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Mechanisms of cancer metastasis to the bone 总被引:14,自引:0,他引:14
Some of the most common human cancers, including breast cancer, prostate cancer, and lung cancer, metastasize with avidity to bone. What is the basis for their preferential growth within the bone microenvironment? Bidirectional interactions between tumor cells and cells that make up bone result in a selective advantage for tumor growth and can lead to bone destruction or new bone matrix deposition. This review discusses our current understanding of the molecular components and mechanisms that are responsible for those interactions. 相似文献
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Fei Huang Yaqiang Cao Gui Wu Junying Chen CaihongWang Wanzun Lin Ruilong Lan Bing Wu Xianhe Xie Jinsheng Hong Lengxi Fu 《Journal of cellular and molecular medicine》2020,24(18):10768-10784
Distant metastases occur when non‐small cell lung cancer (NSCLC) is at late stages. Bone metastasis is one of the most frequent metastases of NSCLC and leads to poor prognosis. It has been reported that high expression of BMP2 in NSCLC correlates with poor survival, but whether BMP2 contributes to NSCLC bone metastasis remains largely unknown. The activation of BMP signalling is found in metastatic bone tumours of mice Lewis lung carcinoma and predicts poor survival in human NSCLC. BMP2 signalling activation can enhance bone metastasis of Lewis lung carcinoma. Moreover, BMP2 secreted by stroma fibroblasts can promote the migration and invasion of NSCLC cells. Besides, in combination with pre‐osteoblast and LLCs, BMP2 could enhance the differentiation of macrophages into osteoclasts to play roles in the osteolytic mechanism of NSCLC bone metastasis. Interestingly, NSCLC cells can also enrich BMP2 to pre‐osteoblasts to function in the osteoblastic mechanism. Our results firstly demonstrate the detailed mechanisms about what roles BMP2 signalling play in enhancing NSCLC bone metastases. These findings provide a new potential therapy choice for preventing bone metastases of NSCLC via the inhibition of BMP2 signalling. 相似文献
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Pulsed electromagnetic fields (PEMF) have been used widely to treat nonunion fractures and related problems in bone healing, as a biological and physical method. With the use of Helmholtz coils and PEMF stimulators to generate uniform time‐varying electromagnetic fields, the effects of extremely low frequency electromagnetic fields on bone mineral density (BMD) and local factor production in disuse osteoporosis (DOP) rats were investigated. Eighty 4‐month‐old female Sprague Dawley (SD) rats were randomly divided into intact (INT) group, DOP group, calcitonin‐treated (CT) group, and PEMF stimulation group. The right hindlimbs of all the rats were immobilized by tibia‐tail fixation except for those rats in the INT group. Rats in the CT group were injected with calcitonin (2 IU/kg, i.p., once a day) and rats in the PEMF group were irradiated with PEMF immediately postoperative. The BMD, serum transforming growth factor‐beta 1 (TGF‐β1), and interleukin‐6 (IL‐6) concentration of the proximal femur were measured 1, 2, 4, and 8 weeks after treatment. Compared with the CT and DOP groups, the BMD and serum TGF‐β1 concentration in the PEMF group increased significantly after 8 weeks. The IL‐6 concentration in the DOP group was elevated significantly after operation. The PEMF group showed significantly lower IL‐6 level than the DOP group. The results found demonstrate that PEMF stimulation can efficiently suppress bone mass loss. We, therefore, conclude that PEMF may affect bone remodeling process through promoting TGF‐β1 secretion and inhibiting IL‐6 expression. Bioelectromagnetics 31:113–119, 2010. © 2009 Wiley‐Liss, Inc. 相似文献
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Prostate cancer (PCa) epithelial cells require a number of factors to facilitate their establishment and growth at a distant site of metastasis. Their ability to adapt to their microenvironment, proliferate and recruit an underlying stroma is integral to the survival and growth of the metastasis. PCa predominantly metastasizes to the bone, and bone metastases are the main cause of morbidity. The bone marrow provides a permissive environment for the formation of a metastasis. In some cases, the cells may remain dormant for some time, eventually proliferating in response to an unknown \"trigger.\" The marrow is rich in progenitor cells that differentiate into numerous cell types, producing new blood vessels, supporting fibroblasts, and an underlying extracellular matrix (ECM) that form the reactive stroma. By secreting a number of cytokines, growth factors and proteases they recruit auxiliary cells required to produce a functional stroma. These components are involved in a reciprocal interaction between the stroma and the PCa cells, allowing for the growth and survival of the tumor. Left unchecked, once a PCa tumor has established itself in the bone marrow it will eventually replace the marrow, interrupting bone homeostasis and typically promoting an osteoblastic response in the bone including osteoclastic events. The abundant deposition of new woven bone results in nerve compression, bone pain and an increase in fractures in patients with PCa bone metastases. This review will examine the tumor microenvironment, its role in facilitating tumor dissemination, growth and the resultant pathologies associated with PCa bone metastasis. 相似文献
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Worman HJ 《Journal of cellular biochemistry》2005,96(6):1185-1192
Recent research has shown that the inner nuclear membrane is a site for regulation of signal transduction from the plasma membrane to the nucleus. This has coincided with discoveries showing that mutations in extrinsic and intrinsic inner nuclear membrane proteins cause a variety of inherited diseases. In most instances, the mechanisms by which mutations in inner nuclear membrane proteins cause disease are not understood. In at least one case, however, an alteration in signal transduction appears to underlie disease pathogenesis. 相似文献
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The migration of vascular smooth muscle cells from the media to intima and their subsequent proliferation are critical causes of arterial wall thickening. In atherosclerotic lesions increases in the thickness of the vascular wall and the impairment of oxygen diffusion capacity result in the development of hypoxic lesions. We investigated the effect of hypoxia on the migration of human coronary artery smooth muscle cells (CASMCs) via HIF-1alpha-dependent expression of thrombospondin-1 (TSP-1). When the cells were cultured under hypoxic conditions, mRNA and protein levels of TSP-1, and mRNA levels of integrin beta(3) were increased with the increase in HIF-1alpha protein. DNA synthesis and migration of the cells were stimulated under the conditions, and a neutralizing anti-TSP-1 antibody apparently suppressed the migration, but not DNA synthesis. The migration was also inhibited by RGD peptide that binds to integrin beta(3). Furthermore, the migration was completely suppressed in HIF-1alpha-knockdown cells exposed to hypoxia, while it was significantly enhanced in HIF-1alpha-overexpressing cells. These results suggest that the hypoxia induces the migration of CASMCs, and that the migration is elicited by TSP-1 of which induction is fully dependent on the stabilization of HIF-1alpha, in autocrine regulation. Thus we suggest that HIF-1alpha plays an important role in the pathogenesis of atherosclerosis. 相似文献
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Fracture repair is a complex regenerative process initiated in response to injury, resulting in optimal restoration of skeletal function. Although histology characteristics at various phases of fracture repair are clear and well established, much remains to be understood about the process of bone healing, particularly at the molecular signaling level. During the past decade, secreted signaling molecules of the Wnt family have been widely investigated and found to play a central role in controlling embryonic development processes. Wnt signaling pathway also plays a pivotal role in the regulation of bone mass. Recent published data reveal that Wnt signaling pathway is activated during postnatal bone regenerative events, such as ectopic endochondral bone formation and fracture repair. Dysregulation of this pathway greatly inhibits bone formation and healing process. Interestingly, activation of Wnt pathway has potential to improve bone healing, but only utilized after mesenchymal cells have become committed to the osteoblast lineage. These advances suggest an essential role of Wnt pathway in bone regeneration. J. Cell. Biochem. 106: 353–362, 2009. © 2009 Wiley‐Liss, Inc. 相似文献
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Weicht B Maitz P Kandler B Fischer MB Watzek G Gruber R 《Journal of cellular biochemistry》2007,102(5):1300-1307
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Transforming growth factor‐beta 2 (encoded by TGFB2) is a growth factor that regulates a plethora of cellular functions. In this study, we sequenced the promoter and full‐length exon region of the chicken TGFB2 and found two mutations (g.‐640C>T and g.‐851_‐790del) within the promoter. The two polymorphisms were genotyped in 1030 pedigreed hens recorded for body weight at 7 (BW7), 9 (BW9), 11 (BW11), 13 (BW13), 17 (BW17) weeks old, egg weight at 36 weeks of age (EW36) and egg numbers from the age at first egg (AFE) to 40 weeks of age (EN40). Despite the fact that no mutations were found to have statistically significant genetic effects on egg production, the association results of growth traits showed that both g.‐640C>T and g.‐851_‐790del had significant effects on body weights and that both genotype g.‐640TT and g.‐851_‐790wt/wt were positive for body weight performance. Therefore, the polymorphisms of TGFB2, especially the g.‐851_‐790del mutation associated with body weight at almost all periods, could be potential useful genetic markers to improve the growth of Beijing You chickens. 相似文献
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Lichun Han Wei Wang Wei Ding Lijian Zhang 《Journal of cellular and molecular medicine》2017,21(9):2000-2008
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Hongjuan He Xiaojuan Zhao Ziqing Zhu Le Du Erfei Chen Shuzhen Liu Qiqi Li Jing Dong Jin Yang Lei Lei 《Journal of biochemical and molecular toxicology》2019,33(6)
Mutations in transforming growth factor beta receptor II (TGFBR2) are detected in up to 30% of overall colorectal cancer (CRC). Dysregulation of some microRNAs participated in the CRC pathogenesis. In this study, we used the gene ontology analyses, the Kyoto Encyclopedia of Genes and Genomes pathway analyses and gene set enrichment analysis to indicate that miR‐3191 was involved in the regulation of transforming growth factor beta (TGF‐BETA) signal pathway in CRC. These bioinformatics results were supported by data obtained from CRC samples and experiments in vitro. The luciferase reporter assay was used to confirm that miR‐3191 modulates TGF‐BETA signal pathway by targeting TGFBR2. By transwell migration and invasion assays, we showed that miR‐3191 promoted CRC cell migration and invasion by downregulating TGFBR2. And it may serve as a novel therapeutic strategy for treating CRC patients. 相似文献
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转化生长因子β的生物学特性、功能及其临床应用前景 总被引:5,自引:0,他引:5
转化生长因子β是一种高度多效性,多功能性的生长与分化因子,它广泛地调节机体的生长,发育,炎症,修复和免疫等许多生理和病理过程,具有重要的生物学功能和广阔的临床应用前景。 相似文献
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Transforming growth factor-beta (TGF-beta) is a bimodal regulator of cellular growth. The cellular effects of TGF-beta depend on the intensity of signals emanating from TGF-beta receptors. Low levels of receptor activity are sufficient to stimulate cell proliferation, while higher degrees of receptor activation are associated with growth inhibition. To study the mechanisms of these effects, a tetracycline-inducible expression system was used to overexpress type II TGF-beta receptors in NIH 3T3 fibroblasts. Overexpressed type II TGF-beta receptors suppressed fibroblast proliferation elicited by TGF-beta1, fibroblast growth factor (FGF) or platelet-derived growth factor (PDGF). Accompanying these anti-proliferative effects, increases in extracellular-signal regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) activity were detected. Furthermore, PDGF alpha-, but not PDGF beta-receptor protein levels were reduced by type II TGF-beta receptor overexpression. In conclusion, our system is an excellent tool to study the molecular mechanisms of growth inhibition by TGF-beta in fibroblasts. Activation of JNK and ERK, or modulation of PDGF receptor expression may be involved in this process. 相似文献
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TGIF (TG-interacting factor) 是 TGF- β信号传导通路的抑制分子, 而 TGF-β早期抑制肿瘤生长,晚期促进肿瘤浸润与转移,但 TGIF 在肿瘤发生中的作用尚不清楚 . 将 TGIF 基因稳定转染胃癌细胞株 SGC-7901 ,采用 MTT 法、平板克隆形成试验、流式细胞术和裸鼠成瘤试验探讨 TGIF 对胃癌细胞生物学行为的影响,通过免疫组织化学分析裸鼠瘤组织基质金属蛋白酶 (matrix metallo proteinases, MMP) MMP2 、 MMP9 和血管内皮生长因子 (vascular eudothelial growth factor, VEGF) 的表达,通过 ELISA 和明胶酶谱试验分别分析 TGIF 转染细胞上清液中 VEGF 和活性 MMP2 与 MMP9 的含量变化 . TGIF 对 SGC-7901 细胞的生长、细胞周期分布和克隆形成率无影响 . TGIF 转染细胞接种裸鼠后无癌栓形成,但对照组有癌栓形成,且其瘤组织 MMP9 和 VEGF 的表达明显低于对照组,但 MMP2 在 3 组间的表达无差别 . TGIF 基因转染细胞、 PcDNA3.1 转染细胞和 SGC-7901 细胞上清液中 VEGF 的浓度分别为 (635 ± 20.3) ng/L 、 (780±25.4) ng/L 和 (791±23.9) ng/L , TGIF 转染细胞 VEGF 的含量明显低于对照组细胞 (P <0.01) , TGIF 转染细胞上清液中活性 MMP9 的含量明显低于对照组 . 尽管 TGIF 能部分拮抗 TGF-β1 介导的生长抑制和细胞周期阻滞作用,但它并不能使胃癌细胞的生物学行为恶化,相反 TGIF 通过下调 VEGF 和 MMP9 的表达降低胃癌细胞的浸润与转移能力 . 相似文献
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目的:研究脾切除对肝纤维化大鼠肝脏TGFβ1的表达和血清TGFβ1水平的影响,探讨脾切除在肝纤维化中的意义。方法:用CCL4建立50例肝纤维化大鼠模型。于建模第3周,6周,及8周分别取大鼠肝脏和脾脏标本。用免疫组化SP方法测定其TGFβ1的表达,HE和姬姆萨染色检测肝纤维化。应用双抗体夹心ELISA方法测定15例模型大鼠行脾脏切除前后的血清TGFβ1水平,以及15例对照组大鼠的血清TGFβ1水平,并于术后4周取两组大鼠的肝脏标本,用免疫组化SP方法测定其TGFβ1的表达。应用CMIAS8彩色图像系统对阳性目标进行分析和处理。结果:随着肝纤维化程度的进展,大鼠肝脏和脾脏TGFβ1的表达也随之增加(P〈0.01)。脾切除组大鼠其血清TGF-β1的水平显著低于对照组大鼠(P〈0.05),且脾切除组大鼠肝脏TGFβ1的表达低于对照组大鼠(P〈0.05)。结论:脾切除术在一定程度上可延缓肝纤维化的发展。 相似文献
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Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid that mediates a wide array of biologic effects through its interaction with a family of five G protein-coupled receptors. Cytokines and growth factors interact with this signaling pathway in a variety of ways, including both activation and regulation of the expression of the enzymes that regulate synthesis and degradation of S1P. Not only do many growth factors and cytokines stimulate S1P production, leading to transactivation of S1P receptors, ligation of S1P receptors by S1P can also transactivate growth factor tyrosine kinase receptors and stimulate growth factor and cytokine signaling cascades. This review discusses the mechanisms involved in cross-talk between S1P, cytokines, and growth factors and the impact of that cross-talk on cell signaling and cell biology. 相似文献