Focal adhesion kinase: a potential target in cancer therapy

Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase that plays an important role in signal transduction pathways that are initiated at sites of integrin-mediated cell adhesions and by growth factor receptors. FAK is a key regulator of survival, proliferation, migration and invasion: processes that are all involved in the development and progression of cancer. FAK is also linked to oncogenes at both a biochemical and functional level. Moreover, overexpression and/or increased activity of FAK is common in a wide variety of human cancers, implicating a role for FAK in carcinogenesis. Given the important role of FAK in a large number of processes involved in tumorigenesis, metastasis and survival signalling FAK should be regarded as a potential target in the development of anti-cancer drugs. Therefore, selective inhibitors of FAK need to be developed. Combination of these selective FAK inhibitors with cytotoxic agents could be a very promising anti-cancer therapy.     

Proliferative Responses to Platelet-Derived Growth Factor in Young and Old Rat Patellar Tendon

Musculoskeletal soft tissue repair is often a slow process that may be complicated by aging, thus we investigated the mitogenic response of young and old rat patellar tendon (PT) explants to platelet-derived growth factor-AB (PDGF-AB). Bilateral PT explants from young (4 months) and old (29 or 36 months) rats of two strains (Fisher 344 and Fisher-Brown-Norway) were cultured for 72 h in platelet-poor horse serum in the presence or absence of 100 ng/ml recombinant human PDGF-AB. The explants were radiolabeled with [³H]-TdR for the final 24 h in culture. Tendon cellularity and DNA synthesis data were analyzed by multiple factor ANOVA (age, strain, and side), Mann-Whitney t-test (cellularity and DNA synthesis), and a sign test (proliferative response to PDGF). Tendon cellularity declined significantly with age in both strains (p < 0.05), while both young and old patellar tendon fibroblasts in both strains had a significant (>100%) increase in DNA synthesis with the addition of PDGF (p < 0.05). Although there was a trend to lower proliferative responses in older tendons, the differences were not significant. Autoradiographic analysis of labeling indices in F344 tendons showed a diminished responsiveness to PDGF (p < 0.04, ANOVA). Strain and side response on a per cell or tissue weight basis were not significant factors. Under appropriate experimental conditions, these two animal models of aging showed declines in responses to high levels of PDGF, suggesting that the PT reflects an age-dependent diminished capacity for wound repair.     

抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制研究

目的 探讨抗精神病药喹硫平对少突胶质细胞周期的影响及其作用机制.方法 采用血小板源性生长因子(PDGF)10 ng/ml、喹硫平10μmol/L及两者混合物处理少突胶质前体细胞(OPCs)48 h,比较各组细胞周期、细胞周期退出指数及细胞分化情况.检测喹硫平干预后小鼠前额皮质8个细胞周期相关mRNA相对表达量.通过RN...     

Diverse role of LDL receptor-related protein in the clearance of proteases and in signaling

Summary.  The low density lipoprotein receptor-related protein (LRP) is a large endocytic receptor that participates in several biological pathways and plays prominent roles in lipoprotein metabolism and in the catabolism of proteinases involved in coagulation and fibrinolysis. LRP also mediates the cellular entry of certain viruses and toxins and facilitates the activation of various lysosomal enzymes. Deletion of the LRP gene in mice is lethal, confirming an important role for this receptor in development, although its exact function in development is still not known. In addition to its role in the endocytosis of numerous ligands, recent studies are emerging that describe a signaling role for this receptor as well.     

Heterogeneity of hepatocellular carcinoma contributes to cancer progression

Hepatocellular carcinoma (HCC) is a highly heterogeneous disease displaying differences in angiogenesis, extracellular matrix proteins, the immune microenvironment and tumor cell populations. Additionally, genetic variations and epigenetic changes of HCC cells could lead to aberrant signaling pathways, induce cancer stem cells and enhance tumor progression. Thus, the heterogeneity in HCC contributes to disease progression and a better understanding of its heterogeneity will greatly aid in the development of strategies for the HCC treatment.     

乳腺癌患者血清PDGF、CEA和CA15—3联合检测的意义水

目的：探讨血小板衍生生长因子（PDGF）、癌胚抗原（CEA） 和糖蛋白抗原15-3（CA15-3） 联合检测在乳腺癌诊断治疗中的意义.方法：收集160 例乳腺癌患者和150 例体检健康者静脉血标本,用ELISA 法检测血清PDGF 含量,用放射免疫法检测CEA 和CA15-3 含量.结果：乳腺癌组PDGF 含量为（600.12±89.57） pg/ml、CEA 含量为（12.53±2.41） ng/ml 和CA15-3 含量（19.6±3.85） mg/L,均高于健康对照组[ 分别为（189.11±100.29） ng/ml、（2.79±0.51） ng/mL 和（3.1±0.9） mg/l],差异有统计学意义（P〈0.01）.血清PDGF、CEA 和CA15-3 联合检测的敏感性、特异性和诊断阳性率分别为79.5%、59.6% 和70.9%.结论：血清PDGF、CEA 和CA15-3 联合检测可提高乳腺癌诊断的敏感性和诊断符合率,为乳腺癌患者术前临床诊治和术后辅助治疗提供帮助.     

Activated human hepatic stellate cells express the renin-angiotensin system and synthesize angiotensin II

BACKGROUND & AIMS: The renin-angiotensin system plays an important role in hepatic fibrogenesis. In other organs, myofibroblasts accumulated in damaged tissues generate angiotensin II, which promotes inflammation and extracellular matrix synthesis. It is unknown whether myofibroblastic hepatic stellate cells, the main hepatic fibrogenic cell type, express the renin-angiotensin system and synthesize angiotensin II. The aim of this study was to investigate whether quiescent and activated human hepatic stellate cells contain the components of the renin-angiotensin system and synthesize angiotensin II. METHODS: Hepatic stellate cells were freshly isolated from normal human livers (quiescent hepatic stellate cells) and from human cirrhotic livers (in vivo activated hepatic stellate cells). Culture-activated hepatic stellate cells were used after a second passage of quiescent hepatic stellate cells. Angiotensinogen, renin, and angiotensin-converting enzyme were assessed by quantitative polymerase chain reaction. Angiotensin II production was assessed by enzyme-linked immunosorbent assay and immunohistochemistry. RESULTS: Quiescent hepatic stellate cells barely express the renin-angiotensin system components--angiotensinogen, renin, and angiotensin-converting enzyme--and do not secrete angiotensin II. In contrast, both in vivo activated hepatic stellate cells and culture-activated hepatic stellate cells highly express active renin and angiotensin-converting enzyme and secrete angiotensin II to the culture media. Mature angiotensin II protein is also detected in the cytoplasm of in vivo activated and culture-activated hepatic stellate cells. Growth factors (platelet-derived growth factor and epidermal growth factor) and vasoconstrictor substances (endothelin-1 and thrombin) stimulate angiotensin II synthesis, whereas transforming growth factor-beta and proinflammatory cytokines have no effect. Vasodilator substances markedly attenuate the effect of endothelin-1. CONCLUSIONS: After activation, human hepatic stellate cells express the components of the renin-angiotensin system and synthesize angiotensin II. These results suggest that locally generated angiotensin II could participate in tissue remodeling in the human liver.     

Platelet-Derived Growth Factor A-Chain Homodimer Stimulated Growth of Cultured Smooth Muscle Cells from Spontaneously Hypertensive Rats

Vascular smooth muscle cells from spontaneously hypertensive rats (SHR) were growth stimulated when cocultured with bovine aortic endothelial cells whereas myoctyes from normotensive, Wistar Kyoto rats (WKY) were growth inhibited. The responsiveness of cells from the two rat sources to the two homodimeric forms of plateletderived growth factor (PDGF-AA or-BB) was different; SHR-derived cells responding equally well to both PDGF forms whereas cells from WKY responded to the B-chain homodimer only. The responses measured included S₆ kinase activation, phospholipase C mediated phosphoinositide catabolism and cell growth. Saturation binding experiments using [¹²⁵ I]-labelled PDGF homodimers (AA or BB) indicated that smooth muscle cells from hypertensive rats possess similar numbers of cell-surface A-chain receptors (α subunits) as Swiss 3T3 cells which have been used to characterize the mitogenic effects of the two PDGF homodimeric forms. The differences in responsiveness of SHR vs WKY cells to PDGF-AA and to the influence of endothelial cells may reside in their differential expression of PDGF receptors.