Bone morphogenetic proteins (BMP) are pluripotent molecules, co-ordinating cellular functions from early embryonic and postnatal development to tissue repair, regeneration and homeostasis. They are also involved in tumourigenesis, disease progression and the metastasis of various solid tumours. Emerging evidence has indicated that BMPs are able to promote disease progression and metastasis by orchestrating communication between cancer cells and the surrounding microenvironment. The interactions occur between BMPs and epidermal growth factor receptor, hepatocyte growth factor, fibroblast growth factor, vascular endothelial growth factor and extracellular matrix components. Overall, these interactions co-ordinate the cellular functions of tumour cells and other types of cell in the tumour to promote the growth of the primary tumour, local invasion, angiogenesis and metastasis, and the establishment and survival of cancer cells in the metastatic niche. Therefore, the present study aimed to provide an informative summary of the involvement of BMPs in the tumour microenvironment.
bone morphogenetic proteincancertumour microenvironmentangiogenesis and metastasis1. Introduction
Bone morphogenetic proteins (BMPs) were originally termed by Urist (1) in 1965 as it induced bone formation ectopically. They are members of the transforming growth factor β (TGFβ) superfamily (2). In humans, there have been >20 BMPs identified. They are pluripotent molecules that co-ordinate cellular differentiation, proliferation and apoptosis in early embryonic and postnatal development (3,4). They are essential in controlling tissue repair, regeneration and homeostasis (4-6).
BMPs serve important roles in tumourigenesis, disease progression and the metastasis of various solid tumours (7-10). BMP signalling has been found to be both oncogenic and tumour suppressing, depending on context. For example, studies have shown that BMPs are upregulated in certain tumours, particularly those originating from soft tissues such as osteosarcomas, chondrosarcoma, ameloblastoma and salivary tumours (11-14). They are actively involved in cancer development and metastasis (7-10). BMP-6 overexpression in prostate cancer is associated with osteoblastic bone metastasis (7). BMP-4 may promote the invasion and motility of breast cancer cells via upregulation of matrix metal-loproteinase (MMP)1 and C-X-C chemokine receptor 4 (8). The above studies indicate an oncogenic effect of BMPs in certain solid tumours. In contrast, impairments in BMP signalling observed in colorectal cancers and polyposis syndromes suggest a tumour suppressor role in these situations (15). Our previous study reported that BMP-10 inhibits prostate cancer cell growth by promoting apoptosis via Smad-independent signalling, and that it can also reduce the invasiveness and motility of cancer cells (9). BMP-4 can also reduce the capacity of myeloid- derived suppressor cells to prevent metastasis of breast cancer cells (10). It appears that the same BMPs may have varied roles in different types of tumour, potentially due to the involvement of distinct downstream molecules.
As pleiotropic growth factors, BMPs are actively involved in tumorigenesis, disease progression and metastasis, not only directly due to their own signalling pathway, but also via complex interactions with other growth factors and other signalling pathways (16-24). More importantly, BMP-mediated interactions between cancer cells and the local environment also occur during the development of both the primary tumour and metastasis, forming a large, intricate network that promotes the epithelial to mesenchymal transition (EMT) of tumours, remodelling of tumour-associated extracellular matrix (ECM), angiogenesis and bone metastasis.
2. Signal transduction of BMP
Both type I receptors [activin A receptor type I (ACVR)-like 1, ACVR1, BMP receptor (BMPR)1A, ACVR1B, TGFβ receptor (TGFβR)1, BMPR1B and ACVR1C] and type II receptors (TGFβR2, TGFβR3, BMPR2, ACVR2A and ACVR2B) are indispensable for signal transduction of TGFβ (25). The type I receptors are also respectively known as activin receptor-like kinase (ALK)1-7. Certain type I receptors (ALK1, ALK3 and ALK6) exhibit a higher binding affinity to BMPs (25). Smad-dependent signalling will be induced by the preformed hetero-oligomeric complexes (PFC) upon binding with BMP ligands (26,27). Alternatively, upon binding between BMP ligands and type I receptors, type II receptors are then recruited, leading to the formation of BMP-induced signalling complexes, which activate the Smad-independent pathway (26,27).
Smad-dependent pathway
As transcription factors, Smad proteins are vital for intracellular transduction of BMP signalling (25,27,28). There are three subgroups of Smad proteins: Smad 1, 2, 3, 5 and 8 are pathway-restricted Smads (R-Smads); Smad 4 is known as a common mediator Smad; and Smad 6 and 7 are inhibitory Smads (I-Smads) (27,28). After BMP homodimers or heterodimers bind to the PFC, the glycine-serine region of type I receptors is phosphorylated by the type II receptor, leading to the activation and translocation of R-Smads (Smad 1, 5 and 8) into the nucleus, and regulation of BMP-responsive genes such as Id1-3, Smad 6/7, type I collagen, JunB and Mix.2 (25). Smad 4 translocates the signal complex into the nucleus, and Smad 6 and 7 act as inhibitory factors for the signal transduction through the Smad-dependent pathway (Fig. 1) (25,29).
Smad-independent pathway
There is greater affinity between BMPs and type I receptors compared with type II receptors (25). Thus, BMP ligands are also able to bind to ALK3 or ALK6, and then recruit BMPR2 into a hetero-oligomeric complex; this activates the Smad-independent pathway (25-27). The X-linked inhibitor of apoptosis protein acts as an adaptor protein to relay signalling from the type I receptor to downstream TGFβ-activated binding protein, leading to activation of TGFβ-activated tyrosine kinase 1 (30-32). BMP-4 can induce apoptosis through this Smad-independent pathway, in which p38, a mitogen-activated protein kinase (MAPK) (26,33,34), Jun N-terminal kinases (JNKs), NF-κB and Nemo-like kinase (35-37) are involved (Fig. 1).
Regulatory factors of BMP signalling
Regulation of BMP pathway activity can be mediated through several positive or negative modulators, which may be extracellular when ligands bind to receptors, intracellular when the signal is being relayed or intranuclear when modulating R-Smad-mediated regulation of BMP-responsive genes (25).
Extracellular regulatory factors
Secreted extracellular BMP antagonists, including Noggin, Gremlin, Chordin and twisted gastrulation-1, provide important regulation (25). These antagonists exert their regulatory role in two ways. BMP antagonists can prevent BMPs from the binding to receptors by binding directly to BMP ligands, thus preventing ligand-receptor interaction (Fig. 1) (25). Antagonists are often target genes of BMP signalling; thus, a negative regulatory feedback loop is formed to ensure signalling homeostasis (38). For example, it has been shown that BMP-2, 4 and 6 can induce Noggin expression in osteoblasts (39). By upregulating their antagonist expression, the BMPs are thus able to regulate their activity (39).
Other factors also regulate BMP signalling extracellularly, such as pseudoreceptors and co-receptors. For example, BMP and activin membrane-bound inhibitor (BAMBI) acts as a pseudoreceptor by competitively binding to the BMP ligands with its extracellular domain, which shares high homology with type I receptor; however, as it lacks intracellular domains, the signal is not transduced (40). Similar to the BMP antagonists, BAMBI can be induced by BMP-4 in mouse embryonic fibroblasts, leading to negative feedback regulation of BMP signalling (41).
In addition to these negative regulators, there are positive regulators for the BMP pathway, such as co-receptors, which enhance BMP signalling (25,42-44). Previous studies showed that repulsive guidance molecules (RGMs; including RGMA, RGMB and RGMC) are co-receptors for BMP-2 and BMP-4. RGMB, also known as Dragon, can bind directly to BMP-2 and BMP-4, enhancing signalling (42-44).
Intracellular regulatory factors
Among the intracellular regulatory factors, I-Smads can prevent R-Smads from the binding to the activated type I receptors, as well as blocking the recruitment of Smad 4 to the activated R-Smads (Fig. 1). For example, it has been reported that Smad 6 and 7 can weaken BMP signalling by preventing Smad 1 and 5 activation by the type I receptor, and that they can also prevent the interaction between Smad 1/5 and Smad 4 (45). In addition, BMP signalling can induce Smad 6/7 expression, enhancing the negative regulation of further BMP signalling (46,47). Secondly, as Smads exhibit low binding affinity to the Smad binding elements (SBEs) of target genes, other transcription factors are required for the regulation of BMP-responsive genes, such as Smad interacting protein-1 (48), activating transcription factor (ATF)2 (49), p53 (50), Runx (51) and Forkhead box HI (FOXHI); FOXHI can specifically help recruit activated Smad 2/4 to the promoters of target genes in TGFβ signalling (52). Additionally, the interactions between certain transcriptional co-activators/repressors and the MH2 binding domain of Smad have been shown to regulate BMP. For example, P300 and CREB-binding protein interactions with Smads can increase the transcription of target genes by making the transcriptional machinery more accessible (53). However, transcriptional co-repressors, including Ski and Ski related novel gene, ecotropic viral integration site-1, TG interacting factor (TGIF)1 and TGIF2, prevent Smad 3/4 from binding to the SBE of BMP-responsive genes (54-57). Lastly, the BMP pathway can be influenced by Smad ubiquitination regulatory factor (Smurf)1/2, which induce degradation of Smads (Fig. 1) (58). The regulatory factors that co-ordinate BMP signal transduction have been summarised previously (59).
3. Interaction between BMP and other signalling pathways
BMP and its signalling pathways are not isolated in normal tissues and tumours, but are intricately linked to numerous other growth factors, such as the epidermal growth factor (EGF) receptor (EGFR) (16), receptor tyrosine kinase (RTK)/MAPK (17-19), PI3K/Akt (20-24,60), Wnt (61-65) and hepatocyte growth factor (HGF)/Met pathway (66,67); together, they form a vast network that regulates various biological functions. There are multiple levels where cross-talk can occur: By regulating ligands, antagonists, receptors, or signalling components expression or activities; by direct interactions with Smads or other signalling components (68); and by incorporating into transcription complexes that alter target gene expression (69-71).
Interaction between BMP and EGFR signalling
EGFR is regarded as an oncogenic factor belonging to the ErbB RTK family, and is overexpressed in various types of cancer, such as colorectal cancer, non-small cell lung cancer, gastric cancer, esophagogastric cancer and pancreatic cancer (72). Intracellular signalling of EGFR is generally mediated through PI3K/Akt, Ras/MAPK and the phospholipase C/protein kinase C (PKC) signalling cascades (73), which are critical for cell proliferation, differentiation, motility and survival (74).
Studies have shown that EGF can directly influence the expression of BMPs. For example, BMP-6 in MCF-7 breast cancer cells can be induced by EGF/EGFR signalling (16). The function of the BMP pathway can also be indirectly regulated intracellularly by signalling molecules downstream of the EGFR, including the RTK/MAPK pathway and the PI3K/Akt pathway.
BMP and the RTK/MAPK pathway
RTK/MAPK signalling can regulate BMP function. Secretion of additional growth factors and cytokines which promote EMT and cell invasion can often result from the interaction between TGFβ and RTK/MAPK pathways (17-19,75,76). ERK has been shown to upregulate Smad 3 in epithelial and smooth muscle cells (77).
The linking region of Smad proteins plays a vital role in interactions between BMP signalling and RTK/MAPK pathways. For example, activation of oncogene Ras can restrict BMP-induced Smad 2/3 signalling, including translocation into the nucleus and binding to the target genes (78). RTK-induced activation of ERK or JNK can phosphorylate endogenous Smad 2/3 (75,76). Furthermore, Thr178, Ser203 and Ser207 within the linker region of Smad 3 can be phosphorylated by ERK, leading to suppression of nuclear translocation (79). However, in MCF10CA1h breast cancer cells, p38 MAPK-induced phosphorylation of the Ser203 and Ser207 residues of Smad 3 facilitate, rather than inhibit, BMP-induced growth inhibition (80). These results suggest that varied phosphorylation of the Smad 2/3 linker region can lead to different results depending on the specific kinase, as well as the specificity of phosphorylation sites in intracellular events downstream of those activated receptors (81).
ERK1/2 can also prevent the nuclear translocation of Smad 1/5 via similar phosphorylation of their linker region (81). Furthermore, the oncogene Ras can reduce the stability of Smad 4 via the ERK pathway (82). Conversely, activation of JNK and p38 can target a tumour-associated mutant Smad 4, leading to degradation of the protein (83). There is suggested involvement of ERK, JNK and p38 in the regulation of Smad 7 transcription (84-86).
In addition to the above direct effects, MAPKs can also indirectly affect the activity of the BMP pathway by phosphorylating other nuclear transcription factors involved in the pathway within the nucleus, including Jun and activator protein-1 proteins such as Maf, Fos and ATFs (87). For example, p38 MAPK can activate ATF1, ATF2 and ATF3, which bind Smads and participate in BMP-regulated activities (Fig. 2) (49,88-91).
BMP and the PI3K/Akt pathway
Various studies have shown that BMP signalling can regulate the PI3K/Akt pathway, affecting cell proliferation (20), invasion (21), migration (22), EMT (92,93) and differentiation (94). This regulation can be achieved via activation of Smad-independent pathways (23,24). Secondly, BMP signalling can regulate the PI3K/Akt pathway by altering the transcriptional level or activity of PTEN. For example, Beck and Carethers (60) showed that long-term exposure to BMP-2 downregulated PTEN in Smad 4-null colon cancer cells through the Ras/ERK pathway. Previous studies showed BMP signalling could enhance PTEN activity (95,96). Conversely, in hematopoietic cells, BMP/Smad signalling can also suppress Akt activity via regulation of SH2 domain-containing 5′ inositol phosphatase, which is a lipid phosphatase targeting phosphatidylinositol (3,4,5)-trisphosphate (Fig. 2) (97). Furthermore, PI3K/Akt activation could promote the nuclear translocation of β-catenin (98,99), increase transcription of EGFR and enhance EGFR signalling, forming a vicious circle comprising Akt, β-catenin and EGFR (Fig. 2).
BMP and the HGF/Met pathway
HGF is a regulator of cell motility, mitogenesis, morphogenesis and angiogenesis (100). HGF and its receptor c-Met are actively involved in tumour growth, invasion and metastasis (101). Targeting HGF/c-Met can inhibit the proliferation and invasion of cancer cells both in vitro and in vivo (101-106).
HGF is mainly produced by fibroblasts and stored in adipose cells (101). Both solid tumour cells and leukaemia cells have also been reported to produce HGF (107-110). For example, overexpression of HGF in prostate cancer has been associated with disease progression and androgen independence (111,112).
There have been studies reporting an interaction between the BMP and HGF signalling. For example, Ye et al (29,100) reported that BMP-7, BMPRIB and BMPR2 were upregulated in prostate cancer cells. Imai et al (66) also showed that HGF was able to regulate BMP receptors. A recent study showed that HGF promoted bone regeneration and the formation of new blood vasculature via upregulation of BMP-2 (67). However, the exact transcriptional regulatory mechanism remains unclear. Further investigation is required to determine how the interaction between BMP and HGF is involved in bone metastasis.
BMP and Wnt pathway
The Wnt signalling pathway is essential for cell proliferation, differentiation, migration, survival and other processes (68). Dysregulated Wnt signalling has been observed in colorectal cancer and leukaemia (113). The Wnt signalling pathway has been extensively studied and reviewed, and comprises canonical and non-canonical pathways, the latter of which include the planar cell polarity pathway and Wnt/calcium pathway (61).
In terms of the canonical pathway, upon binding with Wnt ligand, Frizzled receptors and the transmembrane protein low-density lipoprotein receptor-related protein 5/6 induce intracellular signalling and regulation of responsive genes through β-catenin (68). Outside of Wnt signalling, β-catenin is generally degraded by a protein complex which comprises adenomatous polyposis coli, Axin, casein kinase 1α and glycogen synthase kinase 3β (GSK-3β) (61). Degradation of β-catenin is prevented when GSK-3β and Axin are recruited via the Wnt signalling, leading to nuclear translocation and regulation of Wnt target genes (62-65). Crosstalk between the BMP pathway and the Wnt pathway can occur at multiple levels.
Reciprocal regulation of the expression of pathway ligands and antagonists
The Wnt signalling pathway can regulate the expression of BMPs, BMP co-receptors or their antagonists during embryonic development and in cancerous cells (81). Conversely, BMP-2 and BMP-4 are able to regulate the expression of certain Wnt proteins, such as Wnt-7c (89) and Wnt-8 (114).
Direct interaction between key components in the cytoplasm and nucleus
GSK-3β can regulate the BMP pathway by phosphorylating the linker region of Smad (68,115-117). In the absence of upstream signalling, Smad 3 can be degraded by GSK-3β when it is recruited into a protein complex comprising Axin and GSK-3β (68,116). GSK-3β can also target the BMP-activated R-Smads, Smad 1 or Smad 3, leading to their degradation and the inhibition of downstream signalling (68). However, the regulation of Smad by GSK-3β can be prevented by Wnt signalling, leading to a stabilisation of Smad proteins (Fig. 3) (68).
Certain molecules in the BMP pathway are also involved in the regulation of Wnt signalling, such as Smurf1 (118) and Smurf2 (119). Smurf1 and Smurf2 are key molecules in the degradation of Axin, which may consequently disrupt the Wnt signalling. In addition, Smad 3 is also involved in the nuclear translocation of β-catenin (Fig. 3) (120).
Convergence at transcription complexes
In response to Wnt signalling and BMP signalling, activated transcriptional factors such as Smads, T cell factor/lymphoid enhancer-binding factor 1 and cofactors can co-ordinate the regulation of target genes, including gastrin Xtwin, Msh homeobox (Msx)2 and T-box transcription factor 6 (Fig. 3) (69-71).
Other pathways
In addition to the above, there are also interactions between the BMP pathway and other pathways, including the Hedgehog (Hh) pathway (121-124), Notch pathway (125-128), Janus kinase/STAT pathway (129-133) and NF-κB pathway (134-136). For example, Smads can co-ordinate Hh signalling through regulation of GLI (124). BMP and Notch orchestrate cell differentiation and proliferation by targeting common genes (125). BMP and NF-κB act against each other in co-ordinating immune responses (133).
Overall, the BMP pathway is integrated into various signalling networks through these interactions, thus orchestrating cellular events in tumourigenesis and the progression of malignancies.
4. BMP and tumour-associated angiogenesis
Angiogenesis is essential for the tumour growth and haematological dissemination of cancer cells (137,138). There are two stages in the progression of neovascularisation, an activation phase and a late phase (25). ALK1 and downstream Smad signalling are involved in the activation phase, whilst ALK5 and Smad 2/3 promote maturation of the newly formed vascu-lature at the late phase (139). It has been shown that BMPs can affect angiogenesis via both direct and indirect routes.
Direct regulation of angiogenesis
BMP-2, 4, 6 and 7, and growth differentiation factor (GDF)-5 can directly regulate the proliferation and migration of vascular endothelial cells (140-143). For instance, in a chorioallantoic membrane assay, GDF-5 promotes angiogenesis (140). BMP-2 exhibits pro-angiogenic effect in both in vivo tumour models (144) and in vitro functional assays of vascular endothelial cells (145). In addition to direct effects on vascular endothelial cells, BMP-2 can also promote the motility of vascular smooth muscle cells (146). BMP-4 and BMP-7 can also promote the migration of vascular smooth muscle cell (147,148). Of note, BMP-9/-10 elicit concentration-dependent biphasic effects on angiogenesis, specifically an inhibitory effect at high concentrations and a promotive effect at lower concentrations (Fig. 4) (149).
BMP receptors are important mediators of the pro-angiogenic BMP signal. For example, vascular endothelial cells exhibited higher expression of BMPRIB and BMPR2 in an in vitro tubule formation assay (150).
Studies have shown that distinct Smad pathways may play opposing roles in angiogenesis, and that the same Smad may also play different roles in angiogenesis for distinct types of tissues. For example, Smad 3 mediates an upregulation of vascular endothelial growth factor A (VEGFA), whereas Smad 2 is involved in the regulation of thrombospondin-1 in rat proximal tubular cells NRK52E (151). However, Smad 3-mediated repression of VEGF impaired angiogenesis induced by the gastric cancer cell line SNU484 (152).
As antagonists of BMPs, Noggin and Gremlin are also key regulators of tumour angiogenesis. Noggin can prevent BMP-7-induced angiogenesis (153); conversely, Gremlin can promote angiogenesis by directly targeting VEGF receptors (154).
Indirect regulation of angiogenesis
In addition to these direct effects, BMPs can also indirectly promote angiogenesis via upregulation of VEGF in other cells, such as cancer cells and stromal cells (138). For example, BMP-7 is actively involved in the bone metastasis of prostate cancer cells via regulation of VEGF (153), in addition to its direct regulation of VEGF receptor in vascular endothelial cells (155). BMP-2 promotes tumour-associated angiogenesis via upregulation of VEGF mediated by the p38 pathway in breast cancer (156). In contrast to most BMPs, BMP-9 elicits inhibition of the proliferation of vascular endothelial cells through ALK-1 (157). In addition, BMPs can indirectly induce VEGF (158), basic fibroblast growth factor and TGFβ1 in stromal cells (Fig. 4) (159).
5. BMPs and EMT
EMT is pivotal for the carcinogenesis and aggressive traits acquired by cancer cells during disease progression and metastasis (160,161). BMP-regulated EMT has been implicated in various studies regarding organ development (162,163) and cancer (164-167). In vitro, BMP-4 induces EMT-like properties in mammary epithelial cells, transforming them to express an invasive phenotype (165). BMP-2 can enhance the invasion and migration of breast cancer cells (168,169), and the effect may be mediated by the upregulation of ID-1 (170). However, there are other BMPs that play opposing role, such as BMP-7, which was not able to regulate the EMT in a murine mammary epithelial cell line, NMuMG (166). BMP-7 can prevent EMT in breast cancer cells by decreasing vimentin (171). BMP-6 can impair the metastatic capacity of breast cancer cells by repressing miR-21 and zinc finger E-box-binding homeobox 1 (ZEB1), which subsequently leads to upregulation of E-cadherin (167,172,173). Both Smad-dependent (174-176) and Smad-independent pathways (178,179) have been observed to be involved in BMP-regulated EMT. For example, BMP signalling could directly activate the transcription of Snail, Twist1 and Msx1/2 (174-176). Regarding the Smad-independent pathway, BMP-2 could induce EMT via the PI3K/Akt pathway (177,178). Furthermore, BMPs could influence tumour invasion by regulating MMPs, extracellular matrix components, cytokines, and immune or inflammatory cells in the tumour microenvironment (158). BMP-4-regulated MMP3 and interleukin-6 are involved in the fibroblast-stimulated invasion of breast cancer cells (179).
6. BMP-co-ordinated interaction between cancer cells and other cellular/non-cellular parts within the tumour
BMPs play an important role in co-ordinating the interactions between cancer cells and the surrounding environment in tumourigenesis and disease progression (158,180). For example, BMP released from tumour-associated stromal cells can induce EMT in cancer cells via the induction of ZEB1 (158). Meanwhile, BMP-2 and BMP-4 secreted by breast cancer cells can reciprocally act on stromal cells to synthesise more tenascin-W and MMPs, which can further enhance their invasiveness (158,180). However, BMP-6, BMP-10 and BMP-15 are able to inhibit the invasion and motility of cancer cells, while BMP-4 exhibits biphasic effects (158).
A number of cells located within tissues are embedded in the ECM, which comprises collagens, proteoglycans and adhesion proteins (181). The ECM is very versatile and undergoes remodelling during tumour development (181,182). Within the tumour stroma, both the cancer cells and cancer-associated fibroblasts can remodel the ECM (182). Growth factors and cytokines will be released to the ECM, thus contributing to the tumour-supporting microenvironment (182), which is actively involved in disease progression and metastasis. Studies have shown that the remodelling of ECM can be regulated by BMP (183,184). For example, secretion of collagen type I and type III from hepatic stellate cells can be reduced by recombinant human BMP-7 via inhibition of TGFβ1 and its signalling (183). Another study showed that Type I and type III collagen synthesis was significantly up-regulated following BMP-2 treatment in human scleral fibroblasts (184).
The CCN family, including CCN1-6, are a family of matri-cellular proteins (185-187). CCN proteins are regulators of cell proliferation (188-190), adhesion (191), migration (192,193), survival (194), apoptosis (195), angiogenesis (196) and inflammation (197,198) in numerous types of cells, including vascular endothelial cells and other cells within the stroma.
CCN proteins can directly interact with BMPs; for example, binding of CCN2 to BMP-4 prevents its interaction with BMP receptors, thus inhibiting BMP-induced cell proliferation (199). In addition, there have been reported interactions between CCN3 and BMP-2 (200), CCN4 and BMP-2 (201), and CCN6 and BMP-4 (202). CCN proteins may act as both antagonists and agonists for BMP signalling, depending on the expression profile of related molecules (189,203,204). CCN2 promotes the proliferation of chondrocytes via ERK and JNK signalling pathways, and induces differentiation via p38 (189,203). BMP-2 can suppress the phosphorylation of ERK1/2, which impairs CCN2-promoted proliferation (204). Similarly, CCN2 can abolish BMP-2-promoted cell proliferation by inhibiting Smad-dependent and independent pathways (205).
In addition, studies have shown that certain non-coding RNAs play roles in the interaction between the tumour microenvironment and BMPs. For example, Xiao et al (206) reported that microRNA (miRNA/miR)-885-3p inhibits the in vivo growth of HT-29 colon cells by disrupting angiogen-esis via targeting BMPR1A, leading to a blockage of BMP signalling. Nishida et al (207) found that miR-17-92a and miR-106b-25 clusters were upregulated in colorectal cancer stromal tissues compared with normal stroma; putative targets of these miRNAs predicted by Target Scan were significantly downregulated in cancer stromal tissues, including TGFβR2, Smad 2 and BMP family genes.
7. BMP-related activities in bone metastasis
BMPs enriched in bone matrix are the most potent factors to induce the formation of new bone (58). Numerous studies have reported that BMPs are expressed to varying degrees in a range of benign and malignant bone tumours, such as osteoid osteoma (208), fibrous dysplasia (209), giant-cell tumours (210) and osteosarcoma (211). BMP expression was detected in both human osteosarcoma cell lines (212,213) and human osteosarcoma specimens (214,215). Furthermore, differential expression of BMPs was evident in different histopathological subtypes (215). For example, Yoshikawa et al (215) found that high-grade osteosarcoma with a malignant fibre histio-sarcoma-type pattern exhibited the strongest expression of BMP-2/4. Additionally Sulzbacher et al (216) reported that BMPs are expressed in osteosarcoma specimens, and their expression is related with osteosarcoma histopathological subtype; high expression of BMP-6 was detected in osteosar-comas with chondroblastic differentiation. Aside from this aberrant expression, little is known regarding the biological function of BMPs in bone tumour cells. Li et al (217) showed that BMP-9 inhibited tumour growth and migration by blocking the PI3K/AKT signalling pathway in an osteosarcoma cell line.
In bone metastatic tumours, BMPs can be synthesised by both cancer cells and osteoblasts (218). There is increasing evidence showing that BMPs are implicated in bone metastases of prostate and breast cancer (156,219,220). BMPs are expressed in both primary prostate tumours and bone metastases with different phenotypic patterns. For example, BMP-7 and GDF-15 are reduced in or absent from primary prostate tumours, but overexpression of both molecules is evident in the bone metastases (219,220). In contrast, BMP-6 is consistently expressed at high levels in both primary tumours and bone metastases of prostate cancer (138). The expression profiles of BMP in primary tumours and bone metastases reflects an adaptive phenotype acquired by the cancer cells during disease progression based upon requirements at different metastatic locations. Elevated expression of BMP in cancer cells is more likely to result in osteoblastic bone lesion by enhancing bone formation (138). In addition to BMP ligands, the BMP antagonist Noggin has been associated with the osteolytic bone lesions of prostate cancer in a murine model (221). Moreover, loss of Noggin can also enhance osteoblastic activity in bone metastasis (222).
BMPs released from cancer cells can regulate osteoblastic or osteoclastic activities in bone lesions, leading to bone formation or resorption. BMPs secreted by osteoblasts/osteoclasts or released from disrupted bone can reciprocally induce EMT in cancer cells, promoting the development of bone lesions (218). These interactions form a vicious cycle during the development of bone metastasis (Fig. 5). However, the exact machinery underlying the regulation of BMP signalling utilised by the cancer cells requires more intensive investigation.
In addition to direct stimulation, BMPs can also enhance the vicious cycle during bone metastasis via regulation of other factors. For example, osteoprotegerin can be upregu-lated by BMP-2 in PC-3 cells, acting as a pseudo-receptor for receptor activator of NF-κB (RANK) ligand (RANKL) to prevent RANKL/RANK-induced osteoclastogenesis (223). BMP-7 can enhance osteoblastic activity via upregulation of VEGF in cancer cells (59). As angiogenic factors, BMPs can also facilitate the formation of bone metastasis by promoting tumour-associated angiogenesis.
8. Therapeutic potential and perspectives
The role played by BMP signalling in cancer progression, metastasis and angiogenesis has raised interest in developing targeted therapies. ALK1 appears to be the most attractive target for preventing tumour-associated new vasculature. PF-03446962, a monoclonal antibody against ALK1 from Pfizer, has exhibited dose-dependent anti-angiogenic effects (224). ALK1-Fc, known as Dalantercept or ACE-041, which exhibits high binding affinity to BMP-9 and BMP-10, has demonstrated an inhibitory effect on angiogenesis and thus tumour growth (225). These anti-angiogenic therapies are currently being evaluated for their therapeutic potential in the treatment of advanced cancers and metastases in different clinical trials (Table I). In addition to ALK1, CD105, a co-receptor for BMP-9, has been targeted with a monoclonal antibody, TRC105, to prevent angiogenesis (226). In a recent analysis of BMP and BMP receptors in gastric cancer in our lab (227), it was shown that elevated expression levels of BMP receptors in GC were highly associated with tumour-associated angiogenesis and lymphangiogenesis, which facilitate the tumour growth, expansion and spread. However, BMP signalling is only part of the orchestrated signalling required for the formation of new vasculature in tumours, with interactions with other pro-angiogenic factors and pathways, such as HGF, VEGF and fibroblast growth factor, also involved (138). More targeted and specific therapeutic approaches to meet the requirements of each individual patient are expected when improved understanding of the exact underlying mechanisms has been obtained. Therefore, the side effects, adverse effects, and imbalances between BMPs and BMP antagonists should be comprehensively considered when they are evaluated as targets to prevent bone metastasis. Additionally, antibodies or small inhibitors targeting the BMP pathway may affect human bone formation during development and tissue repair. Relevant side effects should be considered in future clinical studies.
In contrast to the development of anti-angiogenic therapies, BMPs have been evaluated for their direct anti-cancer potential with caution. This is mainly as a result of their biphasic effects in both primary tumours and secondary tumours. Most BMPs elicit inhibition of proliferation while also acting as potent inducers of EMT through Smad signalling (2). In bone metastases, imbalanced BMP signalling may facilitate either osteoblastic or osteolytic lesions. None of these will likely result in a favourable outcome in patients with solid tumours (158). More intensive research is required to elucidate the precise role played by BMP signalling in more specific windows of malignancy.
BMPs play a role in tumorigenesis and disease progression, not only from the activation of BMP signalling pathways (25-28), but also from BMP-mediated crosstalk between tumour cells and local environments comprising vascular endothelial cells (140-143), fibroblasts, ECM (183,184), osteoclasts and osteoblasts (137,217,219). BMPs can directly induce angiogenesis by acting on vascular endothelial cells (140-141), and also indirectly promote the synthesis and secretion of pro-angiogenic factors in both cancer cells and stromal cells (138,153). BMP-2 and BMP-4 secreted by breast cancer cells can facilitate their invasiveness via upregulation of tenascin-W and MMPs in adjacent fibroblasts (158,180). BMPs can also alter the ECM by promoting the secretion of ECM components, generating a tumour-supporting tumour microenvironment (183,184). BMPs also play an important part in the vicious cycle of forming metastatic bone lesions (59,218,223,228). Emerging evidence shows that the BMP signalling is also involved in the regulation of immunity. For example, BMP signalling can regulate the activation and differentiation of T cells (229,230). BMP-2 could robustly activate macrophages through Smad 1/5/8 signalling pathway. However, potential roles of BMPs in immunotherapies targeted against malignancies remain to be fully investigated.
Collectively, BMP, tumour cells and the tumour microenvironment constitute a large, intricate network that regulates tumour proliferation, EMT, invasion, angiogenesis, development of metastasis and immune regulation (Fig. 6).
Acknowledgments
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Funding
This work was supported by a Chinese Scholarship from Cardiff University, and sponsorship by Peking University Cancer Hospital and Institute.
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Authors' contributions
ZS, SC, CZ, CL and LY prepared the figures and drafted the manuscript. ZS, CZ and LY revised the manuscript. All authors read and approved the final manuscript.
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Competing interests
The authors declare that they have no competing interests.
ReferencesUristMRBone: Formation by autoinductionScience150893899196510.1126/science.150.3698.8935319761YeLBokobzaSMJiangWGBone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (review)Int J Mol Med24591597200910.3892/ijmm_0000026919787192YangLMengFMaDXieWFangMBridging Decapentaplegic and Wingless signaling in Drosophila wings through repression of naked cuticle by BrinkerDevelopment140413422201310.1242/dev.082578WuMChenGLiYPTGF-β and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and diseaseBone Res416009201610.1038/boneres.2016.9WilletSGMillsJCStomach organ and cell lineage differentiation: From embryogenesis to adult homeostasisCell Mol Gastroenterol Hepatol2546559201610.1016/j.jcmgh.2016.05.006276426255025260TodiscoARegulation of gastric metaplasia, dysplasia, and neoplasia by bone morphogenetic protein signalingCell Mol Gastroenterol Hepatol3339347201710.1016/j.jcmgh.2017.01.014284623765404023TamadaHKitazawaRGohjiKKitazawaSEpigenetic regulation of human bone morphogenetic protein 6 gene expression in prostate cancerJ Bone Miner Res16487496200110.1359/jbmr.2001.16.3.48711277266GuoDHuangJGongJBone morphogenetic protein 4 (BMP4) is required for migration and invasion of breast cancerMol Cell Biochem363179190201210.1007/s11010-011-1170-1YeLKynastonHJiangWGBone morphogenetic protein-10 suppresses the growth and aggressiveness of prostate cancer cells through a Smad independent pathwayJ Urol18127492759200910.1016/j.juro.2009.01.09819375725CaoYSlaneyCYBidwellBNParkerBSJohnstoneCNRautelaJEckhardtBLAndersonRLBMP4 inhibits breast cancer metastasis by blocking myeloid-derived suppressor cell activityCancer Res7450915102201410.1158/0008-5472.CAN-13-317125224959RavalPHsuHHSchneiderDJSarrasMPJrMasuharaKBonewaldLFAndersonHCExpression of bone morphogenetic proteins by osteoinductive and non-osteoinductive human osteosarcoma cellsJ Dent Res7515181523199610.1177/002203459607500713018876605GuoWGorlickRLadanyiMMeyersPAHuvosAGBertinoJRHealeyJHExpression of bone morphogenetic proteins and receptors in sarcomasClin Orthop Relat Res175183199910.1097/00003086-199908000-00023GaoYHYangLYIn situ hybridization and immunohistochemical detection of bone morphogenetic protein genes in ameloblastomasZhonghua Yi Xue Za Zhi746216236471994In ChineseKusafukaKLuytenFPDe BondtRHirakiYShukunamiCKayanoTTakemuraTImmunohistochemical evaluation of cartilage-derived morphogenic protein-1 and -2 in normal human salivary glands and pleomorphic adenomasVirchows Arch442482490200310.1007/s00428-003-0761-y12707774HardwickJCKodachLLOfferhausGJvan den BrinkGRBone morphogenetic protein signalling in colorectal cancerNat Rev Cancer8806812200810.1038/nrc246718756288ClementJHSangerJHoffkenKExpression of bone morphogenetic protein 6 in normal mammary tissue and breast cancer cell lines and its regulation by epidermal growth factorInt J Cancer80250256199910.1002/(SICI)1097-0215(19990118)80:2<250::AID-IJC14>3.0.CO;2-D9935207LehmannKJandaEPierreuxCERytömaaMSchulzeAMcMahonMHillCSBeugHDownwardJRaf induces TGFbeta production while blocking its apoptotic but not invasive responses: A mechanism leading to increased malignancy in epithelial cellsGenes Dev1426102622200010.1101/gad.18170011040215316988OftMPeliJRudazCSchwarzHBeugHReichmannETGF-beta1 and Ha-Ras collaborate in modulating the phenotypic plasticity and invasiveness of epithelial tumor cellsGenes Dev1024622477199610.1101/gad.10.19.24628843198YueJMulderKMRequirement of Ras/MAPK pathway activation by transforming growth factor beta for transforming growth factor beta 1 production in a Smad-dependent pathwayJ Biol Chem2753076530773200010.1074/jbc.M00003920010843986WilkesMCMitchellHPenheiterSGDoréJJSuzukiKEdensMSharmaDKPaganoRELeofEBTransforming growth factor-beta activation of phosphatidylinositol 3-kinase is independent of Smad2 and Smad3 and regulates fibroblast responses via p21-activated kinase-2Cancer Res651043110440200510.1158/0008-5472.CAN-05-152216288034ChenXLiaoJLuYDuanXSunWActivation of the PI3K/Akt pathway mediates bone morphogenetic protein 2-induced invasion of pancreatic cancer cells Panc-1Pathol Oncol Res17257261201110.1007/s12253-010-9307-1WangSEShinIWuFYFriedmanDBArteagaCLHER2/Neu (ErbB2) signaling to Rac1-Pak1 is temporally and spatially modulated by transforming growth factor betaCancer Res6695919600200610.1158/0008-5472.CAN-06-207117018616KangMHOhSCLeeHJKangHNKimJLKimJSYooYAMetastatic function of BMP-2 in gastric cancer cells: The role of PI3K/AKT, MAPK, the NF-κB pathway, and MMP-9 expressionExp Cell Res31717461762201110.1016/j.yexcr.2011.04.00621570392ZhangLYeYLongXXiaoPRenXYuJBMP signaling and its paradoxical effects in tumorigenesis and disseminationOncotarget778206782182016276610095363655YeLMasonMDJiangWGBone morphogenetic protein and bone metastasis, implication and therapeutic potentialFront Biosci (Landmark Ed)16865897201110.2741/3725NoheAHasselSEhrlichMNeubauerFSebaldWHenisYIKnausPThe mode of bone morphogenetic protein (BMP) receptor oligomerization determines different BMP-2 signaling pathwaysJ Biol Chem27753305338200210.1074/jbc.M102750200NoheAKeatingEKnausPPetersenNOSignal transduction of bone morphogenetic protein receptorsCellular Signal16291299200410.1016/j.cellsig.2003.08.011ShiYMassagueJMechanisms of TGF-beta signaling from cell membrane to the nucleusCell113685700200310.1016/S0092-8674(03)00432-X12809600YeLLewis-RussellJMDaviesGSandersAJKynastonHJiangWGHepatocyte growth factor up-regulates the expression of the bone morphogenetic protein (BMP) receptors, BMPR-IB and BMPR-II, in human prostate cancer cellsInt J Oncol30521529200717203235ShibuyaHYamaguchiKShirakabeKTonegawaAGotohYUenoNIrieKNishidaEMatsumotoKTAB1: An activator of the TAK1 MAPKKK in TGF-beta signal transductionScience27211791182199610.1126/science.272.5265.11798638164YamaguchiKNagaiSNinomiya-TsujiJNishitaMTamaiKIrieKUenoNNishidaEShibuyaHMatsumotoKXIAP, a cellular member of the inhibitor of apoptosis protein family, links the receptors to TAB1-TAK1 in the BMP signaling pathwayEMBO J18179187199910.1093/emboj/18.1.17998780611171113YamaguchiKShirakabeKShibuyaHIrieKOishiIUenoNTaniguchiTNishidaEMatsumotoKIdentification of a member of the MAPKKK family as a potential mediator of TGF-beta signal transductionScience27020082011199510.1126/science.270.5244.20088533096KimuraNMatsuoRShibuyaHNakashimaKTagaTBMP2-induced apoptosis is mediated by activation of the TAK1-p38 kinase pathway that is negatively regulated by Smad6J Biol Chem2751764717652200010.1074/jbc.M90862219910748100MoriguchiTKuroyanagiNYamaguchiKGotohYIrieKKanoTShirakabeKMuroYShibuyaHMatsumotoKA novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3J Biol Chem2711367513679199610.1074/jbc.271.23.136758663074IshitaniTNinomiya-TsujiJNagaiSNishitaMMeneghiniMBarkerNWatermanMBowermanBCleversHShibuyaHMatsumotoKThe TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCFNature399798802199910.1038/2167410391247LeeSWHanSIKimHHLeeZHTAK1-dependent activation of AP-1 and c-Jun N-terminal kinase by receptor activator of NF-kappaBJ Biochem Mol Biol35371376200212296995ShirakabeKYamaguchiKShibuyaHIrieKMatsudaSMoriguchiTGotohYMatsumotoKNishidaETAK1 mediates the ceramide signaling to stress-activated protein kinase/c-Jun N-terminal kinaseJ Biol Chem27281418144199710.1074/jbc.272.13.81419079627AlarmoELKallioniemiABone morphogenetic proteins in breast cancer: Dual role in tumourigenesis?Endocr Relat Cancer17R123R139201010.1677/ERC-09-027320335308GazzerroEGangjiVCanalisEBone morphogenetic proteins induce the expression of noggin, which limits their activity in cultured rat osteoblastsJ Clin Invest10221062114199810.1172/JCI34599854046509165OnichtchoukDChenYGDoschRGawantkaVDeliusHMassaguéJNiehrsCSilencing of TGF-beta signalling by the pseudoreceptor BAMBINature401480485199910.1038/4679410519551GrotewoldLPlumMDildropRPetersTRutherUBambi is coexpressed with Bmp-4 during mouse embryogenesisMech Dev100327330200110.1016/S0925-4773(00)00524-411165491SamadTARebbapragadaABellEZhangYSidisYJeongSJCampagnaJAPerusiniSFabrizioDASchneyerALDRAGON, a bone morphogenetic protein co-receptorJ Biol Chem2801412214129200510.1074/jbc.M41003420015671031BabittJLZhangYSamadTAXiaYTangJCampagnaJASchneyerALWoolfCJLinHYRepulsive guidance molecule (RGMa), a DRAGON homologue, is a bone morphogenetic protein co-receptorJ Biol Chem2802982029827200510.1074/jbc.M50351120015975920BabittJLHuangFWWrightingDMXiaYSidisYSamadTACampagnaJAChungRTSchneyerALWoolfCJBone morphogenetic protein signaling by hemojuvelin regulates hepcidin expressionNat Genet38531539200610.1038/ng177716604073HayashiHAbdollahSQiuYCaiJXuYYGrinnellBWRichardsonMATopperJNGimbroneMAJrWranaJLFalbDThe MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signalingCell8911651173199710.1016/S0092-8674(00)80303-79215638TakaseMImamuraTSampathTKTakedaKIchijoHMiyazonoKKawabataMInduction of Smad6 mRNA by bone morphogenetic proteinsBiochem Biophys Res Commun2442629199810.1006/bbrc.1998.82009514869IshisakiAYamatoKHashimotoSNakaoATamakiKNonakaKten DijkePSuginoHNishiharaTDifferential inhibition of Smad6 and Smad7 on bone morphogenetic protein- and activin-mediated growth arrest and apoptosis in B cellsJ Biol Chem2741363713642199910.1074/jbc.274.19.1363710224135FengXHLinXDerynckRSmad2, Smad3 and Smad4 cooperate with Sp1 to induce p15(Ink4B) transcription in response to TGF-betaEMBO J1951785193200010.1093/emboj/19.19.517811013220302105SanoYHaradaJTashiroSGotoh-MandevilleRMaekawaTIshiiSATF-2 is a common nuclear target of Smad and TAK1 pathways in transforming growth factor-beta signalingJ Biol Chem27489498957199910.1074/jbc.274.13.894910085140CordenonsiMMontagnerMAdornoMZacchignaLMartelloGMamidiASoligoSDupontSPiccoloSIntegration of TGF-beta and Ras/MAPK signaling through p53 phosphorylationScience315840843200710.1126/science.113596117234915MiyazonoKMaedaSImamuraTCoordinate regulation of cell growth and differentiation by TGF-beta superfamily and Runx proteinsOncogene2342324237200410.1038/sj.onc.120713115156178GermainSHowellMEsslemontGMHillCSHomeodomain and winged-helix transcription factors recruit activated Smads to distinct promoter elements via a common Smad interaction motifGenes Dev14435451200010691736316385MiyazonoKten DijkePHeldinCHTGF-beta signaling by Smad proteinsAdv Immunol75115157200010.1016/S0065-2776(00)75003-610879283DurandSHRomeasACoubleMLLangloisDLiJYMagloireHBleicherFStaquetMJFargesJCExpression of the TGF-beta/BMP inhibitor EVI1 in human dental pulp cellsArch Oral Biol52712719200710.1016/j.archoralbio.2007.01.01217328861LuoKStroscheinSLWangWChenDMartensEZhouSZhouQThe Ski oncoprotein interacts with the Smad proteins to repress TGFbeta signalingGenes Dev1321962206199910.1101/gad.13.17.219610485843316985SpagnoliFMBrivanlouAHThe Gata5 target, TGIF2, defines the pancreatic region by modulating BMP signals within the endodermDevelopment135451461200810.1242/dev.008458WottonDMassagueJSmad transcriptional corepressors in TGF beta family signalingCurr Top Microbiol Immunol254145164200111190572ZhuHKavsakPAbdollahSWranaJLThomsenGHA SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formationNature400687693199910.1038/2329310458166YeLLewis-RussellJMKyanastonHGJiangWGBone morphogenetic proteins and their receptor signaling in prostate cancerHistol Histopathol2211291147200717616940BeckSECarethersJMBMP suppresses PTEN expression via RAS/ERK signalingCancer Biol Ther613131317200710.4161/cbt.6.8.4507180591584154563DuchartreYKimYMKahnMThe Wnt signaling pathway in cancerCrit Rev Oncol Hematol99141149201610.1016/j.critrevonc.2015.12.005267757305853106VeemanMTAxelrodJDMoonRTA second canon. Functions and mechanisms of beta-catenin-independent Wnt signalingDev Cell5367377200310.1016/S1534-5807(03)00266-112967557MosimannCHausmannGBaslerKBeta-catenin hits chromatin: Regulation of Wnt target gene activationNat Rev Mol Cell Biol10276286200910.1038/nrm265419305417MoonRTWnt/beta-catenin pathwaySci STKE2005cm1200515713948TeoJLKahnMThe Wnt signaling pathway in cellular proliferation and differentiation: A tale of two coactivatorsAdv Drug Deliv Rev6211491155201010.1016/j.addr.2010.09.01220920541ImaiYTeraiHNomura-FuruwatariCMizunoSMatsumotoKNakamuraTTakaokaKHepatocyte growth factor contributes to fracture repair by upregulating the expression of BMP receptorsJ Bone Miner Res2017231730200510.1359/JBMR.05060716160730ZhenRYangJWangYLiYChenBSongYMaGYangBHepatocyte growth factor improves bone regeneration via the bone morphogenetic protein2mediated NFκB signaling pathwayMol Med Rep1760456053201829436622LuoKSignaling cross talk between TGF-β/smad and other signaling pathwaysCold Spring Harb Perspect Biol9pii: a022137201710.1101/cshperspect.a022137LabbeELetamendiaAAttisanoLAssociation of Smads with lymphoid enhancer binding factor 1/T cell-specific factor mediates cooperative signaling by the transforming growth factor-beta and wnt pathwaysProc Natl Acad Sci USA9783588363200010.1073/pnas.1501526971089091126952NishitaMHashimotoMKOgataSLaurentMNUenoNShibuyaHChoKWInteraction between Wnt and TGF-beta signalling pathways during formation of Spemann's organizerNature403781785200010.1038/3500160210693808HusseinSMDuffEKSirardCSmad4 and beta-catenin co-activators functionally interact with lymphoid-enhancing factor to regulate graded expression of Msx2J Biol Chem2784880548814200310.1074/jbc.M30547220014551209WengXZhangHYeJKanMLiuFWangTDengJTanYHeLLiuYHypermethylated Epidermal growth factor receptor (EGFR) promoter is associated with gastric cancerSci Rep510154201510.1038/srep10154259592504426697LemmonMASchlessingerJCell signaling by receptor tyrosine kinasesCell14111171134201010.1016/j.cell.2010.06.011206029962914105SigismundSAvanzatoDLanzettiLEmerging functions of the EGFR in cancerMol Oncol12320201810.1002/1878-0261.121555748484de CaesteckerMPParksWTFrankCJCastagninoPBottaroDPRobertsABLechleiderRJSmad2 transduces common signals from receptor serine-threonine and tyrosine kinasesGenes Dev1215871592199810.1101/gad.12.11.15879620846316877BrownJDDiChiaraMRAndersonKRGimbroneMAJrTopperJNMEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cellsJ Biol Chem27487978805199910.1074/jbc.274.13.879710085121RossKRCoreyDADunnJMKelleyTJSMAD3 expression is regulated by mitogen-activated protein kinase kinase-1 in epithelial and smooth muscle cellsCell Signal19923931200710.1016/j.cellsig.2006.11.00817197157KretzschmarMDoodyJTimokhinaIMassagueJA mechanism of repression of TGFbeta/ Smad signaling by oncogenic RasGenes Dev13804816199910.1101/gad.13.7.80410197981316599MatsuuraIWangGHeDLiuFIdentification and characterization of ERK MAP kinase phosphorylation sites in Smad3Biochemistry441254612553200510.1021/bi050560g16156666KamarajuAKRobertsABRole of Rho/ROCK and p38 MAP kinase pathways in transforming growth factor-beta-mediated Smad-dependent growth inhibition of human breast carcinoma cells in vivoJ Biol Chem28010241036200510.1074/jbc.M403960200GuoXWangXFSignaling cross-talk between TGF-beta/BMP and other pathwaysCell Res197188200910.1038/cr.2008.302SahaDDattaPKBeauchampRDOncogenic ras represses transforming growth factor-beta /Smad signaling by degrading tumor suppressor Smad4J Biol Chem2762953129537200110.1074/jbc.M10006920011371552LiangMLiangYYWrightonKUngermannovaDWangXPBrunicardiFCLiuXFengXHLinXUbiquitination and proteolysis of cancer-derived Smad4 mutants by SCFSkp2Mol Cell Biol2475247537200410.1128/MCB.24.17.7524-7537.200415314162506984BrodinGAhgrenAten DijkePHeldinCHHeuchelREfficient TGF-beta induction of the Smad7 gene requires cooperation between AP-1, Sp1, and Smad proteins on the mouse Smad7 promoterJ Biol Chem2752902329030200010.1074/jbc.M00281520010843994DowdySCMarianiAJanknechtRHER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor beta inhibitor Smad7 via the ETS protein ER81J Biol Chem2784437744384200310.1074/jbc.M30720220012947087UchidaKSuzukiHOhashiTNittaKYumuraWNiheiHInvolvement of MAP kinase cascades in Smad7 transcriptional regulationBiochem Biophys Res Commun289376381200110.1006/bbrc.2001.598411716483ShaulianEKarinMAP-1 as a regulator of cell life and deathNat Cell Biol4E131E136200210.1038/ncb0502-e13111988758HanafusaHNinomiya-TsujiJMasuyamaNNishitaMFujisawaJShibuyaHMatsumotoKNishidaEInvolvement of the p38 mitogen-activated protein kinase pathway in transforming growth factor-beta-induced gene expressionJ Biol Chem2742716127167199910.1074/jbc.274.38.2716110480932JinEJLeeSYChoiYAJungJCBangOSKangSSBMP-2-enhanced chondrogenesis involves p38 MAPK-mediated down-regulation of Wnt-7a pathwayMol Cells223533592006ThomasDAMassagueJTGF-beta directly targets cytotoxic T cell functions during tumor evasion of immune surveillanceCancer Cell8369380200510.1016/j.ccr.2005.10.01216286245MonzenKHiroiYKudohSAkazawaHOkaTTakimotoEHayashiDHosodaTKawabataMMiyazonoKSmads, TAK1, and their common target ATF-2 play a critical role in cardiomyocyte differentiationJ Cell Biol153687698200110.1083/jcb.153.4.687113529312192375BakinAVTomlinsonAKBhowmickNAMosesHLArteagaCLPhosphatidylinositol 3-kinase function is required for transforming growth factor beta-mediated epithelial to mesenchymal transition and cell migrationJ Biol Chem2753680336810200010.1074/jbc.M00591220010969078LamouilleSDerynckRCell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathwayJ Cell Biol178437451200710.1083/jcb.200611146176463962064840Ghosh-ChoudhuryNAbboudSLNishimuraRCelesteAMahimainathanLChoudhuryGGRequirement of BMP-2-induced phosphatidylinositol 3-kinase and Akt serine/threonine kinase in osteoblast differentiation and Smad-dependent BMP-2 gene transcriptionJ Biol Chem2773336133368200210.1074/jbc.M20505320012084724HeXCZhangJTongWGTawfikORossJScovilleDHTianQZengXHeXWiedemannLMBMP signaling inhibits intestinal stem cell self-renewal through suppression of Wnt-beta-catenin signalingNat Genet3611171121200410.1038/ng143015378062TianQHeXCHoodLLiLBridging the BMP and Wnt pathways by PI3 kinase/Akt and 14-3-3zetaCell Cycle4215216200510.4161/cc.4.2.141215655376Valderrama-CarvajalHCocolakisELacerteALeeEHKrystalGAliSLebrunJJActivin/TGF-beta induce apoptosis through Smad-dependent expression of the lipid phosphatase SHIPNat Cell Biol4963969200210.1038/ncb88512447389LuZGhoshSWangZHunterTDownregulation of caveolin-1 function by EGF leads to the loss of E-cadherin, increased transcriptional activity of beta-catenin, and enhanced tumor cell invasionCancer Cell4499515200310.1016/S1535-6108(03)00304-0JiHWangJNikaHHawkeDKeezerSGeQFangBFangXFangDLitchfieldDWEGF-induced ERK activation promotes CK2-mediated disassociation of alpha-Catenin from beta-Catenin and transactivation of beta-CateninMol Cell36547559200910.1016/j.molcel.2009.09.034199418162784926YeLLewis-RussellJMSandersAJKynastonHJiangWGHGF/SF up-regulates the expression of bone morphogenetic protein 7 in prostate cancer cellsUrol Oncol26190197200810.1016/j.urolonc.2007.03.02718312940JiangWGMartinTAParrCDaviesGMatsumotoKNakamuraTHepatocyte growth factor, its receptor, and their potential value in cancer therapiesCrit Rev Oncol Hematol533569200510.1016/j.critrevonc.2004.09.004DaviesGMasonMDMartinTAParrCWatkinsGLaneJMatsumotoKNakamuraTJiangWGThe HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivoInt J Cancer106348354200310.1002/ijc.1122012845672MartinTAParrCDaviesGWatkinsGLaneJMatsumotoKNakamuraTManselREJiangWGGrowth and angio-genesis of human breast cancer in a nude mouse tumour model is reduced by NK4, a HGF/SF antagonistCarcinogenesis2413171323200310.1093/carcin/bgg07212807719TomiokaDMaeharaNKubaKMizumotoKTanakaMMatsumotoKNakamuraTInhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse modelCancer Res6175187524200111606388AbounaderRRanganathanSLalBFieldingKBookADietzHBurgerPLaterraJReversion of human glioblastoma malignancy by U1 small nuclear RNA/ribozyme targeting of scatter factor/hepatocyte growth factor and c-met expressionJ Natl Cancer Inst9115481556199910.1093/jnci/91.18.154810491431JiangWGGrimshawDMartinTADaviesGParrCWatkinsGLaneJAbounaderRLaterraJManselREReduction of stromal fibroblast-induced mammary tumor growth, by retroviral ribozyme transgenes to hepatocyte growth factor/scatter factor and its receptor, c-METClin Cancer Res942744281200314519655GrenierAChollet-MartinSCrestaniBDelarcheCEl BennaJBouttenAAndrieuVDurandGGougerot-PocidaloMAAubierMDehouxMPresence of a mobilizable intracellular pool of hepatocyte growth factor in human polymorphonuclear neutrophilsBlood9929973004200210.1182/blood.V99.8.299711929792TaiebJDelarcheCParadisVMathurinPGrenierACrestaniBDehouxMThabutDGougerot-PocidaloMAPoynardTChollet-MartinSPolymorphonuclear neutrophils are a source of hepatocyte growth factor in patients with severe alcoholic hepatitisJ Hepatol36342348200210.1016/S0168-8278(01)00276-811867177JaffreSDehouxMPaugamCGrenierAChollet-MartinSSternJBMantzJAubierMCrestaniBHepatocyte growth factor is produced by blood and alveolar neutrophils in acute respiratory failureAm J Physiol Lung Cell Mol Physiol282L310L315200210.1152/ajplung.00121.200111792636NakamuraTNawaKIchiharaAPartial purification and characterization of hepatocyte growth factor from serum of hepatectomized ratsBiochem Biophys Res Commun12214501459198410.1016/0006-291X(84)91253-16477569NakashiroKHayashiYOyasuRImmunohistochemical expression of hepatocyte growth factor and c-Met/HGF receptor in benign and malignant human prostate tissueOnco Rep10114911532003NakashiroKHaraSShinoharaYOyasuMKawamataHShintaniSHamakawaHOyasuRPhenotypic switch from paracrine to autocrine role of hepatocyte growth factor in an androgen-independent human prostatic carcinoma cell line, CWR22RAm J Pathol165533540200410.1016/S0002-9440(10)63318-4152772271618563JanovskaPBryjaVWnt signalling pathways in chronic lymphocytic leukaemia and B-cell lymphomasBr J Pharmacol17447014715201710.1111/bph.13949287032835727250HopplerSMoonRTBMP-2/-4 and Wnt-8 cooperatively pattern the Xenopus mesodermMech Dev71119129199810.1016/S0925-4773(98)00004-59507084FuentealbaLCEiversEIkedaAHurtadoCKurodaHPeraEMDe RobertisEMIntegrating patterning signals: Wnt/GSK3 regulates the duration of the BMP/Smad1 signalCell131980993200710.1016/j.cell.2007.09.027180455392200633MilletCYamashitaMHellerMYuLRVeenstraTDZhangYEA negative feedback control of transforming growth factor-beta signaling by glycogen synthase kinase 3-mediated Smad3 linker phosphorylation at Ser-204J Biol Chem2841980819816200910.1074/jbc.M109.016667194580832740406AragonEGoernerNZaromytidouAIXiQEscobedoAMassaguéJMaciasMJA Smad action turnover switch operated by WW domain readers of a phosphoserine codeGenes Dev2512751288201110.1101/gad.2060811216853633127429FeiCLiZLiCChenYChenZHeXMaoLWangXZengRLiLSmurf1-mediated Lys29-linked nonproteolytic polyubiquitination of axin negatively regulates Wnt/β-catenin signalingMol Cell Biol3340954105201310.1128/MCB.00418-13239597993811687KimSJhoEHThe protein stability of Axin, a negative regulator of Wnt signaling, is regulated by Smad ubiquitination regulatory factor 2 (Smurf2)J Biol Chem2853642036426201010.1074/jbc.M110.137471208588992978571JianHShenXLiuISemenovMHeXWangXFSmad3-dependent nuclear translocation of beta-catenin is required for TGF-beta1-induced proliferation of bone marrow-derived adult human mesenchymal stem cellsGenes Dev20666674200610.1101/gad.1388806165432201413283Aza-BlancPKornbergTBCi: A complex transducer of the hedgehog signalTrends Genet15458462199910.1016/S0168-9525(99)01869-710529809HepkerJBlackmanRKHolmgrenRCubitus inter-ruptus is necessary but not sufficient for direct activation of a wing-specific decapentaplegic enhancerDevelopment12636693677199910409512MullerBBaslerKThe repressor and activator forms of Cubitus interruptus control Hedgehog target genes through common generic gli-binding sitesDevelopment12729993007200010862738DennlerSAndreJAlexakiILiAMagnaldoTten DijkePWangXJVerrecchiaFMauvielAInduction of sonic hedgehog mediators by transforming growth factor-beta: Smad3-dependent activation of Gli2 and Gli1 expression in vitro and in vivoCancer Res6769816986200710.1158/0008-5472.CAN-07-049117638910BlokzijlADahlqvistCReissmannEFalkAMolinerALendahlUIbáñezCFCross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3J Cell Biol163723728200310.1083/jcb.200305112146388572173673AsanoNWatanabeTKitaniAFussIJStroberWNotch1 signaling and regulatory T cell functionJ Immunol18027962804200810.4049/jimmunol.180.5.279618292500SamonJBChamphekarAMinterLMTelferJCMieleLFauqADasPGoldeTEOsborneBANotch1 and TGFbeta1 cooperatively regulate Foxp3 expression and the maintenance of peripheral regulatory T cellsBlood11218131821200810.1182/blood-2008-03-144980185508502518888OstroukhovaMQiZOrissTBDixon-McCarthyBRayPRayATreg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-betaJ Clin Invest1169961004200610.1172/JCI26490165439501401482UlloaLDoodyJMassagueJInhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathwayNature397710713199910.1038/1782610067896IshidaYKondoTTakayasuTIwakuraYMukaidaNThe essential involvement of cross-talk between IFN-gamma and TGF-beta in the skin wound-healing processJ Immunol17218481855200410.4049/jimmunol.172.3.184814734769JenkinsBJGrailDNheuTNajdovskaMWangBWaringPIngleseMMcLoughlinRMJonesSATopleyNHyperactivation of Stat3 in gp130 mutant mice promotes gastric hyperproliferation and desensitizes TGF-beta signalingNat Med11845852200510.1038/nm128216041381HuangMSharmaSZhuLXKeaneMPLuoJZhangLBurdickMDLinYQDohadwalaMGardnerBIL-7 inhibits fibroblast TGF-beta production and signaling in pulmonary fibrosisJ Clin Invest109931937200210.1172/JCI021468511927620150933LetterioJJRobertsABRegulation of immune responses by TGF-betaAnnu Rev Immunol16137161199810.1146/annurev.immunol.16.1.1379597127KangYSiegelPMShuWDrobnjakMKakonenSMCordón-CardoCGuiseTAMassaguéJA multigenic program mediating breast cancer metastasis to boneCancer Cell3537549200310.1016/S1535-6108(03)00132-612842083KangYHeWTulleySGuptaGPSerganovaIChenCRManova-TodorovaKBlasbergRGeraldWLMassaguéJBreast cancer bone metastasis mediated by the Smad tumor suppressor pathwayProc Natl Acad Sci USA1021390913914200510.1073/pnas.0506517102161723831236573FongYCMaaMCTsaiFJChenWCLinJGJengLBYangRSFuWMTangCHOsteoblast-derived TGF-beta1 stimulates IL-8 release through AP-1 and NF-kappaB in human cancer cellsJ Bone Miner Res23961970200810.1359/jbmr.08020618435575TsengJCChenHFWuKJA twist tale of cancer metastasis and tumor angiogenesisHistol Histopathol3012831294201526084282YeLJiangWGBone morphogenetic proteins in tumour associated angiogenesis and implication in cancer therapiesCancer Lett380586597201610.1016/j.canlet.2015.10.036GoumansMJValdimarsdottirGItohSRosendahlASiderasPten DijkePBalancing the activation state of the endothelium via two distinct TGF-beta type I receptorsEMBO J2117431753200210.1093/emboj/21.7.174311927558125949YamashitaHShimizuAKatoMNishitohHIchijoHHanyuAMoritaIKimuraMMakishimaFMiyazonoKGrowth/differentiation factor-5 induces angiogenesis in vivoExp Cell Res235218226199710.1006/excr.1997.36649281371MoriSYoshikawaHHashimotoJUedaTFunaiHKatoMTakaokaKAntiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2Bone2299105199810.1016/S8756-3282(97)00248-29477232YehLCLeeJCOsteogenic protein-1 increases gene expression of vascular endothelial growth factor in primary cultures of fetal rat calvaria cellsMol Cell Endocrinol153113124199910.1016/S0303-7207(99)00076-310459859GlienkeJSchmittAOPilarskyCHinzmannBWeissBRosenthalAThierauchKHDifferential gene expression by endothelial cells in distinct angiogenic statesEur J Biochem26728202830200010.1046/j.1432-1327.2000.01325.x10785405LangenfeldEMLangenfeldJBone morphogenetic protein-2 stimulates angiogenesis in developing tumorsMolc Cancer Res21411492004FinkenzellerGHagerSStarkGBEffects of bone morpho-genetic protein 2 on human umbilical vein endothelial cellsMicrovasc Res848185201210.1016/j.mvr.2012.03.01022487440WilletteRNGuJLLyskoPGAndersonKMMinehartHYueTBMP-2 gene expression and effects on human vascular smooth muscle cellsJ Vasc Re36120125199910.1159/000025634DoraiHVukicevicSSampathTKBone morphogenetic protein-7 (osteogenic protein-1) inhibits smooth muscle cell proliferation and stimulates the expression of markers that are characteristic of SMC phenotype in vitroJ Cell Physiol1843745200010.1002/(SICI)1097-4652(200007)184:1<37::AID-JCP4>3.0.CO;2-M10825232MorrellNWYangXUptonPDJourdanKBMorganNShearesKKTrembathRCAltered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteinsCirculation104790795200110.1161/hc3201.09415211502704DavidLMalletCMazerbourgSFeigeJJBaillySIdentification of BMP9 and BMP10 as functional activators of the orphan activin receptor-like kinase 1 (ALK1) in endothelial cellsBlood10919531961200710.1182/blood-2006-07-034124RegazzoniCWinterhalterKHRohrerLType I collagen induces expression of bone morphogenetic protein receptor type IIBiochem Biophys Res Commun283316322200110.1006/bbrc.2001.481311327700NakagawaTLiJHGarciaGMuWPiekEBöttingerEPChenYZhuHJKangDHSchreinerGFTGF-beta induces proangiogenic and antiangiogenic factors via parallel but distinct Smad pathwaysKidney Int66605613200410.1111/j.1523-1755.2004.00780.x15253713HanSUKimHTSeongDHKimYSParkYSBangYJYangHKKimSJLoss of the Smad3 expression increases susceptibility to tumorigenicity in human gastric cancerOncogene2313331341200410.1038/sj.onc.1207259DaiJKitagawaYZhangJYaoZMizokamiAChengSNörJMcCauleyLKTaichmanRSKellerETVascular endothe-lial growth factor contributes to the prostate cancer-induced osteoblast differentiation mediated by bone morphogenetic proteinCancer Res64994999200410.1158/0008-5472.CAN-03-138214871830StabileHMitolaSMoroniEBelleriMNicoliSColtriniDPeriFPessiAOrsattiLTalamoFBone morphogenic protein antagonist Drm/gremlin is a novel proangiogenic factorBlood10918341840200710.1182/blood-2006-06-032276AkiyamaIYoshinoOOsugaYShiJHaradaMKogaKHirotaYHirataTFujiiTSaitoSKozumaSBone morphogenetic protein 7 increased vascular endothelial growth factor (VEGF)-a expression in human granulosa cells and VEGF receptor expression in endothelial cellsReprod Sci21477482201410.1177/19337191135034113960841RaidaMClementJHLeekRDAmeriKBicknellRNiederwieserDHarrisALBone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesisJ Cancer Res Clin Oncol131741750200510.1007/s00432-005-0024-116136355ScharpfeneckerMvan DintherMLiuZvan BezooijenRLZhaoQPukacLLöwikCWten DijkePBMP-9 signals via ALK1 and inhibits bFGF-induced endothelial cell proliferation and VEGF-stimulated angiogenesisJ Cell Sci120964972200710.1242/jcs.00294917311849ZabkiewiczCResaulJHargestRJiangWGYeLBone morphogenetic proteins, breast cancer, and bone metastases: Striking the right balanceEndocr Relat Cancer24R349R366201710.1530/ERC-17-0139287334695574206RamoshebiLNRipamontiUOsteogenic protein-1, a bone morphogenetic protein, induces angiogenesis in the chick chorioallantoic membrane and synergizes with basic fibroblast growth factor and transforming growth factor-beta1Anat Rec25997107200010.1002/(SICI)1097-0185(20000501)259:1<97::AID-AR11>3.0.CO;2-O10760748LarueLBellacosaAEpithelial-mesenchymal transition in development and cancer: Role of phosphatidylinositol 3' kinase/AKT pathwaysOncogene2474437454200510.1038/sj.onc.120909116288291LamouilleSXuJDerynckRMolecular mechanisms of epithelial-mesenchymal transitionNat Rev Mol Cell Biol15178196201410.1038/nrm3758245568404240281NakajimaYYamagishiTHokariSNakamuraHMechanisms involved in valvuloseptal endocardial cushion formation in early cardiogenesis: Roles of transforming growth factor (TGF)-beta and bone morphogenetic protein (BMP)Anat Rec258119127200010.1002/(SICI)1097-0185(20000201)258:2<119::AID-AR1>3.0.CO;2-U10645959RomanoLARunyanRBSlug is an essential target of TGFbeta2 signaling in the developing chicken heartDev Biol22391102200010.1006/dbio.2000.975010864463YangSZhongCFrenkelBReddiAHRoy-BurmanPDiverse biological effect and Smad signaling of bone morpho-genetic protein 7 in prostate tumor cellsCancer Res6557695777200510.1158/0008-5472.CAN-05-028915994952MontesanoRBone morphogenetic protein-4 abrogates lumen formation by mammary epithelial cells and promotes invasive growthBiochem Biophys Res Commun353817822200710.1016/j.bbrc.2006.12.109PiekEMoustakasAKurisakiAHeldinCHten DijkePTGF-(beta) type I receptor/ALK-5 and Smad proteins mediate epithelial to mesenchymal transdifferentiation in NMuMG breast epithelial cellsJ Cell Sci11245574568199910574705YangSDuJWangZYuanWQiaoYZhangMZhangJGaoSYinJSunBZhuTBMP-6 promotes E-cadherin expression through repressing deltaEF1 in breast cancer cellsBMC Cancer7211200710.1186/1471-2407-7-211179978622217560ClementJHRaidaMSangerJBicknellRLiuJNaumannAGeyerAWaldauAHortschanskyPSchmidtABone morphogenetic protein 2 (BMP-2) induces in vitro invasion and in vivo hormone independent growth of breast carcinoma cellsInt J Oncol27401407200516010421KatsunoYHanyuAKandaHIshikawaYAkiyamaFIwaseTOgataEEhataSMiyazonoKImamuraTBone morpho-genetic protein signaling enhances invasion and bone metastasis of breast cancer cells through Smad pathwayOncogene2763226333200810.1038/onc.2008.23218663362GautschiOTepperCGPurnellPRIzumiyaYEvansCPGreenTPDesprezPYLaraPNGandaraDRMackPCKungHJRegulation of Id1 expression by SRC: Implications for targeting of the bone morphogenetic protein pathway in cancerCancer Res6822502258200810.1158/0008-5472.CAN-07-640318381431BuijsJTHenriquezNVvan OverveldPGvan der HorstGQueISchwaningerRRentschCTen DijkePCleton-JansenAMDriouchKBone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancerCancer Res6787428751200710.1158/0008-5472.CAN-06-249017875715DuJYangSAnDHuFYuanWZhaiCZhuTBMP-6 inhibits microRNA-21 expression in breast cancer through repressing deltaEF1 and AP-1Cell Res19487496200910.1038/cr.2009.3419308091de BoeckMCuiCMulderAAJostCRIkenoSTen DijkePSmad6 determines BMP-regulated invasive behaviour of breast cancer cells in a zebrafish xenograft modelSci Rep624968201610.1038/srep24968271134364844967Luna-ZuritaLPradosBGrego-BessaJLuxánGdel MonteGBenguríaAAdamsRHPérez-PomaresJMde la PompaJLIntegration of a Notch-dependent mesenchymal gene program and Bmp2-driven cell invasiveness regulates murine cardiac valve formationJ Clin Invest12034933507201010.1172/JCI42666208900422947227MaLLuMFSchwartzRJMartinJFBmp2 is essential for cardiac cushion epithelial-mesenchymal transition and myocardial patterningDevelopment13256015611200510.1242/dev.0215616314491DyerLLockyerPWuYSahaACyrCMoserMPiXPattersonCBMPER promotes epithelial-mesenchymal transition in the developing cardiac cushionsPLoS One10e0139209201510.1371/journal.pone.0139209264184554587915KangMHKangHNKimJLKimJSOhSCYooYAInhibition of PI3 kinase/Akt pathway is required for BMP2-induced EMT and invasionOncol Rep22525534200919639199KangMHKimJSSeoJEOhSCYooYABMP2 accelerates the motility and invasiveness of gastric cancer cells via activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathwayExp Cell Res3162437201010.1016/j.yexcr.2009.10.010OwensPPolikowskyHPickupMWGorskaAEJovanovicBShawAKNovitskiySVHongCCMosesHLBone Morphogenetic Proteins stimulate mammary fibroblasts to promote mammary carcinoma cell invasionPLoS One8e67533201310.1371/journal.pone.0067533238407333695869ScherberichATuckerRPDegenMBrown-LuediMAndresACChiquet-EhrismannRTenascin-W is found in malignant mammary tumors, promotes alpha8 integrin-dependent motility and requires p38MAPK activity for BMP-2 and TNF-alpha induced expression in vitroOncogene2415251532200510.1038/sj.onc.1208342GiussaniMTriulziTSozziGTagliabueETumor extracellular matrix remodeling: New perspectives as a circulating tool in the diagnosis and prognosis of solid tumorsCells8pii: E81201910.3390/cells8020081306780586406979EbleJANilandSThe extracellular matrix in tumor progression and metastasisClin Exp Metastasis36171198201910.1007/s10585-019-09966-130972526ZhongLWangXWangSYangLGaoHYangCThe anti-fibrotic effect of bone morphogenic protein-7(BMP-7) on liver fibrosisInt J Med Sci10441450201310.7150/ijms.5765234715553590605LiHCuiDZhaoFHuoLHuJZengJBMP-2 is involved in scleral remodeling in myopia developmentPLoS One10e0125219201510.1371/journal.pone.0125219259659954429026ChenCCLauLFFunctions and mechanisms of action of CCN matricellular proteinsInt J Biochem Cell Biol41771783200910.1016/j.biocel.2008.07.0252668982LeaskAAbrahamDJAll in the CCN family: Essential matricellular signaling modulators emerge from the bunkerJ Cell Sci11948034810200610.1242/jcs.0327017130294HolbournKPAcharyaKRPerbalBThe CCN family of proteins: Structure-function relationshipsTrends Biochem Sci33461473200810.1016/j.tibs.2008.07.006187896962683937KireevaMLMoFEYangGPLauLFCyr61, a product of a growth factor-inducible immediate-early gene, promotes cell proliferation, migration, and adhesionMol Cell Biol1613261334199610.1128/MCB.16.4.13268657105231116YosimichiGNakanishiTNishidaTHattoriTTakano-YamamotoTTakigawaMCTGF/Hcs24 induces chondrocyte differentiation through a p38 mitogen-activated protein kinase (p38MAPK), and proliferation through a p44/42 MAPK/extracellular-signal regulated kinase (ERK)Eur J Biochem26860586065200110.1046/j.0014-2956.2001.02553.x11732999Baguma-NibashekaMKablarBPulmonary hypoplasia in the connective tissue growth factor (Ctgf) null mouseDev Dyn237485493200810.1002/dvdy.2143318213577ChenCCChenNLauLFThe angiogenic factors Cyr61 and connective tissue growth factor induce adhesive signaling in primary human skin fibroblastsJ Biol Chem2761044310452200110.1074/jbc.M008087200LiuHDongWLinZLuJWanHZhouZLiuZCCN4 regulates vascular smooth muscle cell migration and proliferationMol Cells36112118201310.1007/s10059-013-0012-2238070443887954SchutzeNSchenkRFiedlerJMattesTJakobFBrennerRECYR61/CCN1 and WISP3/CCN6 are chemoattractive ligands for human multipotent mesenchymal stroma cellsBMC Cell Biol845200710.1186/1471-2121-8-45179739952211300LeuSJLamSCLauLFPro-angiogenic activities of CYR61 (CCN1) mediated through integrins alphavbeta3 and alpha6beta1 in human umbilical vein endothelial cellsJ Biol Chem2774624846255200210.1074/jbc.M20928820012364323TodorovicVChenCCHayNLauLFThe matrix protein CCN1 (CYR61) induces apoptosis in fibroblastsJ Cell Biol171559568200510.1083/jcb.200504015162757571626352KubotaSTakigawaMCCN family proteins and angiogen-esis: from embryo to adulthoodAngiogenesis10111200710.1007/s10456-006-9058-5KularLPakradouniJKitabgiPLaurentMMartinerieCThe CCN family: A new class of inflammation modulators?Biochimie93377388201110.1016/j.biochi.2010.11.010BaiTChenCCLauLFMatricellular protein CCN1 activates a proinflammatory genetic program in murine macrophagesJ Immunol18432233232201010.4049/jimmunol.0902792201644162832719AbreuJGKetpuraNIReversadeBDe RobertisEMConnective-tissue growth factor (CTGF) modulates cell signalling by BMP and TGF-betaNat Cell Biol4599604200210.1038/ncb826121341602387275MinamizatoTSakamotoKLiuTKokuboHKatsubeKPerbalBNakamuraSYamaguchiACCN3/NOV inhibits BMP-2-induced osteoblast differentiation by interacting with BMP and Notch signaling pathwaysBiochem Biophys Res Commun354567573200710.1016/j.bbrc.2007.01.02917250806OnoMInksonCAKiltsTMYoungMFWISP-1/CCN4 regulates osteogenesis by enhancing BMP-2 activityJ Bone Miner Res26193208201110.1002/jbmr.205NakamuraYWeidingerGLiangJOAquilina-BeckATamaiKMoonRTWarmanMLThe CCN family member Wisp3, mutant in progressive pseudorheumatoid dysplasia, modulates BMP and Wnt signalingJ Clin Invest11730753086200710.1172/JCI32001178236611964511KubotaSKawakiHKondoSYosimichiGMinatoMNishidaTHanagataHMiyauchiATakigawaMMultiple activation of mitogen-activated protein kinases by purified independent CCN2 modules in vascular endothelial cells and chondrocytes in cultureBiochimie8819731981200610.1016/j.biochi.2006.07.00716938382MaedaANishidaTAoyamaEKubotaSLyonsKMKubokiTTakigawaMCCN family 2/connective tissue growth factor modulates BMP signalling as a signal conductor, which action regulates the proliferation and differentiation of chondrocytesJ Biochem145207216200910.1093/jb/mvn1592760593MaedaSAn impact of CCN2-BMP-2 complex upon chondrocyte biology: Evoking a signalling pathway bypasses ERK and Smads?J Biochem150219221201110.1093/jb/mvr08921768122XiaoFQiuHCuiHNiXLiJLiaoWLuLDingKMicroRNA-885-3p inhibits the growth of HT-29 colon cancer cell xenografts by disrupting angiogenesis via targeting BMPR1A and blocking BMP/Smad/Id1 signalingOncogene3419681978201510.1038/onc.2014.134NishidaNNagaharaMSatoTMimoriKSudoTTanakaFShibataKIshiiHSugiharaKDokiYMoriMMicroarray analysis of colorectal cancer stromal tissue reveals upregulation of two oncogenic miRNA clustersClin Cancer Res1830543070201210.1158/1078-0432.CCR-11-107822452939OkudaSMyouiANakaseTWadaEYonenobuKYoshikawaHOssification of the ligamentum flavum associated with osteoblastoma: A report of three casesSkeletal Radiol30402406200110.1007/s00256010032411499782KhuranaJSOginoSShenTParekhHScherbelUDeLongWFeldmanMDZhangPJWolfeHJAlmanBABone morphogenetic proteins are expressed by both bone-forming and non-bone-forming lesionsArch Pathol Lab Med12812671269200415508192KudoNOgoseAAriizumiTKawashimaHHottaTHatanoHMoritaTNagataMSikiYKawaiAExpression of bone morphogenetic proteins in giant cell tumor of boneAnticancer Res2922192225200919528484UristMRGrantTTLindholmTSMirraJMHiranoHFinermanGAInduction of new-bone formation in the host bed by human bone-tumor transplants in athymic nude miceJ Bone Joint Surg Am6112071216197910.2106/00004623-197961080-00011229105AndersonHCHsuHHRavalPHuntTRSchwappachJRMorrisDCSchneiderDJThe mechanism of bone induction and bone healing by human osteosarcoma cell extractsClin Orthop Relat Res12913419957641470HaraAIkedaTNomuraSYagitaHOkumuraKYamauchiYIn vivo implantation of human osteosarcoma cells in nude mice induces bones with human-derived osteoblasts and mouse-derived osteocytesLab Invest7570771719968941216IshiyamaMRelyea-ChewALongstrethWTLewisDHImpact of decompressive craniectomy on brain perfusion scin-tigraphy as an ancillary test for brain death diagnosisAnn Nucl Med33842847201910.1007/s12149-019-01396-z31456011YoshikawaHRettigWJTakaokaKAldermanERupBRosenVWozneyJMLaneJMHuvosAGGarin-ChesaPExpression of bone morphogenetic proteins in human osteo-sarcoma. Immunohistochemical detection with monoclonal antibodyCancer738591199410.1002/1097-0142(19940101)73:1<85::AID-CNCR2820730116>3.0.CO;2-87506120SulzbacherIBirnerPTriebKPichlbauerELangSThe expression of bone morphogenetic proteins in osteosarcoma and its relevance as a prognostic parameterJ Clin Pathol5381385200210.1136/jcp.55.5.381LiBYangYJiangSNiBChenKJiangLAdenovirus-mediated overexpression of BMP-9 inhibits human osteosarcoma cell growth and migration through downregulation of the PI3K/AKT pathwayInt J Oncol4118091819201210.3892/ijo.2012.161722948234YeLKynastonHGJiangWGBone metastasis in prostate cancer: Molecular and cellular mechanisms (Review)Int J Mol Med20103111200717549396MasudaHFukaboriYNakanoKTakezawaYC SuzukiTYamanakaHIncreased expression of bone morphoge-netic protein-7 in bone metastatic prostate cancerProstate54268274200310.1002/pros.1019312539225ThomasRTrueLDLangePHVessellaRLPlacental bone morphogenetic protein (PLAB) gene expression in normal, pre-malignant and malignant human prostate: Relation to tumor development and progressionInt J Cancer934752200110.1002/ijc.129111391620SecondiniCWetterwaldASchwaningerRThalmannGNCecchiniMGThe role of the BMP signaling antagonist noggin in the development of prostate cancer osteolytic bone metastasisPLoS One6e16078201110.1371/journal.pone.0016078212491493020964SchwaningerRRentschCAWetterwaldAvan der HorstGvan BezooijenRLvan der PluijmGLöwikCWAckermannKPyerinWHamdyFCLack of noggin expression by cancer cells is a determinant of the osteoblast response in bone metastasesAm J Pathol170160175200710.2353/ajpath.2007.051276172001911762703BrubakerKDCoreyEBrownLGVessellaRLBone morphogenetic protein signaling in prostate cancer cell linesJ Cell Biochem91151160200410.1002/jcb.10679NecchiAGiannatempoPMarianiLFarèERaggiDPennatiMZaffaroniNCrippaFMarchianòANicolaiNPF-03446962, a fully-human monoclonal antibody against transforming growth-factor β (TGFβ) receptor ALK1, in pre-treated patients with urothelial cancer: An open label, single-group, phase 2 trialInvest New Drugs32555560201410.1007/s10637-014-0074-924566706MitchellDPobreEGMulivorAWGrinbergAVCastonguayRMonnellTESolbanNUcranJAPearsallRSUnderwoodKWALK1-Fc inhibits multiple mediators of angiogenesis and suppresses tumor growthMol Cancer Ther9379388201010.1158/1535-7163.MCT-09-065020124460LiuYTianHBlobeGCTheuerCPHurwitzHINixonABEffects of the combination of TRC105 and bevacizumab on endothelial cell biologyInvest New Drugs32851859201410.1007/s10637-014-0129-y249940974169868SunZLiuCJiangWGYeLDeregulated bone morpho-genetic proteins and their receptors are associated with disease progression of gastric cancerComput Struct Biotechnol J18177188202010.1016/j.csbj.2019.12.0146965205HullingerTGTaichmanRSLinsemanDASomermanMJSecretory products from PC-3 and MCF-7 tumor cell lines upregulate osteopontin in MC3T3-E1 cellsJ Cell Biochem78607616200010.1002/1097-4644(20000915)78:4<607::AID-JCB10>3.0.CO;2-F10861858YoshiokaYOnoMOsakiMKonishiISakaguchiSDifferential effects of inhibition of bone morphogenic protein (BMP) signalling on T-cell activation and differentiationEur J Immunol42749759201210.1002/eji.201141702MartinezVGSacedonRHidalgoLValenciaJFernández-SevillaLMHernández-LópezCVicenteAVarasAThe BMP pathway participates in human naive CD4+ T cell activation and homeostasisPLoS One10e0131453201510.1371/journal.pone.0131453261109064481406
Smad-dependent and -independent signal transduction of BMPs. BMP signalling is mediated via oligomeric complexes of type I and type II receptors. With canonical Smad-dependent signalling, the BMP ligand binds a preformed oligomeric complex, resulting in the phosphorylation of the glycine-serine region of the type I receptor, and subsequent recruitment and phosphorylation of the pathway-restricted Smad 1/5/8 complex. With the common mediator Smad 4, Smad 1/5/8 is able to translocate to the nucleus and form regulatory complexes with co-factors/transcription factors that will ultimately affect transcription of target genes. This may include upregulation of regulatory elements within the signalling pathway such as the I-Smads (Smad 6 and 7), which provide homeostatic negative feedback regulation. Other negative regulators include secreted BMP antagonists, including Noggin, Chordin and Gremlin, which bind the BMP ligands and prevent receptor interaction, and BAMBI, which is a type I pseudoreceptor that can sequester BMP ligands. In addition, Smurf1/2 can directly induce Smad 1/5/8 ubiquitination and degradation. BMP ligands can also induce other cell signalling pathways via the non-canonical Smad independent signalling pathway. This occurs when the BMP ligand initially binds type I receptors and then recruits the type II receptor into the BISC. This initiates a cascade of adaptor proteins and linking molecules, such as XIAP, TAB and TAK1, with resultant activation of several distinct mitogen-activated protein kinase pathways. This figure was prepared using pathway builder tools from www.proteinlounge.com. BAMBI, BMP and activin membrane-bound inhibitor; BMP, bone morphogenic protein; BISC, BMP-induced signalling complex; I-Smad, inhibitory Smad; JNK, Jun N-terminal kinase; P, phosphorylation; Smurf, Smad ubiquitination regulatory factor; TAB, TGFβ-activated binding protein; TAK1, TGFβ-activated tyrosine kinase I; TGFβ, transforming growth factor β; XIAP, X-linked inhibitor of apoptosis protein.
Crosstalk between RTKs and the BMP signalling pathway. BMP activates Smad-dependent pathways through the phosphorylation of R-Smads by its type I receptor, and regulates the translocation of R-Smad and common mediator Smad. The translocation of Smad can be inhibited by ERK signalling. BMP and RTKs also regulate cellular responses through Smad-independent pathways with the involvement of RTK/mitogen-activated protein kinase, RTK/Akt and RTK/Wnt signalling. This figure was prepared using graphical materials from Servier Medical Art (http://servier.com). BMP, bone morphogenic protein; EGFR, epidermal growth factor receptor; JNK, Jun N-terminal kinase; R-Smad, regulatory Smad; RTK, receptor tyrosine kinase; TF, transcription factor.
Interactions between BMPs and Wnt/β-catenin signalling. This figure was prepared using graphical materials from Servier Medical Art (http://servier.com). BMP, bone morphogenic protein; BMPR, BMP receptor; glycogen synthase kinase 3β; GSK-3β; LEF, lymphoid enhancer-binding factor 1; Smurf, Smad ubiquitination regulatory factor; TCF, T cell factor.
BMPs regulate tumour-associated angiogenesis via multiple mechanisms. This figure was prepared using graphic materials from Servier Medical Art (http://servier.com). BMP, bone morphogenic protein; FGF, fibroblast growth factor; VEGF, vascular endothelial growth factor.
BMPs actively engage in a vicious cycle during the development of bone metastasis. Secretion of BMPs and other cytokines by cancer cells within the bone niche can influence the differentiation of mesenchymal stem cells into osteoclasts and/or osteoblasts, and also regulate the cellular behaviour of osteoclasts and osteoblasts. This results in bone deposition or osteolysis, and facilitates secretion of factors that then further support the establishment of tumour cells within the niche, thus propagating a vicious cycle in bone metastasis. This figure was prepared using graphic materials from Servier Medical Art (http://servier.com). BMP, bone morphogenic protein; IGF, insulin-like growth factor; PDGF, platelet-derived growth factor; PTHrP, parathyroid hormone-related protein; TGFβ, transforming growth factor β; VEGF, vascular endothelial growth factor.
BMPs in the tumour microenvironment. This figure was generated using ScienceSlides graphics from Visiscience (https://www.visiscience.com/). BMP, bone morphogenic protein; ECM, extracellular matrix; EMT, epithelial to mesenchymal transition.
Related clinical trials.
Target
Specific agent and effect
Agent(s) used in clinical trial
Tumour type
Clinical trial number and phase
CD105
TRC105, a novel antibody targeting CD105 with anti-angiogenic effects