Studying TGF-&#946; Signaling and TGF-&#946;-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Transforming growth factor-&#946; (TGF-&#946;) is a secreted multifunctional factor that plays a key role in intercellular communication. Perturbations of ...

Leiden University Medical Center

&#x8F6C;&#x5316;&#x751F;&#x957F;&#x56E0;&#x5B50; &beta; (TGF-&beta;) &#x5BB6;&#x5EAD;&#x6210;&#x5458;&#x5DF2;&#x80DA;&#x80CE;&#x53D1;&#x751F;&#x8FC7;&#x7A0B;&#x4E2D;&#x7684;&#x57FA;&#x56E0;&#x4E0E;&#x8840;&#x7BA1;&#x5F62;&#x6210;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x77DB;&#x76FE;&#x7814;&#x7A76;&#x6709;&#x5173; TGF-&beta; &#x548C;&#x62A5;&#x544A;&#x7684;&#x8840;&#x7BA1;&#x529F;&#x80FD;&#xFF0C;&#x5176;&#x4ED6;&#x5BB6;&#x5EAD;&#x6210;&#x5458;&#x7684;&#x4F5C;&#x7528;&#x5982;&#x9AA8;&#x5F62;&#x6001;&#x53D1;&#x751F;&#x86CB;&#x767D; (BMP) 9&#xFF0C;&#x5728;&#x751F;&#x7406;&#x548C;&#x75C5;&#x7406;&#x7684;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x4F7F;&#x9700;&#x8981;&#x7684;&#x673A;&#x7406;&#x7814;&#x7A76;&#x660E;&#x663E;&#x3002;&#x6211;&#x4EEC;&#x8BC1;&#x660E;&#xFF0C;&#x901A;&#x8FC7;&#x9057;&#x4F20;&#x548C;&#x836F;&#x7406;&#x624B;&#x6BB5;&#x3001; TGF-&beta; &#x548C; BMP9 &#x53D7;&#x4F53;&#x6FC0;&#x6D3B;&#x7D20;&#x53D7;&#x4F53;&#x6837;&#x86CB;&#x767D;&#x6FC0;&#x9176; &#xFF08;ALK&#xFF09; 1 &#x8868;&#x793A;&#x80BF;&#x7624;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x6CBB;&#x7597;&#x7684;&#x65B0;&#x9776;&#x70B9;&#x3002;ALK1 &#x57FA;&#x56E0;&#x7528;&#x91CF;&#x6216; ALK1-Fc &#x878D;&#x5408;&#x86CB;&#x767D; RAP-041 &#x7684;&#x5168;&#x8EAB;&#x6CBB;&#x7597;&#x7684;&#x51CF;&#x503C;&#x963B;&#x788D;&#x80BF;&#x7624;&#x7684;&#x751F;&#x957F;&#x548C;&#x8FDB;&#x5C55;&#x7684;&#x8F6C;&#x57FA;&#x56E0;&#x5C0F;&#x9F20;&#x6A21;&#x578B;&#x7684;&#x591A;&#x6B65;&#x80BF;&#x7624;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#x3002;&#x6B64;&#x5916;&#xFF0C;RAP-041 &#x6781;&#x5927;&#x5730;&#x635F;&#x5BB3;&#x4E86;&#x5BF9;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x751F;&#x957F;&#x56E0;&#x5B50; A &#x548C;&#x78B1;&#x6027;&#x6210;&#x7EA4;&#x7EF4;&#x7EC6;&#x80DE;&#x751F;&#x957F;&#x56E0;&#x5B50;&#x5728;&#x4F53;&#x5916;&#x548C;&#x4F53;&#x5185;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x54CD;&#x5E94;&#x3002;&#x5728;&#x5BFB;&#x6C42;&#x89C2;&#x5BDF;&#x5230;&#x7684;&#x5F71;&#x54CD;&#x7684;&#x673A;&#x5236;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#x4E86;&#x610F;&#x5916;&#x7684;&#x4FE1;&#x53F7;&#x534F;&#x540C; TGF-&beta; &#x548C; BMP9&#xFF0C;&#x901A;&#x8FC7;&#x8FD9;&#x4E24;&#x4E2A;&#x56E0;&#x7D20;&#x7684;&#x8054;&#x5408;&#x7684;&#x884C;&#x52A8;&#x589E;&#x5F3A;&#x523A;&#x6FC0;&#x8840;&#x7BA1;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x54CD;&#x5E94;&#x4E4B;&#x95F4;&#x3002;&#x6211;&#x4EEC;&#x5212;&#x5B9A;&#x4E86;&#x51B3;&#x5B9A;&#x6027;&#x7684;&#x4F5C;&#x7528;&#xFF0C;&#x4FE1;&#x53F7;&#x7531; TGF-&beta; &#x5728;&#x80BF;&#x7624;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x4E2D;&#x7684;&#x5BB6;&#x5EAD;&#x6210;&#x5458;&#xFF0C;&#x5E76;&#x63D0;&#x4F9B;&#x5373;&#x5C06;&#x4E34;&#x5E8A;&#x53D1;&#x5C55;&#x7684;&#x836F;&#x7269;&#x5728;&#x80BF;&#x7624;&#x963B;&#x585E; ALK1 &#x673A;&#x68B0;&#x6D1E;&#x5BDF;&#x529B;&#x3002;

&#x9057;&#x4F20;&#x53CA;&#x836F;&#x7406;&#x6D3B;&#x6027;&#x7684;&#x6FC0;&#x6D3B;&#x7D20;&#x53D7;&#x4F53;&#x6837;&#x6FC0;&#x9176; 1 &#x9488;&#x5BF9;&#x635F;&#x5BB3;&#x8840;&#x7BA1;&#x751F;&#x6210;&#x548C;&#x80BF;&#x7624;&#x751F;&#x957F;&#x3002;

Members of the transforming growth factor beta (TGF-beta) family have been genetically linked to vascular formation during embryogenesis. However, contradictory studies about the role of TGF-beta and other family members with reported vascular functions, such as bone morphogenetic protein (BMP) 9, in physiological and pathological angiogenesis make the need for mechanistic studies apparent. We demonstrate, by genetic and pharmacological means, that the TGF-beta and BMP9 receptor activin receptor-like kinase (ALK) 1 represents a new therapeutic target for tumor angiogenesis. Diminution of ALK1 gene dosage or systemic treatment with the ALK1-Fc fusion protein RAP-041 retarded tumor growth and progression by inhibition of angiogenesis in a transgenic mouse model of multistep tumorigenesis. Furthermore, RAP-041 significantly impaired the in vitro and in vivo angiogenic response toward vascular endothelial growth factor A and basic fibroblast growth factor. In seeking the mechanism for the observed effects, we uncovered an unexpected signaling synergy between TGF-beta and BMP9, through which the combined action of the two factors augmented the endothelial cell response to angiogenic stimuli. We delineate a decisive role for signaling by TGF-beta family members in tumor angiogenesis and offer mechanistic insight for the forthcoming clinical development of drugs blocking ALK1 in oncology.

Genetic and pharmacological targeting of activin receptor-like kinase 1 impairs tumor growth and angiogenesis.

Membres de la famille de b&ecirc;ta (TGF-b&ecirc;ta) de facteur de croissance transformant ont &eacute;t&eacute; g&eacute;n&eacute;tiquement li&eacute;e &agrave; vasculaire de formation au cours de l&#39;embryogen&egrave;se. Cependant, contradictoire &eacute;tudes concernant le r&ocirc;le des TGF-b&ecirc;ta et les autres membres de la famille avec les fonctions vasculaires rapport&eacute;es, comme prot&eacute;ine morphog&eacute;n&eacute;tique osseuse (BMP) 9, dans l&#39;angiogen&egrave;se physiologique et pathologique font de la n&eacute;cessit&eacute; d&#39;&eacute;tudes m&eacute;canistes apparent. Nous d&eacute;montrons, par des moyens pharmacologiques et de g&eacute;n&eacute;tiques, que le TGF-beta et BMP9 l&#39;activine comme r&eacute;cepteur kinase du r&eacute;cepteur (ALK) 1 repr&eacute;sente une nouvelle cible th&eacute;rapeutique pour l&#39;angiogen&egrave;se tumorale. Diminution du dosage des g&egrave;nes ALK1 ou un traitement syst&eacute;mique avec la prot&eacute;ine de fusion ALK1-Fc RAP-041 a retard&eacute; la croissance tumorale et progression par l&#39;inhibition de l&#39;angiogen&egrave;se dans un mod&egrave;le de souris transg&eacute;nique de la tumorigen&egrave;se multipas. En outre, RAP-041 r&eacute;duite significativement la r&eacute;ponse angiog&eacute;nique in vitro et in vivo vers le facteur de croissance endoth&eacute;lial vasculaire A et basic fibroblast growth factor. En cherchant le m&eacute;canisme pour les effets observ&eacute;s, que nous avons d&eacute;couverts une synergie de signalisation inattendue entre TGF-b&ecirc;ta et BMP9, &agrave; travers lequel l&#39;action combin&eacute;e des deux facteurs a augment&eacute; la r&eacute;ponse de cellules endoth&eacute;liales &agrave; des stimuli angiog&eacute;niques. Nous d&eacute;limiter un r&ocirc;le d&eacute;cisif pour la signalisation par les membres de la famille TGF-b&ecirc;ta dans l&#39;angiogen&egrave;se tumorale et offrent un aper&ccedil;u m&eacute;caniste pour le prochain d&eacute;veloppement clinique des m&eacute;dicaments bloquant ALK1 en oncologie.

G&eacute;n&eacute;tiques et pharmacologiques ciblant l&#39;activine comme r&eacute;cepteur kinase 1 alt&egrave;re l&#39;angiogen&egrave;se et la croissance tumorale.

Mitglieder der Familie der transformierende Wachstumsfaktor-Beta (TGF-Beta) wurden genetisch verkn&uuml;pften zu vaskul&auml;ren Bildung w&auml;hrend der Embryogenese. Jedoch Studien widerspr&uuml;chliche &uuml;ber die Rolle des TGF-Beta und andere Familienmitglieder mit gemeldeten vaskul&auml;re Funktionen, wie z. B. Knochen morphogenetic Proteins (BMP) 9, in physiologischer und pathologischer Angiogenese mechanistische Untersuchungen deutlich machen. Wir demonstrieren, durch genetische und pharmakologischen Mittel, dass das TGF-Beta und BMP9 Rezeptor Activin Rezeptor-wie Kinase (ALK) 1 ein neues therapeutisches Ziel f&uuml;r Tumorangiogenese darstellt. Eine Verringerung der ALK1 gen Dosierung oder systemische Behandlung mit den ALK1-Fc-Fusionsprotein RAP-041 verz&ouml;gert Tumorwachstum und Progression durch Hemmung der Angiogenese in einem transgenen Mausmodell der multistep Tumorentstehung. Dar&uuml;ber hinaus beeintr&auml;chtigt RAP-041 deutlich die Antwort in vitro und in-vivo-angiogenen Richtung vaskul&auml;ren endothelialen Wachstumsfaktor A und grundlegende Fibroblasten-Wachstumsfaktor. In dem Bem&uuml;hen des Mechanismus f&uuml;r die beobachteten Effekte, entdeckten wir eine unerwartete Signalling Synergie zwischen TGF-Beta und BMP9, durch die das gemeinsame Handeln der beiden Faktoren die endothelial Zelle Antwort auf Angiogenese Reize erg&auml;nzt. Wir beschreiben eine entscheidende Rolle f&uuml;r die Signalisierung durch Mitglieder der TGF-Beta-Familie in Tumorangiogenese und bieten mechanistische Einblicke f&uuml;r die bevorstehenden klinischen Entwicklung von Arzneimitteln blockieren ALK1 in der Onkologie.

Genetische und pharmakologische Ausrichtung der Activin Rezeptor-wie Kinase 1 beeintr&auml;chtigt Tumorwachstum und Angiogenesis.

Transforming growth factor beta (TGF-beta) familiari sono stati geneticamente legati a vascolare formazione durante l&#39;embriogenesi. Tuttavia, contraddittorio studi sul ruolo del TGF-beta e altri membri della famiglia con le funzioni vascolari segnalate, come bone morphogenetic protein (BMP) 9, in fisiologico e patologico angiogenesi rendono la necessit&agrave; di Studi meccanicistici apparente. Dimostriamo, con mezzi farmacologici e genetici, che il TGF-beta e BMP9 del recettore activin receptor-like chinasi (ALK) 1 rappresenta un nuovo obiettivo terapeutico per l&#39;angiogenesi tumorale. Diminuzione del dosaggio del gene ALK1 o trattamento sistemico con la proteina di fusione ALK1-Fc RAP-041 ritardata crescita tumorale e la progressione di inibizione dell&#39;angiogenesi in un modello murino transgenico di tumorigenesi multistep. Inoltre, RAP-041 alterato significativamente la risposta angiogenic in vitro e in vivo verso il fattore di crescita endoteliale vascolare A e fattore di crescita dei fibroblasti di base. Nel cercare il meccanismo per gli effetti osservati, abbiamo scoperto un&#39;inaspettato segnalazione sinergia tra TGF-beta e BMP9, attraverso il quale l&#39;azione combinata di due fattori aumentata la risposta delle cellule endoteliali a stimoli angiogenico. Noi delineare un ruolo decisivo per la segnalazione di membri della famiglia TGF-beta nell&#39;angiogenesi tumorale e offrire comprensione meccanicistica per il prossimo sviluppo clinico di farmaci blocco ALK1 in oncologia.

Genetica e farmacologica di targeting di activin receptor-like chinasi 1 altera l&#39;angiogenesi e la crescita tumorale.

&#x5909;&#x5F62;&#x306E;&#x6210;&#x9577;&#x56E0;&#x5B50; (TGF &#x30D9;&#x30FC;&#x30BF;&#x7248;&#xFF09; &#x306E;&#x30D9;&#x30FC;&#x30BF;&#x7248;&#x5BB6;&#x65CF;&#x306E;&#x30E1;&#x30F3;&#x30D0;&#x30FC;&#x306F;&#x3001;&#x80DA;&#x767A;&#x751F;&#x306B;&#x4F34;&#x3046;&#x8840;&#x7BA1;&#x306B;&#x907A;&#x4F1D;&#x7684;&#x30EA;&#x30F3;&#x30AF;&#x5F62;&#x6210;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x660E;&#x3089;&#x304B;&#x306A;&#x4F5C;&#x7528;&#x6A5F;&#x5E8F;&#x7814;&#x7A76;&#x306E;&#x5FC5;&#x8981;&#x6027;&#x306B;&#x304A;&#x3051;&#x308B;&#x751F;&#x7406;&#x5B66;&#x7684;&#x304A;&#x3088;&#x3073;&#x75C5;&#x7406;&#x5B66;&#x7684;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x9AA8;&#x5F62;&#x6210;&#x56E0;&#x5B50; (BMP) 9 &#x3092;&#x4F5C;&#x308B;&#x3088;&#x3046;&#x77DB;&#x76FE; TGF &#x30D9;&#x30FC;&#x30BF;&#x3068;&#x5831;&#x544A;&#x3055;&#x308C;&#x305F;&#x8840;&#x7BA1;&#x306E;&#x6A5F;&#x80FD;&#x3092;&#x6301;&#x3064;&#x4ED6;&#x306E;&#x5BB6;&#x65CF;&#x306E;&#x30E1;&#x30F3;&#x30D0;&#x30FC;&#x306E;&#x5F79;&#x5272;&#x306B;&#x3064;&#x3044;&#x3066;&#x306E;&#x7814;&#x7A76;&#x3057;&#x307E;&#x3059;&#x3002;&#x6211;&#x3005; &#x3092;&#x793A;&#x3059;&#x907A;&#x4F1D;&#x5B66;&#x7684;&#x304A;&#x3088;&#x3073;&#x85AC;&#x7406;&#x5B66;&#x7684;&#x624B;&#x6BB5;&#x306B;&#x3088;&#x3063;&#x3066;&#x306F; TGF &#x30D9;&#x30FC;&#x30BF;&#x3068; BMP9 &#x53D7;&#x5BB9;&#x4F53;&#x30A2;&#x30AF;&#x30C1;&#x30D3;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x69D8;&#x30AD;&#x30CA;&#x30FC;&#x30BC; (&#x30A2;&#x30EB;&#x30AF;) 1 &#x816B;&#x760D;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306E;&#x305F;&#x3081;&#x306E;&#x65B0;&#x3057;&#x3044;&#x6CBB;&#x7642;&#x4E0A;&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3092;&#x8868;&#x3057;&#x307E;&#x3059;&#x3002;&#x3073; ALK1 &#x907A;&#x4F1D;&#x5B50;&#x91CF;&#x307E;&#x305F;&#x306F;&#x3073; ALK1 Fc &#x878D;&#x5408;&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x30E9;&#x30C3;&#x30D7; 041 &#x5168;&#x8EAB;&#x7642;&#x6CD5;&#x306E;&#x6E1B;&#x5C11;&#x30C8;&#x30E9;&#x30F3;&#x30B9;&#x30B8;&#x30A7;&#x30CB;&#x30C3;&#x30AF; &#x30DE;&#x30A6;&#x30B9; &#x30E2;&#x30C7;&#x30EB;&#x306E;&#x591A;&#x6BB5;&#x968E;&#x767A;&#x764C;&#x306B;&#x304A;&#x3051;&#x308B;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306E;&#x963B;&#x5BB3;&#x306B;&#x3088;&#x308B;&#x816B;&#x760D;&#x5897;&#x6B96;&#x3068;&#x9032;&#x884C;&#x3092;&#x9045;&#x3089;&#x305B;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x30E9;&#x30C3;&#x30D7;-041 &#x8840;&#x7BA1;&#x5185;&#x76AE;&#x5897;&#x6B96;&#x56E0;&#x5B50; A &#x3068;&#x57FA;&#x672C;&#x7684;&#x306A;&#x7E4A;&#x7DAD;&#x82BD;&#x7D30;&#x80DE;&#x6210;&#x9577;&#x56E0;&#x5B50;&#x306B;&#x5BFE;&#x3059;&#x308B; in vitro &#x304A;&#x3088;&#x3073; in vivo &#x8840;&#x7BA1;&#x65B0;&#x751F;&#x53CD;&#x5FDC;&#x304C;&#x8457;&#x3057;&#x304F;&#x640D;&#x306A;&#x308F;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x89B3;&#x6E2C;&#x3055;&#x308C;&#x305F;&#x52B9;&#x679C;&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x6C42;&#x3081;&#x3066;&#x306F;&#x4E88;&#x671F;&#x3057;&#x306A;&#x3044;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x30B7;&#x30CA;&#x30B8;&#x30FC; TGF &#x30D9;&#x30FC;&#x30BF;&#x3068;&#x305D;&#x308C;&#x3092;&#x901A;&#x3057;&#x3066;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x523A;&#x6FC0;&#x306B;&#x5BFE;&#x3059;&#x308B;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x5FDC;&#x7B54;&#x306E; 2 &#x3064;&#x306E;&#x8981;&#x56E0;&#x306E;&#x7D44;&#x307F;&#x5408;&#x308F;&#x305B;&#x306E;&#x30A2;&#x30AF;&#x30B7;&#x30E7;&#x30F3;&#x306F;&#x3001;&#x62E1;&#x5F35;&#x73FE;&#x5B9F;&#x611F; BMP9 &#x9593;&#x3092;&#x767A;&#x898B;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x816B;&#x760D;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x306E; TGF &#x30D9;&#x30FC;&#x30BF;&#x5BB6;&#x65CF;&#x306E;&#x30E1;&#x30F3;&#x30D0;&#x30FC;&#x306B;&#x3088;&#x3063;&#x3066;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0;&#x306E;&#x305F;&#x3081;&#x306E;&#x6C7A;&#x5B9A;&#x7684;&#x306A;&#x5F79;&#x5272;&#x3092;&#x63CF;&#x304F;&#x3057;&#x3001;&#x4ECA;&#x5F8C;&#x306E;&#x81E8;&#x5E8A;&#x958B;&#x767A;&#x3073; ALK1 &#x816B;&#x760D;&#x3067;&#x963B;&#x5BB3;&#x85AC;&#x306E;&#x305F;&#x3081;&#x306E;&#x6A5F;&#x68B0;&#x7684;&#x306A;&#x6D1E;&#x5BDF;&#x529B;&#x3092;&#x63D0;&#x4F9B;&#x3057;&#x307E;&#x3059;&#x3002;

&#x907A;&#x4F1D;&#x7684;&#x304A;&#x3088;&#x3073;&#x85AC;&#x7406;&#x5B66;&#x7684;&#x306B;&#x30A2;&#x30AF;&#x30C1;&#x30D3;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x69D8;&#x30AD;&#x30CA;&#x30FC;&#x30BC; 1 &#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3068;&#x816B;&#x760D;&#x306E;&#x5897;&#x6B96;&#x304A;&#x3088;&#x3073;&#x8840;&#x7BA1;&#x65B0;&#x751F;&#x3092;&#x640D;&#x306A;&#x3044;&#x307E;&#x3059;&#x3002;

&#xBCC0;&#xD615; &#xC131;&#xC7A5; &#xC778;&#xC790; (TGF-&#xBCA0;&#xD0C0;) &#xBCA0;&#xD0C0; &#xAC00;&#xC871;&#xC758; &#xAD6C;&#xC131;&#xC6D0; embryogenesis &#xC911; &#xC720;&#xC804;&#xC801;&#xC73C;&#xB85C; &#xD608;&#xAD00;&#xC5D0; &#xC5F0;&#xACB0; &#xB41C; &#xD615;&#xC131; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, &#xBF08; &#xC804;&#xCCB4;&#xC801; &#xB2E8;&#xBC31;&#xC9C8; (BMP) 9, &#xC0DD;&#xB9AC; &#xC801; &#xBC0F; &#xBCD1; &#xC801;&#xC778; &#xC2E0;&#xC0DD;&#xC5D0; &#xAC8C; &#xAE30;&#xACC4; &#xB860; &#xC801;&#xC778; &#xC5F0;&#xAD6C;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC694;&#xC131; &#xBA85;&#xBC31;&#xD55C; &#xAC19;&#xC740; &#xBAA8;&#xC21C; TGF-&#xBCA0;&#xD0C0;&#xC640; &#xBCF4;&#xACE0; &#xB41C; &#xD608;&#xAD00; &#xAE30;&#xB2A5;&#xC744; &#xAC00;&#xC9C4; &#xB2E4;&#xB978; &#xAC00;&#xC871; &#xAD6C;&#xC131;&#xC6D0;&#xC758; &#xC5ED;&#xD560;&#xC5D0; &#xB300; &#xD55C; &#xC5F0;&#xAD6C;. &#xC2DC;&#xC5F0;, &#xC720;&#xC804; &#xC57D;&#xB9AC;&#xD559; &#xC801;&#xC778; &#xC218;&#xB2E8;&#xC5D0; &#xC758;&#xD574;,&#xB294; TGF-&#xBCA0;&#xD0C0; &#xBC0F; BMP9 &#xC218;&#xC6A9; &#xCCB4; activin &#xC218;&#xC6A9; &#xCCB4;&#xC640; &#xAC19;&#xC740; &#xD0A4; (ALK) 1 &#xC885;&#xC591; &#xD608;&#xAD00; &#xC2E0;&#xC0DD;&#xC5D0; &#xB300; &#xD55C; &#xC0C8;&#xB85C;&#xC6B4; &#xCE58;&#xB8CC; &#xB300;&#xC0C1;&#xC744; &#xB098;&#xD0C0;&#xB0C5;&#xB2C8;&#xB2E4;. &#xAC10;&#xC18C;&#xB294; ALK1 &#xC720;&#xC804;&#xC790; &#xBCF5;&#xC6A9;&#xB7C9; &#xB610;&#xB294; ALK1 Fc &#xC735;&#xD569; &#xB2E8;&#xBC31;&#xC9C8; &#xB7A9;-041 &#xCCB4;&#xACC4;&#xC801; &#xCE58;&#xB8CC; &#xB2E4;&#xB2E8;&#xACC4; tumorigenesis&#xC758; &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD615; &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0;&#xC11C; &#xD608;&#xAD00; &#xC2E0;&#xC0DD;&#xC758; &#xC5B5;&#xC81C; &#xD558; &#xC5EC; &#xC885;&#xC591;&#xC758; &#xC131;&#xC7A5; &#xBC0F; &#xC9C4;&#xD589; &#xC9C0;&#xC9C4; &#xC544;. &#xB610;&#xD55C;, &#xB7A9;-041&#xB294; &#xD06C;&#xAC8C; &#xAE30;&#xBCF8; &#xC12C;&#xC720; &#xC544; &#xC138;&#xD3EC; &#xC131;&#xC7A5; &#xC778;&#xC790;&#xC640; &#xD608;&#xAD00; &#xB0B4; &#xD53C; &#xC131;&#xC7A5; &#xC778;&#xC790; A &#xC0DD;&#xCCB4; &#xC678; &#xBC0F; &#xC0DD;&#xCCB4; &#xC870;&#xAC74; angiogenic &#xC751;&#xB2F5; &#xC7A5;&#xC560;&#xAC00;. &#xAD00;&#xCC30; &#xB41C; &#xD6A8;&#xACFC; &#xB300; &#xD55C; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xCD94;&#xAD6C;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC; TGF-&#xBCA0;&#xD0C0;&#xB294; &#xB450; &#xC694;&#xC778;&#xC758; &#xACB0;&#xD569; &#xB41C; &#xB3D9;&#xC791; &#xC99D;&#xAC15; angiogenic &#xC790;&#xADF9;&#xC5D0; &#xB0B4; &#xD53C; &#xC138;&#xD3EC; &#xC751;&#xB2F5; BMP9 &#xC0AC;&#xC774; &#xC608;&#xAE30;&#xCE58; &#xC54A;&#xC740; &#xC2E0;&#xD638; &#xC2DC;&#xB108;&#xC9C0;&#xB97C; &#xBC1C;&#xACAC;. &#xC6B0;&#xB9AC; &#xC885;&#xC591; &#xC2E0;&#xC0DD; TGF-&#xBCA0;&#xD0C0; &#xAC00;&#xC871; &#xAD6C;&#xC131;&#xC6D0;&#xC774; &#xC2DC;&#xADF8;&#xB110;&#xB9C1;&#xC744; &#xC704;&#xD55C; &#xACB0;&#xC815;&#xC801;&#xC778; &#xC5ED;&#xD560;&#xC758; &#xC724;&#xACFD;&#xC744; &#xADF8;&#xB9AC; &#xB2E4; &#xC885;&#xC591;&#xC5D0;&#xC11C; alk1&#xB97C; &#xCC28;&#xB2E8; &#xD558;&#xB294; &#xC57D;&#xBB3C;&#xC758; &#xCC28;&#xAE30; &#xC784;&#xC0C1; &#xAC1C;&#xBC1C;&#xC744; &#xC704;&#xD55C; &#xAE30;&#xACC4; &#xD1B5;&#xCC30;&#xB825;&#xC744; &#xC81C;&#xACF5; &#xD558; &#xACE0;.

&#xC885;&#xC591;&#xC758; &#xC131;&#xC7A5; &#xBC0F; &#xC2E0;&#xC0DD; &#xC190;&#xC0C1; &#xC720;&#xC804;&#xC790; &#xBC0F; &#xC57D;&#xB9AC; activin &#xC218;&#xC6A9; &#xCCB4;&#xC640; &#xAC19;&#xC740; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; 1&#xC758; &#xB300;&#xC0C1;.

Miembros de la familia de beta (TGF-beta) factor de crecimiento transformante han sido gen&eacute;ticamente vinculada a vascular formaci&oacute;n durante la embriog&eacute;nesis. Sin embargo, contradictorios estudios sobre el papel del TGF-beta y otros miembros de familia con funciones vasculares divulgadas, como la prote&iacute;na morfogen&eacute;tica &oacute;sea (BMP) 9, en la angiog&eacute;nesis fisiol&oacute;gica y patol&oacute;gica hacen la necesidad de estudios mecan&iacute;sticos aparente. Demostramos, por medios gen&eacute;ticos y farmacol&oacute;gicos, que la TGF-beta y BMP9 activina receptor-como cinasa del receptor (ALK) 1 representa una nueva diana terap&eacute;utica para la angiog&eacute;nesis tumoral. Disminuci&oacute;n de la dosis de gene ALK1 o tratamiento sist&eacute;mico con la prote&iacute;na de fusi&oacute;n ALK1-Fc RAP-041 hab&iacute;a retardado crecimiento tumoral y la progresi&oacute;n por la inhibici&oacute;n de la angiog&eacute;nesis en un modelo de rat&oacute;n transg&eacute;nico de tumorig&eacute;nesis varias fases. Adem&aacute;s, RAP-041 hab&iacute;a deteriorado significativamente la respuesta angiog&eacute;nica in vitro e in vivo hacia el factor de crecimiento endotelial vascular A y factor de crecimiento b&aacute;sico del fibroblasto. Al buscar el mecanismo de los efectos observados, descubrimos una inesperado se&ntilde;alizaci&oacute;n sinergia entre TGF-beta y BMP9, a trav&eacute;s del cual la acci&oacute;n combinada de los dos factores hab&iacute;a aumentada la respuesta de la c&eacute;lula endotelial a est&iacute;mulos angiog&eacute;nicos. Estamos delinear un papel decisivo para la se&ntilde;alizaci&oacute;n por miembros de la familia TGF-beta en la angiog&eacute;nesis tumoral y ofrecer la visi&oacute;n mecanicista para el pr&oacute;ximo desarrollo cl&iacute;nico de f&aacute;rmacos bloqueo ALK1 en oncolog&iacute;a.

Gen&eacute;ticos y farmacol&oacute;gicos dirigidos contra como receptor de activina quinasa 1 perjudica el crecimiento tumoral y la angiog&eacute;nesis.

Genetic and molecular studies suggest that activin receptor-like kinase 1 (ALK1), a transforming growth factor β (TGF-β) type I receptor, and endoglin, a TGF-β co-receptor, play an essential role in vascular development and pathological angiogenesis. Several agents that interfere with ALK1 and endoglin function are currently in clinical trials for antiangiogenic activity in cancer therapy. One of these agents, PF-03446962 (anti-hALK1 antibody), shows promising results in the clinic. However, its effects on endothelial cell function and mechanism of action are unclear. Here we demonstrate that anti-hALK1 antibody selectively recognizes human ALK1. The anti-hALK1 antibody interfered with bone morphogenetic protein 9 (BMP9)-induced signaling in endothelial cells. Consistent with this notion, anti-hALK1 antibody was found to compete highly efficiently with the binding of the ALK1 ligand BMP9 and TGF-β to ALK1. Moreover, it prevented BMP9-dependent recruitment of co-receptor endoglin into this angiogenesis-mediating signaling complex. In addition, we demonstrated that anti-hALK1 antibody inhibited endothelial cell sprouting but did not directly interfere with vascular endothelial growth factor (VEGF) signaling, VEGF-induced proliferation, and migration of endothelial cells. Finally, we demonstrated that BMP9 in serum is essential for endothelial sprouting and that anti-hALK1 antibody inhibits this potently. Our data suggest that both the VEGF/VEGF receptor and the BMP9/ALK1 pathways are essential for stimulating angiogenesis, and targeting both pathways simultaneously may be an attractive strategy to overcome resistance to antiangiogenesis therapy.

Anti-human activin receptor-like kinase 1 (ALK1) antibody attenuates bone morphogenetic protein 9 (BMP9)-induced ALK1 signaling and interferes with endothelial cell sprouting.

ENDOGLIN (ENG) is a co-receptor for transforming growth factor-β (TGF-β) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA-mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis.

ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis.

Endoglin (ENG) is a coreceptor of the transforming growth factor-β (TGFβ) family signaling complex, which is highly expressed on endothelial cells and plays a key role in angiogenesis. Its extracellular domain can be cleaved and released into the circulation as soluble ENG (sENG). High circulating levels of sENG contribute to the pathogenesis of preeclampsia (PE). Circulating bone morphogenetic protein 9 (BMP9), a vascular quiescence and endothelial-protective factor, binds sENG with high affinity, but how sENG participates in BMP9 signaling complexes is not fully resolved. sENG was thought to be a ligand trap for BMP9, preventing type II receptor binding and BMP9 signaling. Here we show that, despite cell-surface ENG being a dimer linked by disulfide bonds, sENG purified from human placenta and plasma from PE patients is primarily in a monomeric form. Incubating monomeric sENG with the circulating form of BMP9 (prodomain-bound form) in solution leads to the release of the prodomain and formation of a sENG:BMP9 complex. Furthermore, we demonstrate that binding of sENG to BMP9 does not inhibit BMP9 signaling. Indeed, the sENG:BMP9 complex signals with comparable potency and specificity to BMP9 on human primary endothelial cells. The full signaling activity of the sENG:BMP9 complex required transmembrane ENG. This study confirms that rather than being an inhibitory ligand trap, increased circulating sENG might preferentially direct BMP9 signaling via cell-surface ENG at the endothelium. This is important for understanding the role of sENG in the pathobiology of PE and other cardiovascular diseases.

Role of soluble endoglin in BMP9 signaling.

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1 arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3b and Pik3ca to generate high-grade diffuse gliomas. Mechanistically, Acvr1 upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

Midory Thorikay

Oncode Institute and Department of Cell Chemical Biology

Leiden University Medical Center

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Midory Thorikay

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Oncode Institute and Department of Cell Chemical Biology

Leiden University Medical Center

Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells

Oncode Institute and Department of Cell Chemical Biology