骨形态发生蛋白与肿瘤

骨形态发生蛋白(BMP)是一种多功能的细胞因子,不仅可以促进新骨形成,而且参与调控细胞生长、分化、迁移、凋亡以及胚胎和器官发生等过程。研究显示BMP还与肿瘤的发生和转移密切相关,在肿瘤治疗中具有重要的应用价值。     

骨形成蛋白与肿瘤相关性研究进展

骨形成蛋白(bone morphogenetic proteins，BMP)最初是作为一种可在异位诱导骨和软骨形成的蛋白质被发现，但后来的研究发现，广泛分布于人体多种组织和细胞，行使多方面功能。它参与胚胎的形成、发育及组织细胞的分化和增殖。BMP基因突变和异常表达将导致胚胎死亡、组织器官发育异常及其它疾病的发生。BMP与某些肿瘤的发生、发展及转移密切相关。本文就近年来BMP与某些肿瘤的相关性研究作一综述。     

骨形态发生蛋白与乳腺癌的研究进展

骨形态发生蛋白（BMP）是一类具有诱导骨活性的多功能糖蛋白,它不但能促进骨的生成,诱导成骨和间充质干细胞成骨分化,而且在多种肿瘤的恶性进展中发挥重要作用。乳腺癌是女性最常见的恶性肿瘤,在我国发病率逐年升高,约70%的乳腺癌患者发生肺、骨等部位的转移。目前,BMP在乳腺癌发生、发展过程中的作用机制及寻找乳腺癌新的治疗靶点已经成为医学界的研究热点。本文就近10年BMP对乳腺癌细胞生长、侵袭和转移的影响及机制的研究进展作一综述。     

BMP在骨肿瘤中的存在和意义

1965年,Urist发现脱钙骨基质的提取物在肌肉内使间充质细胞转化为骨系细胞发生异位成骨,随后分离出了一种小分子量的糖蛋白,即骨形态发生蛋白.Wezney在1988年对这种骨提取物的肽链进行分析,并测出其氨基酸的序列,首次克隆出BMP2,BMP3,BMP4,至今,已有15种BMP及40种BMP相关蛋白被成功的分离.目前利用基因重组技术可以大量获得BMP,为临床应用提供了可能.BMP在骨肿瘤的作用也正日益引起人们的关注。     

骨形态发生蛋白7与肿瘤关系的研究进展

骨形态发生蛋白7（BMP7）属于转化生长因子－β（TGF-β）超家族的成员之一，最初在研究体内诱导骨与软骨形成的因子时发现，对骨骼的胚胎发育和再生修复起重要作用。研究发现它还参与调节多种细胞的增殖、分化及凋亡的生物学过程。现就BMP7的生物学结构、信号传导机制以及与肿瘤的发生和转移的关系等方面的研究进展介绍如下。     

骨折修复过程中骨形态发生蛋白2对趋化因子12表达的调控及其意义

目的探讨骨形态发生蛋白2(bone morphogenetic protein,BMP2)对趋化因子12(chemokine C-X-C motif-ligand-12,CXCL12)表达调节及其在骨折修复过程中的意义。方法构建BMP2敲除鼠BMP2~(cKO/+)和BMP2~(cKO/cKO)。免疫组化分析正常小鼠、BMP2~(cKO/+)小鼠及BMP2~(cKO/cKO)小鼠胫骨骨折模型中骨内膜细胞CXCL12的表达及其随时间的变化。实时定量PCR(RT-q PCR)比较对照组与BMP2~(cKO/+)小鼠骨内膜细胞及其分化细胞CXCL12、骨钙蛋白、α-SMA表达差异。结果BMP2~(cKO/+)和BMP2~(cKO/cKO)小鼠BMP2显著低于对照组。小鼠骨折修复过程中骨内膜细胞和成骨细胞CXCL12表达明显升高,且表达CXCL12细胞先增多再减少;BMP2~(cKO/+)小鼠骨折修复过程中表达CXCL12的骨内膜细胞和成骨细胞逐渐增加。BMP2~(cKO/+)小鼠分离的骨内膜细胞CXCL12表达显著高于正常小鼠。在诱导分化的小鼠骨内膜细胞中添加rh BMP2,CXCL12的表达减少,骨钙蛋白和α-SMA表达显著增加。诱导分化的BMP2~(cKO/cKO)骨内膜细胞CXCL12表达显著高于正常小鼠,而骨钙蛋白的表达则显著降低。CXCL12受体拮抗剂AMD3100处理诱导分化的BMP2~(cKO/cKO)骨内膜细胞,骨钙蛋白和α-SMA表达显著增加。结论骨折修复过程中,BMP2下调CXCL12的表达有助于成骨细胞的分化从而促进骨折的修复。     

骨形成蛋白与肿瘤转移

胚性通路被认为影响着肿瘤干细胞的生存及复杂微环境的形成,进而促进肿瘤发生发展.全文重点介绍胚性通路中的代表骨形成蛋白(bone morpho-genetic protein,BMP)以及其在肿瘤转移调节中的作用.     

骨形态发生蛋白2在腰椎融合术中应用的效果与并发症

正骨形态发生蛋白(bone morphogenetic protein,BMP)是由骨基质分泌的一种疏水性非胶原蛋白,属于转化生长因子-β(TGF-β)超家族成员~([1-3])。是美国Marshall R.Urist教授于1965年发现的,Urist将脱钙骨基质(decalcified bone matrix,DBM)置于动物肌肉袋中诱导异位骨形成。其属于BMP家族,其中BMP-2,4和7的生物活性最高,成骨活性最强~([4-6])。现已证实BMP是一种酸性多     

BMP4在胶质母细胞瘤的多药耐药中的作用及机制研究

背景与目的：近年来的一系列实验证实,骨形成发生蛋白4（bone morphogenetic proteins 4,BMP41在体内外可以抑制肿瘤的生长,但其机制还不清楚。本研究旨在探讨BMP4在胶质母细胞瘤多药耐药中的作用及机制。方法：检测人脑胶质母细胞瘤和正常脑组织标本中BMPd的表达量：构建多药耐药细胞株并进行鉴定．检测在多药耐药细胞株和正常胶质母细胞瘤细胞株内BMP4的表达量：通过在多药耐药细胞株中高表达BMP4．检测BMP4逆转多药耐药的可能性：通过检测高表达BMP4后耐药相关基因的表达变化．初步筛选出BMPd调节胶质母细胞瘤多药耐药的可能机制。结果：在胶质母细胞瘤内,BMP4表达量降低：多药耐药细胞株构建成功．且与对照组相比,多药耐药细胞株的BMP4表达量明显降低,高表达BMP4可以逆转多药耐药：高表达BMP4后,多药耐药相关的基因中,BCL-2和GDNF表达量明显降低。结论：BMP4可以逆转胶质母细胞瘤多药耐药．其可能机制是通过调节BCL-2和GDNF的表达．     

骨形态发生蛋白与肿瘤

骨形态发生蛋白（bone morphogenetic proteins ,BMPs ）最初作为诱骨因子被发现,在骨缺损修复中起重要作用.随着研究的不断深入,人们发现它还是一个多功能因子,是具有多种生物学功能的形态原（morphogen）,在神经造血﹑组织发育、诱导细胞凋亡和促进细胞增殖等方面有重要作用[1].Wozney[2]在1988年首次报道人BMP-1、BMP-2A、BMP-2B和BMP-3的cDNA克隆与表达;迄今,已经克隆16种人骨形态发生蛋白cDNA和多种BMP亚型的cDNA,成功地分离40多种BMPs 蛋白.在翻译完成时,它们是一个大的前体蛋白,约由100～125个氨基酸组成,包括一个信号肽部分,一个前结构域及一个羧基（C）末端区.因为其C端有7个保守的半胱氨酸残基,所以BMPs这个结构和功能相似的多肽因子家族被归为转化生长因子（TGF-β）超家族.现已发现BMPs与肿瘤的发生发展相关,进一步阐明它们的关系,有助于提高肿瘤的诊断、治疗水平及改善预后.     

Role of bone morphogenetic proteins in transitional cell carcinoma cells

Bone morphogenetic proteins (BMPs) are pleiotropic growth factors that signal through an interaction with the membrane receptors-type--IA, -IB, and -II (BMP-RIA, -RIB, and -RII, respectively). Although the prototypical members of this group of growth factors were isolated as osteoinductive factors, recently accumulated data have suggested that these factors regulate malignant cells. Herein, we review the data concerning BMPs in transitional cell carcinoma cells.     

Bone morphogenetic proteins induce apoptosis in multiple myeloma cells by Smad-dependent repression of MYC

Bone morphogenetic proteins (BMPs) have been shown to induce apoptosis and growth arrest in myeloma cells. However, the molecular mechanisms behind these events are not known. The MYC oncogene is a master regulator of cell growth and protein synthesis and MYC overexpression has been proposed to be associated with the progression of multiple myeloma. Here, we show that BMP-induced apoptosis in myeloma cells is dependent on downregulation of MYC. Moreover, the results suggest that targeting the MYC addiction in multiple myeloma is an efficient way of killing a majority of primary myeloma clones. We also found that myeloma cells harboring immunoglobulin (IG)-MYC translocations evaded BMP-induced apoptosis, suggesting a novel way for myeloma cells to overcome potential tumor suppression by BMPs.     

Bone morphogenetic proteins in melanoma: Angel or devil?

Bone morphogenetic proteins (BMPs) are members of the transforming growth factor-β (TGF-β) superfamily serving multiple functions in many cell and tissue types including proliferation, apoptosis, differentiation, chemotaxis, angiogenesis, and matrix production during embryogenic development as well as in adult life. Despite the tremendous progress in delineating functional derangements of BMP pathways in carcinogenesis during the last decade, the biological significance of BMPs in human melanoma has received very little attention. It is now clear that biological responses to BMPs are cell type-specific and divergent effects, i.e., both oncogenic and tumor suppressor activities, have been described. Thus, knowledge generated in one system may not translate directly to another. In this review, we summarize the current understanding of BMP signaling in various human cancers and discuss original data pertaining to cutaneous melanoma obtained in our laboratory.     

Bone morphogenetic proteins induce expression of metalloproteinases in melanoma cells and fibroblasts

Bone morphogenetic proteins are secreted growth factors which belong to the TGFbeta super family. In recent studies, we showed that the expression of BMP-4 and -7 is induced in melanoma cells in comparison to normal melanocytes. Functional analyses revealed that BMPs are inevitable factors for migration and invasion processes of melanoma cells; however, the role of BMPs in degradation and remodelling of the extracellular matrix remained unknown. We discovered that melanoma cell clones with reduced BMP activity, generated by stable transfection with an antisense BMP-4 construct or with the BMP inhibitor chordin, showed reduced expression of MMP-1, -2, -3 and -9. Moreover, BMPs displayed paracrine effects on stromal fibroblasts. Treatment of fibroblasts with BMP-2 or -4 led to increased MMP-1, -2, -3 and -13 expression. These data show that BMPs play an important role in dissemination of tumour cells from the primary tumour, either by enhancing the matrix degrading capacity of melanoma cells themselves or by stimulating tumour surrounding fibroblasts to induce expression of matrix metalloproteinases.     

Bone morphogenetic protein (BMP)-2 induces apoptosis in human myeloma cells

BMPs (bone morphogenetic proteins), members of the transforming growth factor (TGF)-beta superfamily, are a group of related proteins which are capable of inducing the formation of cartilage and bone, but are now regarded as multifunctional cytokines. However, little is known about their role in hematopoiesis. Recently, we found a novel function of BMPs to hematopoietic cells in that BMP-2 induces apoptosis not only in human myeloma cell lines, but also in primary samples from patients with multiple myeloma in vitro. BMP-2 caused cell cycle arrest in the G1 phase which was associated with accumulation of p21CIP1/WAF1 and p27KIP1, and the subsequent apoptosis of myeloma cells. Further analysis showed that BMP-2 induced down-regulation of Bcl-X(L) through the inactivation of STAT3, resulting in the induction of apoptosis in myeloma cells. We conclude that BMP-2 may have the potential to be one of the novel therapeutic agents for treatment in patients with multiple myeloma because of the beneficial effects on both myeloma cells and bone diseases. In this review, we summarize data concerning BMPs and BMP-2-induced apoptosis of myeloma cells including our own recent experimental data.     

骨形成蛋白与前列腺癌

前列腺癌是西方国家男性最常见的恶性肿瘤之一,目前我国前列腺癌的发病率亦明显增加。前列腺和前列腺癌组织中有骨形成蛋白(bone morphogenetic proteins,BMPs)及其受体的表达。BMPs能够诱导异位成骨、细胞趋化、分化和胚胎发育。某些BMPs及其受体在前列腺癌细胞表达,可以作为前列腺癌发生、发展和预后的标志物。BMPs对前列腺癌细胞生物学行为的调控作用是多样的,与肿瘤细胞类型、分化状态和局部微环境有关。BMPs在前列腺癌进展过程中,特别是在促进前列腺癌骨转移并在成骨反应中发挥重要作用。研究BMPs与前列腺癌的关系,有助于阐明前列腺癌的发病及转移机制,为前列腺癌的治疗提供实验依据。