the downstream signalling molecules, the SMADs, which regulate the expression of BMP-responsive genes including those involved in processes such as differentiation, proliferation and apoptosis. BMP signalling is coordinated by both extrinsic and intrinsic mechanisms in order to ensure the control of these important processes. Irregularities however, can occur at any step during the downstream BMP pathway, and aberrations have been implicated in the pathogenesis of several tumour types including: prostate, colorectal, osteosarcomas, myelomas and breast cancer, amongst others. As so many signalling molecules take part in the BMP network, the specific role that these characters play in the pathogenesis of these tumours is rather complex, and hence unclear. In this review, we summarise and consider current literature on BMP signalling, its regulation, and any aberrations in the pathway, focusing on the role of BMPRs, and SMADs on the development, progression and metastasis of solid tumours

GDF-9 promotes the growth of prostate cancer cells by protecting them from apoptosis

Bone morphogenetic proteins (BMPs) have long been implicated in the process of prostate cancer progression and bone metastasis. This current study investigates the role of GDF-9, a BMP member, in prostate cancer. GDF-9 was over-expressed in PC-3 cells using a mammalian expression construct. Additionally, GDF-9 ribozyme transgenes were generated in order to knock down the expression of GDF-9 in PC-3 and DU-145 cells. These cells were then used in in vitro growth assays in order to determine the effect of GDF-9 on prostate cancer cell growth. Recombinant GDF-9 was also generated and used to treat both cell lines before carrying out further growth assays. Levels of apoptosis were subsequently analyzed using flow cytometry. Cell growth was significantly increased in the GDF-9 over-expressing cells compared to the two controls. The cell growth rate at day 5 was significantly greater in the PC-3GDF-9exp. (1,131.1 ± 79.1%) compared to both PC-3WT (563.9 ± 90.6%) and PC-3pEF (763.3 ± 82.0%), P ≤ 0.001 versus both controls. The opposite effect was seen in both PC-3 and DU-145 GDF-9 knockdown cells. The PC-3WT cells treated with rh-GDF-9 (1.35 ± 0.28) had a significantly increased absorbance and hence growth rate compared to the untreated PC-3 cells (0.79 ± 0.05), P = 0.026. Finally, flow cytometry and Hoechst 33342 DNA staining demonstrated decreased apoptosis and caspase-3 expression levels in PC-3GDF-9exp. cells and rh-GDF-9-treated PC-3WT cells. This study shows that GDF-9 can promote the growth rate of both PC-3 and DU-145 cells by protecting the cells from caspase-3-mediated apoptosis, and suggests that GDF-9 may aid in the progression of prostate cancer by acting as a survival factor

Growth and differentiation factor 9 (GDF-9) induces epithelial-mesenchymal transition in prostate cancer cells

The role of bone morphogenetic proteins in the progression and metastasis of prostate cancer is a topic that has undergone extensive research. This study investigates the role of BMP member growth and differentiation factor 9 (GDF-9) in the progression of this disease. GDF-9 was over-expressed and knocked-down in PC-3 cells, respectively. Furthermore, along with the use of a generated recombinant GDF-9 protein, these cells were then analyzed for any changes in their invasiveness and expression of epithelial–mesenchymal transition (EMT) associated genes. GDF-9 was shown to promote the invasiveness of PC-3 cells together with an induction in the expression of genes including SNAI1, RhoC, ROCK-1, and N-cadherin, while reducing levels of E-cadherin. These expression changes are characteristic of the onset of EMT, and resulted in the cells having a more mesenchymal-like morphology. Treating these cells with activin-like kinase-5 (ALK-5) inhibitor, demonstrated that GDF-9 induced up-regulation of these molecules was ALK-5 dependant. This study shows that in PC-3 cells, GDF-9 signaling via ALK-5, can promote cell invasiveness via a complex network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancer cells

Reduced expression of BMPR-IB correlates with poor prognosis and increased proliferation of breast cancer cells

Background: Breast cancer is the leading female cancer in the UK. Recent work has shown that Bone Morphogenetic Proteins (BMPs) and their receptors may be involved in the progression of breast cancer. The aim of the current study is to identify the role of BMPR-IB, one of these receptors, in breast cancer. Materials and Methods: Expression of BMPR-IB was examined in a cohort of breast tissue samples. The transcript level was determined using quantitative real time-PCR and protein levels were assessed with immunohistochemical staining (IHC). Constructed ribozyme transgenes were used to knock-down BMPR-IB in MDA-MB-231 cells, and the effect this had on in vitro cell growth was examined. Results: Decreased staining of BMPR-IB was seen in most of the breast tumour samples examined compared to normal breast tissues. Q-PCR analysis revealed lower expression levels of BMPR-IB transcript in patient samples with a predicted poor prognosis (Nottingham prognosis index (NPI) >5.4) (8.2±17, p=0.03) compared to samples with a good prognosis (NPI <3.4) (469±244). Higher BMPR-IB expression was seen in samples from disease free patients compared to those with poorer prognosis; including patients with metastasis, local recurrence and breast cancer deaths, (p=0.026). Furthermore, down-regulation of BMPR-IB in MDA-MB-231cells led to a promotion of in vitro cell growth. Conclusion: This study shows that decreased expression of BMPR-IB correlates with poor prognosis in breast cancer patients and leads to increased cell proliferation of breast cancer cells in vitro. This suggests that BMPR-IB mediates an inhibitory effect on breast cancer cells

Bone morphogenetic protein-10 (BMP-10) inhibits aggressiveness of breast cancer cells and correlates with poor prognosis in breast cancer

Our recent study showed that a novel member of bone morphogenetic protein (BMP) family, BMP-10, was decreased in prostate cancer. In the present study, we investigated the implication of BMP-10 in breast cancer, particularly the relation of its expression with clinical aspects. The expression of BMP-10 was examined in a cohort of human breast cancer specimens (normal, n = 23; cancer, n = 97), using both quantitative real-time PCR and immunohistochemical staining. The full-length human BMP-10 was cloned into a mammalian expression plasmid vector and then transfected into breast cancer cells. The effect on growth, cell matrix adhesion, motility, and invasion of MDA-MB-231 cells by BMP-10 was then investigated using in vitro growth assays. Immunohistochemical staining and quantitative real-time PCR revealed a decreased expression of BMP-10 in breast cancer. Further analysis of BMP-10 transcript level against the clinical aspect demonstrated that the decreased BMP-10 expression correlated with disease progression, bone metastasis, and poor prognosis. The disease-free survival of the patients with a higher level of BMP-10 was 132.8 (95% CI, 122.0–143.5) months, significantly longer compared to 93.7 (95% CI, 60.3–127.2) months for patients with a lower level of BMP-10 expression (P = 0.043). The overexpression of BMP-10 has broad inhibitory effects on the in vitro growth, invasion, and motility of breast cancer cells. Taken together, BMP-10 can inhibit the cell growth of breast cancer cells, and decreased BMP-10 expression correlates to poor prognosis and disease progression, particularly the lymphatic and bone metastasis. Bone morphogenetic protein-10 (BMP-10) may function as a tumor suppressor in breast cancer. (Cancer Sci 2010