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Silzle T Randolph GJ Kreutz M Kunz-Schughart LA 《International journal of cancer. Journal international du cancer》2004,108(2):173-180
Development and progression of epithelial malignancies are frequently accompanied by complex phenotypic alterations of resident tissue fibroblasts. Some of these changes, such as myofibroblastic differentiation and an oncofetal extracellular matrix (ECM) expression profile, are also implicated in inflammation and tissue repair. Studies over the past decade revealed the relevance of reciprocal interactions between tumor cells and tumor-associated host fibroblasts (TAF) in the malignant process. In many tumors, a considerable fraction of the inflammatory infiltrate is located within the fibroblast- and ECM-rich stromal compartment. However, while fibroblasts are known as "sentinel cells" in various nonneoplastic diseases, where they often regulate the composition and function of recruited leucocytes, they are hardly considered active participants in the inflammatory host response in tumors. This article focuses on the functional impact of TAF on immune cells. The complex network of immune-modulating effects transduced by TAF and TAF-derived factors is highlighted, and recent reports that support the hypothesis that TAF are involved in the inflammatory response and immune suppression in tumors are reviewed. The role of TAF-dependent ECM remodeling and TAF-derived peptide growth factors, cytokines, and chemokines in the immune modulation is stressed and the idea of TAF as an important therapeutic target is emphasized. 相似文献
63.
Hepatic fibrosis results from excess extracellular matrix produced primarily by hepatic stellate cells (HSC). In response to injury, HSC differentiate to a myofibroblastic phenotype expressing smooth muscle actin and fibrillar collagens. Relaxin is a polypeptide hormone shown to have antifibrotic effects in fibrosis models. In this study, activated HSC from rat liver were treated with relaxin to determine if relaxin can reverse markers of HSC activation. Relaxin treatment resulted in a decrease in the expression of smooth muscle actin, but had no effect on cell proliferation rate. The levels of total collagen and type I collagen were reduced, while the synthesis of new collagen was inhibited. Furthermore, relaxin caused an increase in the expression and secretion of rodent interstitial collagenase (MMP-13), but there was no effect on the gelatinases MMP-2 or MMP-9. Relaxin also increased secretion of TIMP-1 and TIMP-2. The effective concentration of relaxin to induce these effects was consistent with action through the relaxin receptor. In conclusion, relaxin reversed markers of the activated phenotype of HSC including the production of fibrillar collagen. At the same time, the activity of a fibrillar collagenase was increased. These data suggest that relaxin not only inhibits HSC properties that contribute to the progression of hepatic fibrosis, but also promotes the clearance of fibrillar collagen. Therefore, relaxin may be a useful approach in the treatment of hepatic fibrosis. 相似文献
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Yukihiko Kubota Kiyotaka Ohkura Katsuyuki K. Tamai Kayo Nagata Kiyoji Nishiwaki 《Proceedings of the National Academy of Sciences of the United States of America》2008,105(52):20804-20809
Mutations in the a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS) family of secreted proteases cause diseases linked to ECM abnormalities. However, the mechanisms by which these enzymes modulate the ECM during development are mostly unexplored. The Caenorhabditis elegans MIG-17/ADAMTS protein is secreted from body wall muscle cells and localizes to the basement membrane (BM) of the developing gonad where it controls directional migration of gonadal leader cells. Here we show that specific amino acid changes in the ECM proteins fibulin-1C (FBL-1C) and type IV collagen (LET-2) result in bypass of the requirement for MIG-17 activity in gonadal leader cell migration in a nidogen (NID-1)-dependent and -independent manner, respectively. The MIG-17, FBL-1C and LET-2 activities are required for proper accumulation of NID-1 at the gonadal BM. However, mutant FBL-1C or LET-2 in the absence of MIG-17 promotes NID-1 localization. Furthermore, overexpression of NID-1 in mig-17 mutants substantially rescues leader cell migration defects. These results suggest that functional interactions among BM molecules are important for MIG-17 control of gonadal leader cell migration. We propose that FBL-1C and LET-2 act downstream of MIG-17-dependent proteolysis to recruit NID-1 and that LET-2 also activates a NID-1-independent pathway, thereby inducing the remodeling of the BM required for directional control of leader cell migration. 相似文献
67.
Ana Silva Jorge Pereira Catarina R. Oliveira João Bettencourt Relvas A. Cristina Rego 《Journal of neuroscience research》2009,87(9):1986-1996
Differentiation of neurosphere‐derived cells is regulated by extracellular cues, namely, growth factors and proteins of the extracellular matrix (ECM). In this study we analyzed the influence of nerve growth factor (NGF), brain‐derived neurotrophic factor (BDNF), retinoic acid plus potassium chloride (RA‐KCl), and the nonsynthetic ECMs laminin (LN) and fibronectin (FN) versus the synthetic adhesion substrate poly‐L ‐lysine (PLL) in the in vitro differentiation of postnatal neurosphere cells. BDNF increased the number of differentiated neurons and decreased the number of neuronal precursors (nestin‐positive cells) compared with NGF or RA‐KCl. Moreover, cells treated with BDNF plus B27 supplement acquired a γ‐aminobutyric acid (GABA)–ergic phenotype and showed increased survival. No significant differences were found in the number of differentiated neurons in the presence of the ECMs alone. Nevertheless, FN or PLL in combination with BDNF promoted the acquisition of a GABAergic phenotype. The results obtained in this study highlight the importance of growth factors and ECM proteins for the potential of neurosphere cells to differentiate into neurons. © 2009 Wiley‐Liss, Inc. 相似文献
68.
目的 观察阿托伐他汀对进行性肾小球硬化大鼠肾脏的保护作用 ,并探讨其作用机制。方法 用免疫组织化学检测肾组织胶原Ⅳ、纤维连接蛋白 (FN) ;用RT PCR检测肾组织基质金属蛋白酶 2 (MMP 2 )及其组织抑制因子 1(TIMP 1)和TIMP 2mRNA的表达。结果 阿托伐他汀能降低肾小球硬化指数 ,减少胶原Ⅳ、FN表达 ,减少尿蛋白排泄 ,降低血胆固醇 (P <0 0 1)、低密度脂蛋白和肌酐水平 ,增加MMP 2mRNA的表达 ,减少TIMP 1和TIMP 2mRNA的表达。结论 阿托伐他汀可能通过减少 5 / 6肾切除大鼠尿蛋白排泄量 ,纠正脂质代谢紊乱以及减轻肾小球硬化细胞外基质 (ECM)的聚积等而延缓肾功能减退 相似文献
69.
机体组织具有复杂的三维动态结构,且受到多种形式的作用力。细胞从细胞外基质(extracellular matrix, ECM)中感受力学刺激,ECM构建的力学微环境调控细胞不同生物学功能。制备可模拟机体组织ECM力学微环境的生物材料是生物力学领域研究的热点和难点之一。生物材料的不同理化性质赋予材料特定的力学性能,进而影响细胞行为和功能。本文结合2021年材料生物力学领域的最新文献,特别关注新型材料生物力学对细胞生物学行为的调控和在组织工程中的应用,并探讨材料生物力学研究领域的未来发展方向。 相似文献
70.
目的以糖尿病家兔肾脏组织、细胞外基质的改变和炎症因子表达为判断标准,探讨模型胰岛素(Ins)用药治疗的适宜方案。方法雄性家兔40只,随机分成对照组(N组)、糖尿病模型组(D组)、多次Ins治疗组(A组)、50R混合Ins治疗组(B组)、30R混合Ins治疗组(c组)。治疗组用Ins治疗30d后处死动物,同时处死其他组动物;观察各治疗组血糖达标时间及达标时Ins用量。比较各组血糖、糖化血红蛋白(HbAlc)、白天平均血糖水平(MBG)、血糖标准差平均值(MOS)、每只兔血糖绝对差值的平均值(MODD)、肿瘤坏死因子-α(TNF-α)、细胞外基质部分成分(ECM)、NF—kB的表达情况。结果A组达标时间最短,c组最长(P〈0.01)。治疗各组血糖和HbAlc较D组下降(P〈0.05)。A、D两组较C、N两组NF-KB灰度值明显降低,TNF-α、ECM明显升高(P〈0.05)。A组的MOS、MODD较c组和N组明显升高(P〈0.001);HbAlc与MBG呈正相关(P〈0.001),与MOS、MODD无相关。D组血糖及NF—KB灰度值与TNF-α呈正相关(P均〈0.02)。肾脏组织病变受损严重程度及炎症因子表达明显度D组〉A组〉B组〉C组。结论30R预混胰岛素治疗方案最佳。提供一个较高的基础胰岛素浓度加少量餐时胰岛素峰值量治疗糖尿病,血糖平稳缓降,对糖尿病肾组织有治疗和保护作用。多次胰岛素3短加1中或长的强化治疗及太短时间达标的方法不主张首选。 相似文献