Coculture System with an Organotypic Brain Slice and 3D Spheroid of Carcinoma Cells

Patients with cerebral metastasis of carcinomas have a poor prognosis. However, the process at the metastatic site has barely been investigated, in ...

university of göttingen

Transforming growth factor beta1 (TGF-beta1) has been implicated as an inhibitor of cell proliferation and a potent inducer of apoptosis. Scutellaria baicalensis Georgi (SbG) has been widely used in Asia and recent investigations have shown that SbG has anticancer, antiviral, and anti-inflammatory effects. The aim of this study is to investigate the modulatory effect of SbG on TGF-beta1 gene expression. By using RAW 264.7 cell line as an in vitro model, the effects of SbG on TGF-beta1 gene expression were evaluated by ELISA, reverse-transcription polymerase chain reaction (RT-PCR) and quantitative PCR. Many inhibitors such as mitogen-activated protein kinase (MAPK) inhibitor (PD98059), p38-MAPK inhibitor (SB203580), NF-kappaB inhibitor (aspirin) and protein kinase C inhibitor (H7) were used to determine the possible signal transduction pathways. The results showed that crude extracts of SbG as well as its pure compounds, baicalin, baicalein and chrysin up-regulated TGF-beta1 gene expression on RAW 264.7 cells in a concentration-dependent manner. However, the flavonoid of SbG, wogonin, did not up-regulate TGF-beta1 expression on gene and protein levels on RAW264.7 cells. The facts that aspirin and H7 but not PD98059 and SB203580 blocked the enhancing effect suggested that NF-kappaB and PKC might be involved in baicalin-enhanced TGF-beta1 gene expression. We conclude that SbG up-regulates TGF-beta1 gene expression on RAW264.7 cells through NF-kappaB and PKC pathways and this might provide evidence to explain the therapeutic effect and potential adverse effects on the clinical use of Scutellaria baicalensis Georgi.

Enhancing effects of Scutellaria baicalensis and some of its constituents on TGF-beta1 gene expression in RAW 264.7 murine macrophage cell line.

The aim of this study is to elucidate the effects of Scutellaria baicalensis Georgi (SbG) extract and its constituents on macrophage-hepatocyte interaction in primary cultures. By using trans-well primary Kupffer cell culture or conditioned medium (CM) from murine macrophage RAW264.7 cell line (RAW cells), effects of SbG on hepatocyte growth were evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide and trypan blue exclusion assay. Cytokine production, antibody-neutralization studies, and molecular mechanisms of transforming growth factor (TGF)-beta1 gene expression were elucidated on SbG-treated RAW264.7 cells. In addition, recombinant human TGF-beta1 (r-human TGF-beta1) was added to elucidate the mechanisms of SbG effects on cultured hepatocytes. Immunohistochemistry using anti-NF-kappaB antibody was used to determine the possible signal transduction pathways in primary hepatocyte culture. The results showed that SbG stimulated the proliferation of cultured hepatocytes, possibly through NF-kappaB, but not of Toll-like receptor 4 activation; whereas SbG-RAW-CM and SbG in trans-well significantly suppressed the proliferation of hepatocytes. Antibody-neutralization studies revealed that TGF-beta1 was the main antimitotic cytokine in SbG-treated RAW cells CM. The growth stimulation effect of SbG on cultured hepatocytes was inhibited by exogenous administration of r-human TGF-beta1. Furthermore, SbG induced NF-kB translocation into the nuclei of cultured cells. In the RAW264.7 line, SbG and baicalin stimulated TGF-beta1 gene expression via NF-kappaB and protein kinase C activation. We conclude that SbG stimulates hepatocyte growth via activation of the NF-kappaB pathway and induces TGF-beta1 gene expression through the Kupffer cell-hepatocyte interaction, which subsequently results in the inhibition of SbG-stimulated hepatocyte growth.

Effects of Scutellaria baicalensis Georgi on macrophage-hepatocyte interaction through cytokines related to growth control of murine hepatocytes.

&#x867D;&#x7136;&#x8D8A;&#x6765;&#x8D8A;&#x591A;&#x8BC1;&#x636E;&#x8868;&#x660E;&#xFF0C;&#x8840;&#x6E90;&#x6027;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#x652F;&#x6301;&#x80BF;&#x7624;&#x7684;&#x5F62;&#x6210;&#x8FC7;&#x7A0B;&#xFF0C;&#x5B83;&#x662F;&#x76EE;&#x524D;&#x5C1A;&#x4E0D;&#x6E05;&#x695A;&#x662F;&#x5426;&#x4E13;&#x95E8;&#x9A7B;&#x5730;&#x7684;&#x5DE8;&#x566C;&#x7EC6;&#x80DE;&#xFF0C;&#x5982;&#x8111;&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#xFF0C;&#x4E5F;&#x53D1;&#x6325;&#x4E86;&#x7A81;&#x51FA;&#x7684;&#x4F5C;&#x7528;&#x8F6C;&#x79FB;&#x5F62;&#x6210;&#x7684;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x663E;&#x793A;&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x589E;&#x5F3A;&#x5165;&#x4FB5;&#x548C;&#x6B96;&#x6C11;&#x5316;&#x8111;&#x7EC4;&#x7EC7;&#x7684;&#x4E73;&#x817A;&#x764C;&#x7EC6;&#x80DE;&#xFF0C;&#x65E2;&#x4F5C;&#x4E3A;&#x79EF;&#x6781;&#x7684;&#x8F6C;&#x8FD0;&#x670D;&#x52A1;&#x548C;&#x6307;&#x5BFC;&#x5BFC;&#x8F68;&#x3002;&#x8FD9;&#x88AB;&#x4E0D;&#x60A6;&#x7531;&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x7684;&#x706D;&#x6D3B;&#x548C; Wnt Dickkopf-2 &#x6291;&#x5236;&#x5242;&#x3002;Proinvasive &#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x8868;&#x73B0;&#x51FA;&#x6539;&#x53D8;&#x7684;&#x5F62;&#x6001;&#xFF0C;&#x4F46;&#x65E2;&#x4E0D; M2 &#x6837;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x7684;&#x8868;&#x8FBE;&#x4E0A;&#x8C03;&#x4E5F;&#x5DEE;&#x5F02;&#x8868;&#x8FBE;&#x57FA;&#x56E0;&#x3002;&#x7EC6;&#x83CC;&#x5185;&#x6BD2;&#x7D20;&#x5230;&#x53E4;&#x5178;&#x7684; M1 &#x578B;&#x8F6C;&#x79FB;&#x80BF;&#x7624;&#x6559;&#x80B2;&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x3001; &#x964D;&#x4F4E;&#x4E86;&#x5176; proinvasive &#x51FD;&#x6570;&#x548C; unmasks &#x708E;&#x75C7;&#x548C;&#x6700;&#x5F3A;&#x70C8; Wnt &#x4FE1;&#x53F7;&#x8C03;&#x8282;&#x901A;&#x8DEF;&#x3002;&#x5728;&#x4EBA;&#x7C7B;&#x7684;&#x8111;&#x8F6C;&#x79FB;&#x7624;&#x7684;&#x7EC4;&#x7EC7;&#x5B66;&#x7ED3;&#x679C;&#x5F3A;&#x8C03;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x7684;&#x610F;&#x4E49;&#x3002;&#x6700;&#x540E;&#xFF0C;&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x662F;&#x5173;&#x952E;&#x6210;&#x529F;&#x6B96;&#x6C11;&#x5316;&#x7684;&#x4E0A;&#x76AE;&#x7EC6;&#x80DE;&#xFF0C;&#x5927;&#x8111;&#x5EFA;&#x8BAE;&#x4F5C;&#x4E3A;&#x4E00;&#x79CD;&#x6709;&#x524D;&#x9014;&#x7684;&#x6297;&#x80BF;&#x7624;&#x8F6C;&#x79FB;&#x6218;&#x7565; proinvasive &#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#x3002;

&#x5C0F;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x4FC3;&#x8FDB;&#x8111;&#x7EC4;&#x7EC7;&#x7684;&#x4E73;&#x817A;&#x764C;&#x7EC6;&#x80DE; Wnt &#x4F9D;&#x8D56;&#x65B9;&#x5F0F;&#x7684;&#x6B96;&#x6C11;&#x5316;&#x3002;

Although there is increasing evidence that blood-derived macrophages support tumor progression, it is still unclear whether specialized resident macrophages, such as brain microglia, also play a prominent role in metastasis formation. Here, we show that microglia enhance invasion and colonization of brain tissue by breast cancer cells, serving both as active transporters and guiding rails. This is antagonized by inactivation of microglia as well as by the Wnt inhibitor Dickkopf-2. Proinvasive microglia demonstrate altered morphology, but neither upregulation of M2-like cytokines nor differential gene expression. Bacterial lipopolysacharide shifts tumor-educated microglia into a classical M1 phenotype, reduces their proinvasive function, and unmasks inflammatory and Wnt signaling as the most strongly regulated pathways. Histological findings in human brain metastases underline the significance of these results. In conclusion, microglia are critical for the successful colonization of the brain by epithelial cancer cells, suggesting inhibition of proinvasive microglia as a promising antimetastatic strategy.

Microglia promote colonization of brain tissue by breast cancer cells in a Wnt-dependent way.

Bien qu&#39;il est plus en plus &eacute;vident que les d&eacute;riv&eacute;s du sang macrophages soutiennent la progression tumorale, on ignore encore si les macrophages r&eacute;sidents sp&eacute;cialis&eacute;s, tels que de la microglie du cerveau, jouent &eacute;galement un r&ocirc;le important dans la formation de m&eacute;tastases. Ici, nous montrons que microglies am&eacute;liorer invasion et la colonisation des tissus du cerveau par les cellules de cancer du sein, desservant tous les deux comme des transporteurs actifs et de guidage rails. C&#39;est antagonis&eacute;e par inactivation des microglies ainsi que par l&#39;inhibiteur de Wnt Dickkopf-2. Proinvasive microglia montrent une morphologie alt&eacute;r&eacute;e, mais aucune augmentation des cytokines de type M2 ni expression diff&eacute;rentielle des g&egrave;nes. Lipopolysaccharide bact&eacute;rien d&eacute;cale la microglie tumeur instruits dans un ph&eacute;notype classique de M1, r&eacute;duit leur fonction de proinvasive et d&eacute;masque inflammatoire et signalisation Wnt le plus fortement r&eacute;glement&eacute;s des voies. Les r&eacute;sultats histologiques dans les m&eacute;tastases c&eacute;r&eacute;brales humaines soulignent l&#39;importance de ces r&eacute;sultats. En conclusion, les microglies sont critiques pour la colonisation r&eacute;ussie du cerveau par les cellules &eacute;pith&eacute;liales canc&eacute;reuses, sugg&eacute;rant l&#39;inhibition de la microglie proinvasive comme une strat&eacute;gie prometteuse antim&eacute;tastatique.

La microglie favorisent la colonisation des tissus du cerveau par les cellules canc&eacute;reuses du sein de fa&ccedil;on d&eacute;pendante Wnt.

Obwohl es Beweise zunimmt, die Blut-abgeleitet Makrophagen unterst&uuml;tzen Tumor Fortschreiten, es ist noch unklar, ob spezielle residente Makrophagen, wie Gehirn Mikroglia, auch spielen eine herausragende Rolle in Metastasenbildung. Hier zeigen wir, dass Mikroglia Invasion und Kolonisation des Hirngewebes von Brustkrebszellen, dienen sowohl als aktive Transporter und guiding Schienen. Dies ist durch Inaktivierung von Mikroglia sowie der Wnt-Inhibitor Dickkopf-2 gegen sich aufgebracht. Proinvasive Mikroglia zeigen ver&auml;nderte Morphologie, jedoch weder Hochregulation von M2-artigen Zytokinen oder differenzielle Genexpression. Bakterielle Lipopolysacharide Tumor ausgebildete Mikroglia in einem klassischen M1-Ph&auml;notyp verschoben, verringert ihre Proinvasive Funktion und entlarvt entz&uuml;ndliche und Wnt signalisieren Wege als besonders stark reguliert. Histologische Befunde im menschlichen Gehirn Metastasen unterstreichen die Bedeutung dieser Ergebnisse. Abschlie&szlig;end Mikroglia sind entscheidend f&uuml;r die erfolgreiche Besiedlung des Gehirns durch epitheliale Krebszellen, Hemmung der Proinvasive Mikroglia als vielversprechende antimetastatic Strategie vorschlagen.

Mikroglia f&ouml;rdern Kolonisation des Hirngewebes von Brustkrebszellen Wnt-abh&auml;ngigen Weise.

Anche se c&#39;&egrave; crescente evidenza che derivati da sangue macrofagi supportano progressione del tumore, non &egrave; ancora chiaro se specializzati macrofagi residenti, come la microglia cerebrali, giocano anche un ruolo prominente nella formazione di metastasi. Qui, vi mostriamo che le microglia migliorare invasione e colonizzazione del tessuto cerebrale da cellule tumorali del seno, che serve sia come trasportatori attivi e guida di rotaie. Questo &egrave; antagonizzato da inattivazione della microglia, cos&igrave; come con il Wnt inibitore Dickkopf-2. Le microglia Proinvasive dimostrare la morfologia alterata, ma n&eacute; sovraregolazione di M2-come citochine n&eacute; espressione genica differenziale. Lipopolysacharide batterica turni microglia tumore-educato in un fenotipo classico M1, riduce la loro funzione proinvasive e smaschera infiammatoria e segnalazione Wnt come il pi&ugrave; fortemente regolamentato percorsi. Istologico in metastasi al cervello umano sottolinea l&#39;importanza di questi risultati. In conclusione, le microglia sono critici per il successo colonizzazione del cervello da parte delle cellule di cancro epiteliale, suggerendo l&#39;inibizione della microglia proinvasive come una strategia promettente antimetastatica.

Le microglia promuovere la colonizzazione del tessuto cerebrale da cellule cancro al seno in modo Wnt-dipendente.

&#x8840;&#x7531;&#x6765;&#x306E;&#x8A3C;&#x62E0;&#x304C;&#x5897;&#x52A0;&#x3057;&#x3066;&#x3044;&#x308B;&#x304C;&#x816B;&#x760D;&#x306E;&#x9032;&#x884C;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x3092;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x306F;&#x3001;&#x8133;&#x306E;&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x306A;&#x3069;&#x5C02;&#x9580;&#x306E;&#x30DE;&#x30AF;&#x30ED;&#x30D5;&#x30A1;&#x30FC;&#x30B8;&#x3092;&#x307E;&#x305F;&#x8EE2;&#x79FB;&#x5F62;&#x6210;&#x306E;&#x8457;&#x540D;&#x306A;&#x5F79;&#x5272;&#x518D;&#x751F;&#x304B;&#x3069;&#x3046;&#x304B;&#x306F;&#x307E;&#x3060;&#x4E0D;&#x660E;&#x3067;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x3092;&#x9AD8;&#x3081;&#x308B;&#x4FB5;&#x7565;&#x3068;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x306A;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30DD;&#x30FC;&#x30BF;&#x30FC;&#x306E;&#x4E21;&#x65B9;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x3001;&#x5C0E;&#x304F;&#x306E;&#x4E73;&#x623F;&#x764C;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x8133;&#x7D44;&#x7E54;&#x306E;&#x690D;&#x6C11;&#x5730;&#x5316;&#x306E;&#x30EC;&#x30FC;&#x30EB;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x306F;&#x3001;wnt &#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x963B;&#x5BB3;&#x5264;&#x306B;&#x304A;&#x3051;&#x308B; Dkk 2 &#x3068;&#x540C;&#x69D8;&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x306E;&#x4E0D;&#x6D3B;&#x5316;&#x306B;&#x3088;&#x3063;&#x3066;&#x304B;&#x3063;&#x3055;&#x3044;&#x3067;&#x3059;&#x3002;Proinvasive &#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x3001;&#x3069;&#x3061;&#x3089;&#x3082; m 2 &#x306E;&#x3088;&#x3046;&#x306A;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x306E;&#x30A2;&#x30C3;&#x30D7;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x307E;&#x305F;&#x5DEE;&#x52D5;&#x907A;&#x4F1D;&#x5B50;&#x767A;&#x73FE;&#x306E;&#x5909;&#x66F4;&#x3055;&#x308C;&#x305F;&#x5F62;&#x614B;&#x3092;&#x793A;&#x3057;&#x307E;&#x3059;&#x3002;&#x7D30;&#x83CC;&#x306E; lipopolysacharide &#x816B;&#x760D;&#x6559;&#x80B2;&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x306F;&#x53E4;&#x5178;&#x306E; M1 &#x306E;&#x8868;&#x73FE;&#x578B;&#x306B;&#x30B7;&#x30D5;&#x30C8;&#x3001;&#x5F7C;&#x3089; proinvasive &#x306E;&#x6A5F;&#x80FD;&#x304C;&#x524A;&#x6E1B;&#x3055;&#x308C;&#x708E;&#x75C7; unmasks &#x3057;&#x3001;wnt &#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x3092;&#x898F;&#x5236;&#x3067;&#x6700;&#x3082;&#x5F37;&#x304F;&#x3002;&#x3072;&#x3068;&#x8133;&#x8EE2;&#x79FB;&#x306E;&#x6240;&#x898B;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306E;&#x610F;&#x7FA9;&#x3092;&#x5F37;&#x8ABF;&#x3057;&#x307E;&#x3059;&#x3002;&#x7D50;&#x8AD6;&#x3068;&#x3057;&#x3066;&#x3001;&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x91CD;&#x8981;&#x6210;&#x529F;&#x6709;&#x671B;&#x306A;&#x6297;&#x8EE2;&#x79FB;&#x6226;&#x7565;&#x3068;&#x3057;&#x3066; proinvasive &#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x306E;&#x6291;&#x5236;&#x3092;&#x793A;&#x5506;&#x8133;&#x4E0A;&#x76AE;&#x764C;&#x7D30;&#x80DE;&#x306E;&#x690D;&#x6C11;&#x5730;&#x3067;&#x3059;&#x3002;

&#x30DF;&#x30AF;&#x30ED;&#x30B0;&#x30EA;&#x30A2;&#x306F; wnt &#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x306B;&#x4F9D;&#x5B58;&#x3059;&#x308B;&#x65B9;&#x6CD5;&#x3067;&#x4E73;&#x764C;&#x7D30;&#x80DE;&#x306B;&#x3088;&#x308B;&#x8133;&#x7D44;&#x7E54;&#x306E;&#x690D;&#x6C11;&#x5730;&#x5316;&#x3092;&#x4FC3;&#x9032;&#x3057;&#x307E;&#x3059;&#x3002;

&#xBE44;&#xB85D; &#xD608;&#xC561; &#xD30C;&#xC0DD; &#xC99D;&#xAC70; &#xC99D;&#xAC00; &#xB300; &#xC2DD; &#xC138;&#xD3EC;&#xB294; &#xC885;&#xC591;&#xC758; &#xC9C4;&#xD589;&#xC744; &#xC9C0;&#xC6D0;, &#xC544;&#xC9C1; &#xBD88;&#xBD84;&#xBA85; &#xC5EC;&#xBD80; &#xB1CC; microglia &#xB4F1; &#xC804;&#xBB38;&#xB41C; &#xC0C1;&#xC8FC; &#xB300; &#xC2DD; &#xB610;&#xD55C; &#xC804;&#xC774; &#xD615;&#xC131;&#xC5D0; &#xB208;&#xC5D0; &#xB744;&#xB294; &#xC5ED;&#xD560;&#xC744; &#xD560; &#xAC83; &#xC774;&#xB2E4;. &#xC5EC;&#xAE30;, &#xC6B0;&#xB9AC;&#xAC00; microglia &#xCE68;&#xB7B5; &#xAC15;&#xD654; &#xBC0F; &#xC720;&#xBC29;&#xC554; &#xC138;&#xD3EC;&#xB97C; &#xD65C;&#xC131; &#xC804;&#xC1A1;&#xAE30;&#xB85C; &#xBAA8;&#xB450;&#xB97C; &#xC81C;&#xACF5; &#xD558; &#xACE0; &#xC778;&#xB3C4; &#xD558; &#xC5EC; &#xB1CC; &#xC870;&#xC9C1;&#xC758; &#xC2DD;&#xBBFC;&#xC9C0; &#xB808;&#xC77C;&#xC744; &#xBCF4;&#xC5EC;&#xC90D;&#xB2C8;&#xB2E4;. &#xC774; microglia&#xC758; &#xBE44;&#xD65C;&#xC131;&#xD654; &#xBB3C;&#xB860; Wnt &#xC5B5;&#xC81C;&#xC81C; Dickkopf 2 &#xBC18;&#xAC10; &#xB429;&#xB2C8;&#xB2E4;. Proinvasive microglia M2 &#xAC19;&#xC740; &#xD06C;&#xB9B0; &#xC2DC; &#xD1A0; &#xD0A8;&#xC758; upregulation &#xC5B4;&#xB290;&#xB3C4; &#xCC28;&#xB3D9; &#xC720;&#xC804;&#xC790; &#xBC1C;&#xD604; &#xD558;&#xC9C0;&#xB9CC; &#xBCC0;&#xACBD; &#xB41C; &#xD615;&#xD0DC;&#xB97C; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. &#xC138;&#xADE0; lipopolysacharide &#xC885;&#xC591; &#xAD50;&#xC721; microglia &#xD074;&#xB798;&#xC2DD; m 1 &#xD615;&#xC73C;&#xB85C; &#xC774;&#xB3D9;, &#xADF8;&#xB4E4;&#xC758; proinvasive &#xAE30;&#xB2A5;&#xC744; &#xAC10;&#xC18C; &#xBC0F; &#xC5FC;&#xC99D; unmasks &#xBC0F; &#xD1B5;&#xB85C; &#xAC00;&#xC7A5; &#xAC15;&#xB825; &#xD558; &#xAC8C; &#xB808; &#xADE4; &#xB808;&#xC774;&#xD2B8; Wnt &#xC2E0;&#xD638;. &#xC778;&#xAC04;&#xC758; &#xB1CC; &#xC804;&#xC774;&#xC5D0; &#xC870;&#xC9C1;&#xD559; &#xC5F0;&#xAD6C; &#xACB0;&#xACFC; &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC;&#xC758; &#xC758;&#xBBF8;&#xC5D0; &#xBC11;&#xC904;. &#xB05D;&#xC73C;&#xB85C;, microglia &#xC5B5;&#xC81C; proinvasive microglia&#xC758; &#xC720;&#xB9DD;&#xD55C; antimetastatic &#xC804;&#xB7B5;&#xC73C;&#xB85C; &#xC81C;&#xC548; &#xC0C1;&#xD53C; &#xC554; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xB1CC;&#xC758; &#xC131;&#xACF5;&#xC801;&#xC778; &#xC2DD;&#xBBFC;&#xC9C0;&#xC5D0; &#xB300; &#xD55C; &#xC911;&#xC694; &#xD55C; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

Microglia Wnt &#xC885;&#xC18D;&#xC801;&#xC778; &#xBC29;&#xBC95;&#xC73C;&#xB85C; &#xC720; &#xBC29; &#xC554; &#xC138;&#xD3EC;&#xC5D0; &#xC758;&#xD574; &#xB1CC; &#xC870;&#xC9C1;&#xC758; &#xC2DD;&#xBBFC;&#xC744; &#xCD09;&#xC9C4; &#xD569;&#xB2C8;&#xB2E4;.

Aunque existe una creciente evidencia que derivadas de sangre progresi&oacute;n tumoral de la ayuda de los macr&oacute;fagos, no est&aacute; todav&iacute;a claro si macr&oacute;fagos residentes especializados, como la microgl&iacute;a del cerebro, tambi&eacute;n juegan un papel destacado en la formaci&oacute;n de met&aacute;stasis. Aqu&iacute;, demostramos que microglia mejorar la invasi&oacute;n y colonizaci&oacute;n de tejido cerebral por c&eacute;lulas de c&aacute;ncer de mama, que sirve tanto como transportadores activos y guiar los carriles. Esto es contrariado por la inactivaci&oacute;n de la microgl&iacute;a, as&iacute; como por el inhibidor de Wnt Dickkopf-2. Proinvasive microgl&iacute;a demostrar morfolog&iacute;a alterada, pero ni upregulation de citoquinas M2-como ni expresi&oacute;n g&eacute;nica diferencial. Concedidos bacteriana cambia de puesto microglia tumor-educado en un fenotipo cl&aacute;sico de M1, reduce su funci&oacute;n proinvasive y desenmascara inflamatoria y se&ntilde;alizaci&oacute;n de Wnt como el m&aacute;s fuertemente regulado v&iacute;as. Hallazgos histol&oacute;gicos en las met&aacute;stasis del cerebro humano subrayan la importancia de estos resultados. En conclusi&oacute;n, microgl&iacute;a son cr&iacute;ticos para la colonizaci&oacute;n exitosa del cerebro por las c&eacute;lulas de c&aacute;ncer epitelial, sugiriendo inhibici&oacute;n de microglia proinvasive como una estrategia prometedora de la antimetast&aacute;ticos.

Microglia promover la colonizaci&oacute;n del tejido cerebral por las c&eacute;lulas de c&aacute;ncer de mama en forma de Wnt-dependiente.

The sentinel and immune functions of microglia require rapid and appropriate reactions to infection and damage. Their Toll-like receptors (TLRs) sense both as threats. However, whether activated microglia mount uniform responses or whether subsets conduct selective tasks is unknown. We demonstrate that murine microglia reorganize their responses to TLR activations postnatally and that this process comes with a maturation of TLR4-organized functions. Although induction of MHCI for antigen presentation remains as a pan-populational feature, synthesis of TNFÎ± becomes restricted to a subset, even within adult central nervous system regions. Response heterogeneity is evident ex vivo, in situ, and in vivo, but is not limited to TNFÎ± production or to TLR-triggered functions. Also, clearance activities for myelin under physiological and pathophysiological conditions, IFNÎ³-enforced upregulation of MHCII, or challenged inductions of other proinflammatory factors reveal dissimilar microglial contributions. Notably, response heterogeneity is also confirmed in human brain tissue. Our findings suggest that microglia divide by constitutive and inducible capacities. Privileged production of inflammatory mediators assigns a master control to subsets. Sequestration of clearance of endogenous material versus antigen presentation in exclusive compartments can separate potentially interfering functions. Finally, subsets rather than a uniform population of microglia may assemble the reactive phenotypes in responses during infection, injury, and rebuilding, warranting consideration in experimental manipulation and therapeutic strategies.

Toll-like receptor activation reveals developmental reorganization and unmasks responder subsets of microglia.

The metastatic colonization of the brain by carcinoma cells is still barely understood, in particular when considering interactions with the host tissue. The colonization comes with a substantial destruction of the surrounding host tissue. This leads to activation of damage responses by resident innate immune cells to protect, repair, and organize the wound healing, but may distract from tumoricidal actions. We recently demonstrated that microglia, innate immune cells of the CNS, assist carcinoma cell invasion. Here we report that this is a fatal side effect of a physiological damage response of the brain tissue. In a brain slice coculture model, contact with both benign and malignant epithelial cells induced a response by microglia and astrocytes comparable to that seen at the interface of human cerebral metastases. While the glial damage response intended to protect the brain from intrusion of benign epithelial cells by inducing apoptosis, it proved ineffective against various malignant cell types. They did not undergo apoptosis and actually exploited the local tissue reaction to invade instead. Gene expression and functional analyses revealed that the C-X-C chemokine receptor type 4 (CXCR4) and WNT signaling were involved in this process. Furthermore, CXCR4-regulated microglia were recruited to sites of brain injury in a zebrafish model and CXCR4 was expressed in human stroke patients, suggesting a conserved role in damage responses to various types of brain injuries. Together, our findings point to a detrimental misuse of the glial damage response program by carcinoma cells resistant to glia-induced apoptosis.

Han-Ning Chuang

Department of Hematology and Oncology

university of göttingen

Coculture System with an Organotypic Brain Slice and 3D Spheroid of Carcinoma Cells

Han-Ning Chuang

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Hematology and Oncology

university of göttingen

Coculture System with an Organotypic Brain Slice and 3D Spheroid of Carcinoma Cells

Department of Hematology and Oncology