creating-anatomically-accurate-reproducible-intracranial-xenografts

Creating Anatomically Accurate and Reproducible Intracranial Xenografts of Human Brain Tumors

Orthotopic tumor models are currently the best way to study the characteristics of a tumor type, with and without intervention, in the context of a live ...

University of Colorado School of Medicine

La kinase Mer r&#xE9;cepteur de la tyrosine, clon&#xE9; &#xE0; partir d&#x26;#39;une biblioth&#xE8;que B-lymphoblasto&#xEF;des, est l&#x26;#39;orthologue mammif&#xE8;re de l&#x26;#39;oncog&#xE8;ne v-r&#xE9;troviral de poulet Eyk et envoie des signaux anti-apoptotiques et la transformation lorsqu&#x26;#39;il est activ&#xE9;. Pour d&#xE9;terminer si l&#x26;#39;expression ectopique Mer est en T-cellules de leuc&#xE9;mie lymphoblastique aigu&#xEB; (LLA) et potentiellement important dans la leuc&#xE9;mogen&#xE8;se, nous avons analys&#xE9; l&#x26;#39;expression Mer en thymocytes humains normaux et de lymphocytes et p&#xE9;diatriques Tous les &#xE9;chantillons des patients.

L&#x26;#39;expression ectopique de la Mer proto-oncog&#xE8;ne en p&#xE9;diatrie cellules T leuc&#xE9;mie aigu&#xEB; lymphoblastique

Mer-Tyrosinkinase, geklont aus einer B-Lymphoblastoidzellen-Bibliothek ist die S&auml;ugetier-Orthologue das Huhn retrovirale Onkogen V-Eyk und sendet Antiapoptotic und Umwandlung von Signalen, wenn aktiviert. Um festzustellen, ob Mer Ausdruck ektopische in T-Zelle akute lymphoblastische Leuk&auml;mie (ALL) und potenziell ist analysiert in Leukemogenesis wichtig, wir Mer Ausdruck in normalen menschlichen Thymozyten und Lymphozyten und in p&auml;diatrischen alle Patientenproben.

Ektopische Expression der Proto-oncogene Mer in p&auml;diatrische T-Zell-akute lymphoblastische Leuk&auml;mie.

La Mer recettore tirosina chinasi, clonata da una raccolta di B-linfoblastoidi, &egrave; il mammifero orthologue del pollo del oncogene retrovirale v-eyk e invia antiapoptotici e trasformando segnali quando attivato. Per determinare se Mer espressione ectopica in una T-cellula leucemia linfoblastica acuta (ALL) e potenzialmente importante nella leucemogenesi, abbiamo analizzato Mer espressione in linfociti e timociti umani normali e in pediatrica tutti i campioni dei pazienti.

Espressione ectopica della Mer proto-oncogene di leucemia linfoblastica acuta a cellule T pediatrica.

&#x4ECE; B &#x6C38;&#x751F;&#x5E93;&#xFF0C;&#x514B;&#x9686;&#x7684; Mer &#x53D7;&#x4F53;&#x916A;&#x6C28;&#x9178;&#x6FC0;&#x9176;&#x662F;&#x54FA;&#x4E73;&#x52A8;&#x7269;&#x7684;&#x9E21;&#x9006;&#x8F6C;&#x5F55;&#x75C5;&#x6BD2;&#x764C;&#x57FA;&#x56E0; v-eyk orthologue &#x5E76;&#x53D1;&#x9001;&#x6297;&#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x548C;&#x6539;&#x53D8;&#x65F6;&#x6FC0;&#x6D3B;&#x7684;&#x4FE1;&#x53F7;&#x3002;&#x8981;&#x786E;&#x5B9A;&#x662F;&#x5426; Mer &#x8868;&#x8FBE;&#x5F0F;&#x662F;&#x5F02;&#x4F4D; T &#x7EC6;&#x80DE;&#x6025;&#x6027;&#x6DCB;&#x5DF4;&#x7EC6;&#x80DE;&#x6027;&#x767D;&#x8840;&#x75C5; (&#x5168;&#x90E8;) &#x548C;&#x6F5C;&#x5728;&#x91CD;&#x8981;&#x7684;&#x767D;&#x8840;&#x75C5;&#x7EC6;&#x80DE;&#xFF0C;&#x6211;&#x4EEC;&#x5206;&#x6790;&#x4E86; Mer &#x8868;&#x8FBE;&#x5728;&#x6B63;&#x5E38;&#x4EBA;&#x4F53;&#x80F8;&#x817A;&#x7EC6;&#x80DE;&#x548C;&#x6DCB;&#x5DF4;&#x7EC6;&#x80DE;&#x548C;&#x513F;&#x79D1;&#x6240;&#x6709;&#x60A3;&#x8005;&#x6837;&#x672C;&#x3002;

&#x539F;&#x764C;&#x57FA;&#x56E0; Mer &#x5C0F;&#x513F; T &#x7EC6;&#x80DE;&#x6025;&#x6027;&#x6DCB;&#x5DF4;&#x7EC6;&#x80DE;&#x767D;&#x8840;&#x75C5;&#x7684;&#x5F02;&#x4F4D;&#x8868;&#x8FBE;&#x3002;

The Mer receptor tyrosine kinase, cloned from a B-lymphoblastoid library, is the mammalian orthologue of the chicken retroviral oncogene v-eyk and sends antiapoptotic and transforming signals when activated. To determine if Mer expression is ectopic in T-cell acute lymphoblastic leukemia (ALL) and potentially important in leukemogenesis, we analyzed Mer expression in normal human thymocytes and lymphocytes and in pediatric ALL patient samples.

Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia.

B-&#x30EA;&#x30F3;&#x30D1;&#x82BD;&#x7403;&#x30E9;&#x30A4;&#x30D6;&#x30E9;&#x30EA;&#x30FC;&#x304B;&#x3089;&#x30AF;&#x30ED;&#x30FC;&#x30CB;&#x30F3;&#x30B0;&#x3055;&#x308C;&#x305F;Mer&#x306E;&#x53D7;&#x5BB9;&#x4F53;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x306F;&#x3001;&#x30CB;&#x30EF;&#x30C8;&#x30EA;&#x30EC;&#x30C8;&#x30ED;&#x30A6;&#x30A4;&#x30EB;&#x30B9;&#x764C;&#x907A;&#x4F1D;&#x5B50;V-eyk&#x306E;&#x54FA;&#x4E73;&#x985E;&#x30AA;&#x30EB;&#x30BD;&#x30ED;&#x30B0;&#x3067;&#x3042;&#x308A;&#x3001;&#x6D3B;&#x6027;&#x5316;&#x3055;&#x308C;&#x308B;&#x3068;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x3068;&#x5909;&#x63DB;&#x4FE1;&#x53F7;&#x3092;&#x9001;&#x4FE1;&#x3057;&#x307E;&#x3059;&#x3002; Mer&#x306E;&#x767A;&#x73FE;&#x306F;&#x3001;&#x767D;&#x8840;&#x75C5;&#x3067;T&#x7D30;&#x80DE;&#x6025;&#x6027;&#x30EA;&#x30F3;&#x30D1;&#x82BD;&#x7403;&#x6027;&#x767D;&#x8840;&#x75C5;&#xFF08;ALL&#xFF09;&#x306B;&#x304A;&#x3051;&#x308B;&#x7570;&#x6240;&#x6027;&#x3068;&#x6F5C;&#x5728;&#x7684;&#x306B;&#x91CD;&#x8981;&#x3067;&#x3042;&#x308B;&#x304B;&#x3069;&#x3046;&#x304B;&#x3092;&#x5224;&#x65AD;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x3001;&#x6211;&#x3005;&#x306F;&#x6B63;&#x5E38;&#x30D2;&#x30C8;&#x80F8;&#x817A;&#x7D30;&#x80DE;&#x3084;&#x30EA;&#x30F3;&#x30D1;&#x7403;&#x3067;&#x306F;&#x3001;&#x5C0F;&#x5150;ALL&#x60A3;&#x8005;&#x30B5;&#x30F3;&#x30D7;&#x30EB;&#x4E2D;&#x306E;Mer&#x306E;&#x767A;&#x73FE;&#x3092;&#x89E3;&#x6790;&#x3057;&#x305F;&#x3002;

&#x5C0F;&#x5150;T&#x7D30;&#x80DE;&#x6025;&#x6027;&#x30EA;&#x30F3;&#x30D1;&#x6027;&#x767D;&#x8840;&#x75C5;&#x306B;&#x304A;&#x3051;&#x308B;&#x30D7;&#x30ED;&#x30C8;&#x30AA;&#x30F3;&#x30B3;&#x30B8;&#x30FC;&#x30F3;Mer&#x306E;&#x7570;&#x6240;&#x6027;&#x767A;&#x73FE;

B lymphoblastoid &#xB77C;&#xC774;&#xBE0C;&#xB7EC;&#xB9AC;&#xC5D0;&#xC11C; &#xBCF5;&#xC81C; &#xB41C; &#xBA54; &#xB974; &#xC218;&#xC6A9; &#xCCB4; &#xD2F0;&#xB85C;&#xC2E0; &#xD0A4; &#xCE58;&#xD0A8; retroviral oncogene v eyk&#xC758; &#xD3EC;&#xC720;&#xB958; orthologue &#xC774;&#xBA70; antiapoptotic &#xBC0F; &#xBCC0;&#xD615; &#xC2E0;&#xD638; &#xD65C;&#xC131;&#xD654; &#xB420; &#xB54C; &#xBCF4;&#xB0C5;&#xB2C8;&#xB2E4;. T &#xC138;&#xD3EC; &#xAE09;&#xC131; &#xB9BC;&#xD504; &#xAD6C;&#xC131; &#xBC31;&#xD608;&#xBCD1; (ALL)&#xC640; &#xC7A0;&#xC7AC;&#xC801;&#xC73C;&#xB85C; &#xBA54; &#xB974; &#xC2DD; &#xC18C;&#xC131; &#xC778;&#xC9C0; &#xD655;&#xC778; &#xD558;&#xB824;&#xBA74; leukemogenesis&#xC5D0;&#xC11C; &#xC911;&#xC694; &#xD55C; &#xC6B0;&#xB9AC; &#xBD84;&#xC11D; &#xBA54; &#xB974; &#xC2DD; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC778;&#xAC04;&#xC758; thymocytes&#xACFC; &#xC138;&#xD3EC;&#xC640; &#xC18C;&#xC544;&#xC5D0;&#xC11C; &#xBAA8;&#xB4E0; &#xD658;&#xC790; &#xC0D8;&#xD50C;.

Proto-oncogene &#xBA54; &#xB974; &#xC18C;&#xC544;&#xACFC; T &#xC138;&#xD3EC; &#xAE09;&#xC131; &#xB9BC;&#xD504; &#xAD6C;&#xC131; &#xBC31;&#xD608;&#xBCD1;&#xC5D0;&#xC11C;&#xC758; &#xC18C;&#xC131; &#xC2DD;.

El receptor de la tirosina quinasa Mer, clonado a partir de una biblioteca B-linfoblastoide, es el ort&#xF3;logo mam&#xED;fero del oncog&#xE9;n retroviral pollo v-EYK y env&#xED;a se&#xF1;ales antiapopt&#xF3;ticas y transformaci&#xF3;n cuando se activa. Para determinar si la expresi&#xF3;n de Mer es ect&#xF3;pico en las c&#xE9;lulas T leucemia linfobl&#xE1;stica aguda (LLA) y potencialmente importante de la leucemia, analizamos la expresi&#xF3;n-Mer en condiciones normales de timocitos y linfocitos humanos y en TODAS las muestras de pacientes pedi&#xE1;tricos.

La expresi&#xF3;n ect&#xF3;pica de la Mer en el proto-oncogen Pedi&#xE1;trica de c&#xE9;lulas T leucemia linfobl&#xE1;stica aguda

Tyro-3, Axl, and Mer constitute the TAM family of receptor tyrosine kinases (RTKs) characterized by a conserved sequence within the kinase domain and adhesion molecule-like extracellular domains. This small family of RTKs regulates an intriguing mix of processes, including cell proliferation/survival, cell adhesion and migration, blood clot stabilization, and regulation of inflammatory cytokine release. Genetic or experimental alteration of TAM receptor function can contribute to a number of disease states, including coagulopathy, autoimmune disease, retinitis pigmentosa, and cancer. In this chapter, we first provide a comprehensive review of the structure, regulation, biologic functions, and downstream signaling pathways of these receptors. In addition, we discuss recent evidence which suggests a role for TAM receptors in oncogenic mechanisms as family members are overexpressed in a spectrum of human cancers and have prognostic significance in some. Possible strategies for targeted inhibition of the TAM family in the treatment of human cancer are described. Further research will be necessary to evaluate the full clinical implications of TAM family expression and activation in cancer.

TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer.

The MerTK plays several important roles in normal macrophage physiology, including regulation of cytokine secretion and clearance of apoptotic cells. Mer signaling in other cell types, including malignant cells that ectopically overexpress the RTK, leads to downstream prosurvival pathway activation. We explored the hypothesis that Mer has a prosurvival role in macrophages exposed to oxidative stress. H(2)O(2) treatment of peritoneal exudate murine macrophages and J774 cells rapidly stimulated Mer phosphorylation in a concentration-dependent manner. Mer phosphorylation was dependent on the ligand Gas6, as treatment with warfarin or MerFc (a fusion protein of the extracellular domain of Mer and the Fc portion of human Ig), inhibitors of Gas6 activity, blocked H(2)O(2)-mediated activation of Mer. Antiapoptotic signals including pAkt and pErk 1/2 were increased dramatically (threefold and 4.5-fold, respectively) in WT Mer-positive macrophages compared with Mer KO macrophages stimulated with H(2)O(2). In a consistent manner, Mer expression led to decreased cleavage of proapoptotic indicators PARP and Caspase-3. Furthermore, Mer provided up to twofold enhanced cellular survival to primary macrophages exposed to H(2)O(2). These data represent the first report of Mer activation in response to oxidative stress and demonstrate the ability of Mer RTK to promote macrophage survival in disease states that involve an oxidative stress environment.

Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress.

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 80%. However, additional changes using available drugs are unlikely to provide significant improvement in survival. New therapies are warranted given the risk of severe therapy-associated toxicities including infertility, organ damage, and secondary malignancy. Here, we report ectopic expression of the receptor tyrosine kinase Mer in pediatric B-cell ALL. Inhibition of Mer prevented Erk 1/2 activation, increased the sensitivity of B-ALL cells to cytotoxic agents in vitro by promoting apoptosis, and delayed disease onset in a mouse model of leukemia. In addition, we discovered cross-talk between the Mer and mammalian target of rapamycin (mTOR) signaling pathways. Our results identify Mer as a novel therapeutic target in ALL and suggest that inhibitors of Mer will interact synergistically with currently used therapies. This strategy may allow for dose reduction resulting in decreased toxicity and increased survival rates. Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.

Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia.

Thymoma is an uncommon and slow-growing neoplasm. It is derived from thymic epithelial cells and comprises about 20% to 30% of mediastinal masses in adults, but only about 1% in pediatric patients. Patients usually present with mass-associated respiratory symptoms, superior vena cava syndrome, or paraneoplastic syndrome including myasthenia gravis, pure red cell aplasia, or acquired hypogammaglobulinemia, and connective tissue disorders. Due to the limited number of cases, knowledge, and experience with thymoma in pediatric patients, the diagnosis and treatment are very challenging for this age group. In this article, we report 2 cases of thymoma in childhood and provide a comprehensive review and analysis of the reported pediatric cases in the past 30 years (total of 32 cases). We found that patients younger than age 10 years were predominantly male (M:F = 6:1) and had advanced tumor stage more frequent than patients older than age 10 (P = .03). There were also significant associations of male sex with more advanced tumor stage and less favorable outcome (P = .03). These findings suggest that age and sex may be additional potential prognostic contributors in pediatric patients with thymoma. The clinicopathologic features, differential diagnosis, and current therapeutic recommendations of this uncommon tumor in pediatric patients are also addressed.

Thymoma in children: report of 2 cases and review of the literature.

&#x661F;&#x5F62;&#x7EC6;&#x80DE;&#x7624;&#xFF0C;&#x5360;&#x5927;&#x591A;&#x6570;&#x7684;&#x6210;&#x4EBA;&#x548C;&#x513F;&#x7AE5;&#x60A3;&#x8005;&#x5728;&#x8BCA;&#x65AD;&#x4E3A;&#x6076;&#x6027;&#x8111;&#x80BF;&#x7624;&#x3002;&#x53EF;&#x7528;&#x6765;&#x5BF9;&#x5F85;&#x8FD9;&#x4E9B;&#x80BF;&#x7624;&#x7684;&#x6CBB;&#x7597;&#x65B9;&#x6CD5;&#x662F;&#x6709;&#x9650;&#x7684;&#x548C;&#x5173;&#x8054;&#x9AD8;&#x6863;&#x75C5;&#x53D8;&#x7684;&#x9884;&#x540E;&#x662F;&#x6781;&#x5DEE;&#x3002;Mer (MerTK) &#x548C; Axl &#x53D7;&#x4F53;&#x916A;&#x6C28;&#x9178;&#x6FC0;&#x9176; &#xFF08;RTK&#xFF09;&#xFF0C;&#x8868;&#x793A;&#x5728;&#x5404;&#x79CD;&#x6076;&#x6027;&#x80BF;&#x7624;&#xFF0C;&#x5F02;&#x5E38;&#x9AD8;&#x4E00;&#x7EA7;&#xFF0C;&#x4F17;&#x6240;&#x5468;&#x77E5;&#xFF0C;&#x8FD9;&#x4E9B;&#x53D7;&#x4F53;&#x6FC0;&#x6D3B;&#x5F3A;&#x70C8;&#x6297;&#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x4FE1;&#x53F7;&#x901A;&#x8DEF;&#xFF0C;&#x4EE5;&#x4FC3;&#x8FDB;&#x53D1;&#x751F;&#x3002;&#x5728;&#x6B64;&#x7814;&#x7A76;&#x4E2D;&#xFF0C;&#x6211;&#x4EEC;&#x53D1;&#x73B0;&#xFF0C;Mer &#x548C; Axl &#x8A8A;&#x672C;&#x53CA;&#x86CB;&#x767D;&#x8868;&#x8FBE;&#x88AB;&#x63D0;&#x5347;&#x5728;&#x661F;&#x5F62;&#x80F6;&#x8D28;&#x7EC6;&#x80DE;&#x7684;&#x60A3;&#x8005;&#x6837;&#x672C;&#x548C;&#x5355;&#x5143;&#x683C;&#x7684;&#x884C;&#x3002;Mer &#x548C; Axl RTK &#x8868;&#x8FBE;&#x4ECB;&#x5BFC; shRNA &#x7EC4;&#x5408;&#x5F0F;&#x5BFC;&#x81F4;&#x661F;&#x5F62;&#x7EC6;&#x80DE;&#x7624;&#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x589E;&#x52A0;&#x3002;&#x51CB;&#x4EA1;&#x4FE1;&#x53F7;&#x4F20;&#x5BFC;&#x901A;&#x8DEF;&#x5305;&#x62EC; Akt &#x548C;&#x7EC6;&#x80DE;&#x5916;&#x4FE1;&#x53F7;&#x8C03;&#x8282;&#x6FC0;&#x9176; 1/2&#xFF0C;&#x5DF2;&#x8868;&#x660E;&#x8981;&#x6FC0;&#x6D3B;&#x6297;&#x8111;&#x661F;&#x5F62;&#x7EC6;&#x80DE;&#x7624;&#x4E2D;&#xFF0C;&#x5DF2;&#x7F16;&#x7801;&#x4E0E; Mer &#x548C; Axl &#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#xFF0C;&#x800C; poly(ADP-ribose) &#x805A;&#x5408;&#x9176;&#x88C2;&#x89E3;&#x589E;&#x52A0;&#x3002;&#x6B64;&#x5916;&#xFF0C;Mer &#x548C; Axl shRNA &#x7EC4;&#x5408;&#x5F0F;&#x5BFC;&#x81F4;&#x6DF1;&#x523B;&#x8DCC;&#x5E45;&#x7684;&#x661F;&#x5F62;&#x7EC6;&#x80DE;&#x7624;&#x7EC6;&#x80DE;&#x589E;&#x6B96;&#x8F6F;&#x743C;&#x8102;&#x548C;&#x836F;&#x654F;&#x8BD5;&#x9A8C;&#x4E2D;&#x5BF9;&#x66FF;&#x83AB;&#x5511;&#x80FA;&#x3001; &#x5361;&#x94C2;&#x3001; &#x957F;&#x6625;&#x65B0;&#x78B1;&#x6CBB;&#x7597;&#x7684;&#x53CD;&#x5E94;&#x663E;&#x8457;&#x589E;&#x52A0;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x7ED3;&#x679C;&#x8868;&#x660E; Mer &#x548C; Axl RTK &#x6291;&#x5236;&#x4F5C;&#x4E3A;&#x4E00;&#x79CD;&#x65B0;&#x9896;&#x7684;&#x65B9;&#x6CD5;&#x6539;&#x5584;&#x51CB;&#x4EA1;&#x53CD;&#x5E94;&#x548C;&#x661F;&#x5F62;&#x7EC6;&#x80DE;&#x7624;&#x836F;&#x654F;&#x8BD5;&#x9A8C;&#xFF0C;&#x5E76;&#x4E3A;&#x8FD9;&#x4E9B;&#x764C;&#x57FA;&#x56E0;&#x4E3A;&#x661F;&#x5F62;&#x7EC6;&#x80DE;&#x7624;&#x836F;&#x7269;&#x5F00;&#x53D1;&#x7684;&#x5438;&#x5F15;&#x529B;&#x751F;&#x7269;&#x76EE;&#x6807;&#x63D0;&#x4F9B;&#x652F;&#x6301;&#x3002;

Mer &#x548C; Axl &#x53D7;&#x4F53;&#x916A;&#x6C28;&#x9178;&#x6FC0;&#x9176;&#x5728;&#x661F;&#x5F62;&#x80F6;&#x8D28;&#x7624;&#x7EC6;&#x80DE;&#x7684;&#x6291;&#x5236;&#x4F5C;&#x7528;&#x5BFC;&#x81F4;&#x7EC6;&#x80DE;&#x51CB;&#x4EA1;&#x589E;&#x52A0;&#x548C;&#x6539;&#x8FDB;&#x836F;&#x7269;&#x654F;&#x611F;&#x6027;&#x3002;

Astrocytomas account for the majority of malignant brain tumors diagnosed in both adult and pediatric patients. The therapies available to treat these neoplasms are limited, and the prognosis associated with high-grade lesions is extremely poor. Mer (MerTK) and Axl receptor tyrosine kinases (RTK) are expressed at abnormally high levels in a variety of malignancies, and these receptors are known to activate strong antiapoptotic signaling pathways that promote oncogenesis. In this study, we found that Mer and Axl mRNA transcript and protein expression were elevated in astrocytic patient samples and cell lines. shRNA-mediated knockdown of Mer and Axl RTK expression led to an increase in apoptosis in astrocytoma cells. Apoptotic signaling pathways including Akt and extracellular signal-regulated kinase 1/2, which have been shown to be activated in resistant astrocytomas, were downregulated with Mer and Axl inhibition whereas poly(ADP-ribose) polymerase cleavage was increased. Furthermore, Mer and Axl shRNA knockdown led to a profound decrease of astrocytoma cell proliferation in soft agar and a significant increase in chemosensitivity in response to temozolomide, carboplatin, and vincristine treatment. Our results suggest Mer and Axl RTK inhibition as a novel method to improve apoptotic response and chemosensitivity in astrocytoma and provide support for these oncogenes as attractive biological targets for astrocytoma drug development.

Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity.

Compte astrocytomes pour la majorit&#xE9; des tumeurs c&#xE9;r&#xE9;brales malignes diagnostiqu&#xE9;es chez les patients adultes et p&#xE9;diatriques. Les th&#xE9;rapies disponibles pour traiter ces tumeurs sont limit&#xE9;es, et le pronostic associ&#xE9; &#xE0; l&#xE9;sions de haut grade est extr&#xEA;mement pauvre. Mer (MerTK) et des kinases Axl r&#xE9;cepteurs tyrosine (RTK) sont exprim&#xE9;s &#xE0; des niveaux anormalement &#xE9;lev&#xE9;s dans une vari&#xE9;t&#xE9; de tumeurs malignes, et ces r&#xE9;cepteurs sont connus pour activer forts anti-apoptotiques des voies de signalisation qui favorisent l&#x26;#39;oncogen&#xE8;se. Dans cette &#xE9;tude, nous avons constat&#xE9; que Mer et de la transcription d&#x26;#39;ARNm Axl et expression de la prot&#xE9;ine ont &#xE9;t&#xE9; &#xE9;lev&#xE9;s dans des &#xE9;chantillons de patients astrocytaires et des lign&#xE9;es cellulaires. shRNA m&#xE9;diation knockdown de la Mer et Axl RTK expression a conduit &#xE0; une augmentation de l&#x26;#39;apoptose dans les cellules d&#x26;#39;astrocytome. Voies de signalisation apoptotiques dont l&#x26;#39;Akt et extracellular signal-regulated kinase 1/2, qui ont &#xE9;t&#xE9; montr&#xE9;s &#xEA;tre activ&#xE9;s dans r&#xE9;sistante astrocytomes, &#xE9;taient r&#xE9;gul&#xE9;s &#xE0; la baisse avec une inhibition Mer et Axl alors clivage poly polym&#xE9;rase (ADP-ribose) a &#xE9;t&#xE9; augment&#xE9;. En outre, Mer et Axl shRNA knockdown conduit &#xE0; une diminution profonde de la prolif&#xE9;ration cellulaire d&#x26;#39;astrocytome dans la g&#xE9;lose molle et une augmentation significative de la chimiosensibilit&#xE9; en r&#xE9;ponse au t&#xE9;mozolomide, le carboplatine et le traitement de vincristine. Nos r&#xE9;sultats sugg&#xE8;rent Mer et Axl RTK inhibition comme une nouvelle m&#xE9;thode pour am&#xE9;liorer la r&#xE9;ponse apoptotique et la chimiosensibilit&#xE9; dans astrocytome et fournir un soutien pour ces oncog&#xE8;nes comme des cibles int&#xE9;ressantes pour le d&#xE9;veloppement de m&#xE9;dicaments biologiques pour l&#x26;#39;astrocytome.

L&#x26;#39;inhibition de la Mer et kinases de r&#xE9;cepteurs tyrosine Axl dans cellules d&#x26;#39;astrocytome m&#xE8;ne &#xE0; une apoptose accrue et am&#xE9;lior&#xE9;e Chimiosensibilit&#xE9;

Astrozytome machen die meisten b&ouml;sartigen Hirntumoren, die sowohl f&uuml;r Erwachsene als auch f&uuml;r P&auml;diatrische Patienten diagnostiziert. Die Therapien zur Verf&uuml;gung, diese Tumoren zu behandeln sind begrenzt, und die Prognose verbunden mit hochwertigem L&auml;sionen ist extrem schlecht. Mer (MerTK) und Axl-Rezeptor-Tyrosin-Kinasen (RTK) werden auf au&szlig;ergew&ouml;hnlich hohem Niveau in einer Vielzahl von Krebserkrankungen ausgedr&uuml;ckt, und diese Rezeptoren sind daf&uuml;r bekannt, starke Antiapoptotic Bahnen, die F&ouml;rderung der Onkogenese Signalisierung zu aktivieren. In dieser Studie, die wir fanden, dass Mer und Axl mRNA-Transkript und Protein-Ausdruck in astrozytische Patientenproben und Zelllinien erh&ouml;ht wurden. ShRNA-vermittelte Niederschlag Mer und Axl RTK Ausdrucksformen f&uuml;hrte zu einem Anstieg der Apoptose in Zellen Astrozytom. Apoptotischen Signalwege Akt und extrazellul&auml;re Signal-regulierte Kinase 1/2, die nachweislich in best&auml;ndig Astrozytome aktiviert werden, einschlie&szlig;lich waren Downregulated mit Mer und Axl Hemmung poly(ADP-ribose) Polymerase Dekollet&eacute; angehoben wurde. Dar&uuml;ber hinaus f&uuml;hrte Mer und Axl ShRNA-Niederschlag zu einem profunden R&uuml;ckgang von Astrozytom Zellproliferation weiche N&auml;hrboden und eine deutliche Zunahme der Chemosensitivity in Reaktion auf die Behandlung von Temozolomid, Carboplatin und Vincristin. Unsere Ergebnisse legen nahe, Mer und Axl RTK Hemmung als eine neuartige Methode zur Verbesserung der Apoptotic Antwort und Chemosensitivity in Astrozytom und bieten Unterst&uuml;tzung f&uuml;r diese Onkogene als attraktive biologische Ziele f&uuml;r Astrozytom Medikamentenentwicklung.

Hemmung der Mer und Axl Rezeptor-Tyrosin-Kinasen in Astrozytom Zellen f&uuml;hrt zu erh&ouml;hten Apoptose und verbesserte Chemosensitivity.

Astrocitomi rappresentano la maggior parte dei tumori cerebrali maligni diagnosticati in pazienti adulti e pediatrici. Le terapie disponibili per il trattamento di queste neoplasie sono limitate e la prognosi associata a lesioni di alto grado &egrave; estremamente povera. Mer (MerTK) e le Axl recettore tirosina chinasi (RTK) sono espressi a livelli anormalmente elevati in una variet&agrave; di tumori maligni, e questi recettori sono conosciuti per attivare forti antiapoptotici signaling pathways che promuovono l&#39;oncogenesi. In questo studio, abbiamo trovato che Mer e Axl espressione della proteina e la trascrizione del mRNA furono elevati in astrocitari sieri e linee cellulari. mediata da shRNA atterramento di Mer e Axl RTK espressione ha portato ad un aumento di apoptosi nelle cellule di astrocitoma. Percorsi di segnalazione apoptotic Akt e chinasi segnale-regolata extracellulare 1/2, che hanno dimostrato di essere attivato in astrocitomi resistenti, erano downregolata con inibizione Mer e Axl mentre clivaggio della polimerasi poly(ADP-ribose) &egrave; stato aumentato. Inoltre, atterramento di shRNA Mer e Axl ha condotto ad una profonda diminuzione della proliferazione delle cellule di astrocitoma in agar molle e un aumento significativo di chemosensitivity in risposta al trattamento con temozolomide, carboplatino e vincristina. I nostri risultati suggeriscono Mer e Axl RTK inibizione come un nuovo metodo per migliorare la risposta apoptotica e chemosensitivity in astrocitoma e forniscono il supporto per questi oncogeni come bersagli biologici attraente per lo sviluppo di farmaci di astrocitoma.

Inibizione delle Mer e Axl recettore tirosina chinasi in cellule di astrocitoma porta ad aumentata apoptosi e chemosensitivity migliorata.

&#x6210;&#x4EBA;&#x304A;&#x3088;&#x3073;&#x5C0F;&#x5150;&#x60A3;&#x8005;&#x306E;&#x4E21;&#x65B9;&#x3067;&#x8A3A;&#x65AD;&#x60AA;&#x6027;&#x8133;&#x816B;&#x760D;&#x306E;&#x5927;&#x534A;&#x3092;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x3092;&#x5360;&#x3081;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x816B;&#x760D;&#x3092;&#x6CBB;&#x7642;&#x3059;&#x308B;&#x305F;&#x3081;&#x306B;&#x5229;&#x7528;&#x53EF;&#x80FD;&#x306A;&#x6CBB;&#x7642;&#x6CD5;&#x306F;&#x9650;&#x3089;&#x308C;&#x3066;&#x304A;&#x308A;&#x3001;&#x9AD8;&#x54C1;&#x4F4D;&#x306A;&#x75C5;&#x5909;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x308B;&#x4E88;&#x5F8C;&#x306F;&#x6975;&#x3081;&#x3066;&#x4E0D;&#x826F;&#x3067;&#x3042;&#x308B;&#x3002;&#x30E1;&#x30FC;&#x30EB;&#xFF08;MerTK&#xFF09;&#x3068;&#x30A2;&#x30AF;&#x30BB;&#x30EB;&#x53D7;&#x5BB9;&#x4F53;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#xFF08;RTK&#xFF09;&#x306F;&#x60AA;&#x6027;&#x816B;&#x760D;&#x306E;&#x69D8;&#x3005;&#x306A;&#x7570;&#x5E38;&#x306B;&#x9AD8;&#x3044;&#x30EC;&#x30D9;&#x30EB;&#x3067;&#x767A;&#x73FE;&#x3055;&#x308C;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x53D7;&#x5BB9;&#x4F53;&#x306F;&#x767A;&#x764C;&#x3092;&#x4FC3;&#x9032;&#x3059;&#x308B;&#x5F37;&#x529B;&#x306A;&#x6297;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x3092;&#x6D3B;&#x6027;&#x5316;&#x3059;&#x308B;&#x3053;&#x3068;&#x304C;&#x77E5;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x672C;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;Mer&#x306E;&#x3068;&#x30A2;&#x30AF;&#x30BB;&#x30EB;mRNA&#x8EE2;&#x5199;&#x3068;&#x86CB;&#x767D;&#x8CEA;&#x306E;&#x767A;&#x73FE;&#x306F;&#x30A2;&#x30B9;&#x30C8;&#x30ED;&#x30B5;&#x30A4;&#x30C8;&#x306E;&#x60A3;&#x8005;&#x30B5;&#x30F3;&#x30D7;&#x30EB;&#x304A;&#x3088;&#x3073;&#x7D30;&#x80DE;&#x682A;&#x3067;&#x4E0A;&#x6607;&#x3057;&#x3066;&#x3044;&#x305F;&#x3053;&#x3068;&#x304C;&#x308F;&#x304B;&#x3063;&#x305F;&#x3002; Mer&#x306E;&#x3068;&#x30A2;&#x30AF;&#x30BB;&#x30EB;RTK&#x306E;&#x767A;&#x73FE;&#x306E;shRNA&#x306B;&#x3088;&#x308B;&#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3;&#x306F;&#x3001;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x306E;&#x5897;&#x52A0;&#x306B;&#x3064;&#x306A;&#x304C;&#x3063;&#x305F;&#x3002;&#x30DD;&#x30EA;&#xFF08;ADP-&#x30EA;&#x30DC;&#x30FC;&#x30B9;&#xFF09;&#x30DD;&#x30EA;&#x30E1;&#x30E9;&#x30FC;&#x30BC;&#x306E;&#x5207;&#x65AD;&#x304C;&#x5897;&#x52A0;&#x3057;&#x305F;&#x4E00;&#x65B9;&#x3001;Akt&#x304A;&#x3088;&#x3073;&#x8010;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x3067;&#x6D3B;&#x6027;&#x5316;&#x3055;&#x308C;&#x308B;&#x3053;&#x3068;&#x304C;&#x793A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x7D30;&#x80DE;&#x5916;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x5236;&#x5FA1;&#x30AD;&#x30CA;&#x30FC;&#x30BC;1/2&#x3001;&#x3092;&#x542B;&#x3080;&#x3001;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x7D4C;&#x8DEF;&#x306F;&#x3001;MER&#x3068;&#x30A2;&#x30AF;&#x30BB;&#x30EB;&#x6291;&#x5236;&#x3068;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3055;&#x308C;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;MER&#x3084;&#x30A2;&#x30AF;&#x30BB;&#x30EB;&#x306E;shRNA&#x30CE;&#x30C3;&#x30AF;&#x30C0;&#x30A6;&#x30F3;&#x306F;&#x3001;&#x8EDF;&#x5BD2;&#x5929;&#x3068;&#x30C6;&#x30E2;&#x30BE;&#x30ED;&#x30DE;&#x30A4;&#x30C9;&#x306B;&#x53CD;&#x5FDC;&#x3057;&#x3066;&#x611F;&#x53D7;&#x6027;&#x306E;&#x6709;&#x610F;&#x306A;&#x5897;&#x52A0;&#x3001;&#x30AB;&#x30EB;&#x30DC;&#x30D7;&#x30E9;&#x30C1;&#x30F3;&#x3001;&#x30D3;&#x30F3;&#x30AF;&#x30EA;&#x30B9;&#x30C1;&#x30F3;&#x6CBB;&#x7642;&#x306B;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x7D30;&#x80DE;&#x5897;&#x6B96;&#x306E;&#x6DF1;&#x9060;&#x306A;&#x6E1B;&#x5C11;&#x306B;&#x3064;&#x306A;&#x304C;&#x3063;&#x305F;&#x3002;&#x6211;&#x3005;&#x306E;&#x7D50;&#x679C;&#x306F;&#x3001;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x306E;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x5FDC;&#x7B54;&#x3068;&#x611F;&#x53D7;&#x6027;&#x3092;&#x6539;&#x5584;&#x3057;&#x3001;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x3001;&#x85AC;&#x5264;&#x958B;&#x767A;&#x306E;&#x305F;&#x3081;&#x306E;&#x9B45;&#x529B;&#x7684;&#x306A;&#x751F;&#x7269;&#x5B66;&#x7684;&#x6A19;&#x7684;&#x3068;&#x3057;&#x3066;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x305F;&#x3081;&#x306E;&#x30B5;&#x30DD;&#x30FC;&#x30C8;&#x3092;&#x63D0;&#x4F9B;&#x3059;&#x308B;&#x65B0;&#x305F;&#x306A;&#x65B9;&#x6CD5;&#x3068;&#x3057;&#x3066;Mer&#x306E;&#x3068;&#x30A2;&#x30AF;&#x30BB;&#x30EB;RTK&#x963B;&#x5BB3;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

Mer&#x306E;&#x3068;&#x661F;&#x72B6;&#x7D30;&#x80DE;&#x816B;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;&#x30A2;&#x30AF;&#x30BB;&#x30EB;&#x53D7;&#x5BB9;&#x4F53;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x306E;&#x963B;&#x5BB3;&#x306F;&#x3001;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;&#x306E;&#x5897;&#x52A0;&#x3068;&#x6539;&#x5584;&#x3055;&#x308C;&#x305F;&#x6297;&#x764C;&#x5264;&#x611F;&#x53D7;&#x6027;&#x306B;&#x5C0E;&#x304F;

Astrocytomas &#xC131;&#xC778; &#xBC0F; &#xC18C;&#xC544; &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xC9C4;&#xB2E8; &#xD558;&#xB294; &#xC545;&#xC131; &#xB1CC;&#xC885;&#xC591;&#xC758; &#xB300;&#xB2E4;&#xC218;&#xB97C; &#xCC28;&#xC9C0;. &#xC774;&#xB7EC;&#xD55C; neoplasms &#xCE58;&#xB8CC; &#xC218; &#xCE58;&#xB8CC;&#xB294; &#xC81C;&#xD55C; &#xB41C;, &#xADF8;&#xB9AC;&#xACE0; &#xACE0;&#xAE09; &#xBCD1; &#xBCC0;&#xC774;&#xC640; &#xAD00;&#xB828; &#xB41C; &#xC608; &#xD6C4;&#xB294; &#xB9E4;&#xC6B0; &#xAC00;&#xB09C;. &#xBA54; &#xB974; (MerTK) &#xBC0F; Axl &#xC218;&#xC6A9; &#xCCB4; &#xD2F0;&#xB85C;&#xC2E0; kinases (RTK) &#xB2E4;&#xC591; &#xD55C; &#xC545;&#xC131; &#xC885;&#xC591;, &#xBE44;&#xC815;&#xC0C1;&#xC801;&#xC73C;&#xB85C; &#xB192;&#xC740; &#xC218;&#xC900;&#xC5D0;&#xC11C; &#xD45C;&#xD604; &#xB429;&#xB2C8;&#xB2E4; &#xADF8;&#xB9AC;&#xACE0; &#xC774;&#xB7EC;&#xD55C; &#xC218;&#xC6A9; &#xCCB4; &#xAC15;&#xD55C; antiapoptotic &#xD1B5;&#xB85C; &#xBC1C;&#xC554;&#xC744; &#xCD09;&#xC9C4; &#xD558;&#xB294; &#xC2E0;&#xD638;&#xB97C; &#xD65C;&#xC131;&#xD654; &#xD558;&#xB824;&#xBA74; &#xC54C;&#xB824;&#xC838; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC774; &#xC5F0;&#xAD6C;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC;&#xAC00; &#xBC1C;&#xACAC; &#xD558;&#xB294; &#xBA54; &#xB974;&#xC640; &#xC561; &#xC2AC; mRNA &#xC0AC;&#xBCF8; &#xBC0F; &#xB2E8;&#xBC31;&#xC9C8; &#xC2DD; astrocytic &#xD658;&#xC790; &#xC0D8;&#xD50C; &#xBC0F; &#xC140; &#xB77C;&#xC778;&#xC5D0; &#xC0C1;&#xC2B9; &#xD588;&#xB2E4;. &#xBA54; &#xB974;&#xC640; &#xC561; &#xC2AC; RTK &#xC2DD;&#xC758; &#xCD5C;&#xC800; shRNA &#xC911;&#xC7AC; astrocytoma &#xC140;&#xC5D0; apoptosis&#xC758; &#xC99D;&#xAC00;&#xB97C; &#xC774;&#xB04C;&#xC5C8;&#xB2E4;. Apoptotic &#xC2E0;&#xD638; &#xACBD;&#xB85C; &#xC800;&#xD56D; astrocytomas&#xC5D0;&#xC11C; &#xD65C;&#xC131;&#xD654; &#xB420; &#xD45C;&#xC2DC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4; Akt &#xBC0F; &#xC138;&#xD3EC; &#xC678; &#xC2E0;&#xD638; &#xADDC;&#xC81C; &#xB2C8; 1/2, &#xD3EC;&#xD568; &#xD55C; poly(ADP-ribose) &#xD6A8;&#xC18C; &#xBD84;&#xC5F4; &#xC99D;&#xAC00; &#xD558;&#xB294; &#xBC18;&#xBA74; &#xBA54; &#xB974;&#xC640; &#xC561; &#xC2AC; &#xC800;&#xD574;&#xC640; downregulated &#xD588;&#xB2E4;. &#xB610;&#xD55C;, &#xBA54; &#xB974;&#xC640; &#xC561; &#xC2AC; shRNA &#xCD5C;&#xC800;&#xC758; &#xBD80;&#xB4DC;&#xB7EC;&#xC6B4; agar&#xC640; chemosensitivity temozolomide carboplatin, &#xADF8;&#xB9AC;&#xACE0; vincristine &#xCE58;&#xB8CC;&#xC5D0; &#xB300; &#xD55C; &#xC751;&#xB2F5;&#xC5D0;&#xC11C;&#xC5D0; &#xC0C1;&#xB2F9;&#xD55C; &#xC99D;&#xAC00; astrocytoma &#xC138;&#xD3EC; &#xC99D;&#xC2DD;&#xC758; &#xC2EC;&#xC624;&#xD55C; &#xAC10;&#xC18C;&#xB97C; &#xC774;&#xB04C;&#xC5B4; &#xB0C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xACB0;&#xACFC; &#xBA54; &#xB974;&#xC640; &#xC561; &#xC2AC; RTK &#xC800;&#xD574;&#xB97C; apoptotic &#xC751;&#xB2F5;&#xACFC; astrocytoma&#xC5D0; chemosensitivity &#xD5A5;&#xC0C1;&#xACFC; astrocytoma &#xC57D;&#xBB3C; &#xAC1C;&#xBC1C;&#xC744; &#xC704;&#xD55C; &#xB9E4;&#xB825;&#xC801;&#xC778; &#xC0DD;&#xBB3C; &#xD559;&#xC801; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xC774;&#xB7EC;&#xD55C; oncogenes &#xC9C0;&#xC6D0; &#xC0C8;&#xB85C;&#xC6B4; &#xBC29;&#xBC95;&#xC73C;&#xB85C; &#xC88B;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xBA54; &#xB974;&#xC640; &#xC561; &#xC2AC; &#xC218;&#xC6A9; &#xCCB4; tyrosine kinases astrocytoma &#xC140;&#xC5D0;&#xC11C;&#xC758; &#xC800;&#xD574; &#xC99D;&#xAC00; apoptosis&#xC640; &#xD5A5;&#xC0C1; &#xB41C; chemosensitivity&#xC774; &#xB048;&#xB2E4;.

Los astrocitomas representan la mayor&#xED;a de los tumores cerebrales malignos diagnosticados en los pacientes adultos y pedi&#xE1;tricos. Las terapias disponibles para tratar estos tumores son limitados, y el pron&#xF3;stico asociado con lesiones de alto grado es extremadamente pobre. Mer (MerTK) y los receptores de tirosina quinasas Axl (RTK) se expresan en niveles anormalmente altos en una variedad de tumores malignos, y estos receptores se sabe que activar las v&#xED;as antiapopt&#xF3;ticas fuertes de se&#xF1;alizaci&#xF3;n que promueven la oncog&#xE9;nesis. En este estudio, encontramos que-Mer y la transcripci&#xF3;n del mRNA y Axl expresi&#xF3;n de la prote&#xED;na estaban elevados en las muestras de pacientes astroc&#xED;ticos y l&#xED;neas celulares. shRNA mediada desmontables de Mer y la expresi&#xF3;n de Axl RTK llevado a un aumento en la apoptosis en c&#xE9;lulas de astrocitoma. Las v&#xED;as de se&#xF1;alizaci&#xF3;n apopt&#xF3;tica, incluyendo Akt y la se&#xF1;al extracelular-quinasa regulada 1/2, que se ha demostrado que se activan en resistente a los astrocitomas, fueron regulados a la baja con la inhibici&#xF3;n de Mer y Axl, mientras que la poli (ADP-ribosa) polimerasa divisi&#xF3;n se increment&#xF3;. Adem&#xE1;s, Mer y desmontables Axl ARNhc condujo a una disminuci&#xF3;n profunda de proliferaci&#xF3;n celular astrocitoma en agar blando y un aumento significativo de quimiosensibilidad en respuesta a la temozolomida, carboplatino y vincristina tratamiento. Nuestros resultados sugieren Mer y Axl inhibici&#xF3;n de RTK como un m&#xE9;todo novedoso para mejorar la respuesta de apoptosis y la quimiosensibilidad en el astrocitoma y prestar apoyo a estos oncogenes como atractivas dianas biol&#xF3;gicas para el desarrollo de astrocitomas de drogas.

La inhibici&#xF3;n de la Mer y quinasas del receptor de la tirosina Axl en las c&#xE9;lulas Astrocitoma conduce a la apoptosis y el aumento de Mejora de la quimiosensibilidad

Axl and/or Mer expression correlates with poor prognosis in several cancers. Until recently, the role of these receptor tyrosine kinases (RTKs) in development and progression of cancer remained unexplained. Studies demonstrating that Axl and Mer contribute to cell survival, migration, invasion, metastasis and chemosensitivity justify further investigation of Axl and Mer as novel therapeutic targets in cancer.

Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors.

Modifications to the treatment of acute lymphoblastic leukaemia (ALL) in children have led to a dramatic increase in survival in the past 40 years. Despite this success, a significant subset of paediatric leukaemia patients either relapse or fail to ever achieve a complete remission. Additionally, some patients necessitate treatment with intensified chemotherapy regimens due to clinical or laboratory findings which identify them as high risk. These patients are unlikely to respond to further minor adjustments to the dosing or timing of administration of the same chemotherapy medications. Many novel targeted therapies for the treatment of childhood ALL provide potential mechanisms to further improve cure rates, and provide the possibility of minimizing toxicity to non-malignant cells, given their specificity to malignant cell phenotypes. This article explores many of the potential targeted therapies in varying stages of development, from those currently in clinical trials to those still being refined in the research laboratory.

Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development.

Cystathionine beta-synthase (CBS) deficient homocystinuria (HCU) is an inherited metabolic defect that if untreated, typically results in cognitive impairment, connective tissue disturbances, atherosclerosis and thromboembolic disease. In recent years, chronic inappropriate expression of the inflammatory response has emerged as a major driving force of both thrombosis and atherosclerotic lesion development. We report here a characterization of the abnormalities in cytokine expression induced in both a mouse model of HCU and human subjects with the disease in the presence and absence of homocysteine lowering therapy. HCU mice exhibited highly significant induction of the pro-inflammatory cytokines Il-1alpha, Il-1beta and TNF-alpha. Similarly, in untreated/poorly compliant human subjects with HCU we observed constitutive induction of multiple pro-inflammatory cytokines (IL-1alpha, IL-6, TNF-alpha, Il-17 and IL-12(p70)) and chemotactic chemokines (fractalkine, MIP-1alpha and MIP-1beta) compared to normal controls. These HCU patients also exhibited significant induction of IL-9, TGF-alpha and G-CSF. The expression levels of anti-inflammatory cytokines were unaffected in both HCU mice and human subjects with the disease. In the human subjects, homocysteine lowering therapy was associated with either normalization or significant reduction of all of the pro-inflammatory cytokines and chemokines investigated. We conclude that HCU is a disease of chronic inflammation and that aberrant cytokine expression has the potential to contribute to multiple aspects of pathogenesis. Our findings indicate that anti-inflammatory strategies could serve as a useful adjuvant therapy for this disease.

Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria.

Total body irradiation (TBI) is an important component of hematopoietic stem cell transplant (SCT) for pediatric malignancies. With increasing survival rates, late effects of SCT become more important. Younger children may be at particular risk of late effects of radiation and SCT.

Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age.

Acute lymphoblastic leukemia (ALL) is currently treated with an intense regimen of chemotherapy yielding cure rates near 85%. However, alterations to treatment strategies using available drugs are unlikely to provide significant improvement in survival or decrease therapy-associated toxicities. Here, we report ectopic expression of the Mer receptor tyrosine kinase in pre-B-cell ALL (B-ALL) cell lines and pediatric patient samples. Inhibition of Mer in B-ALL cell lines decreased activation of AKT and MAPKs and led to transcriptional changes, including decreased expression of antiapoptotic PRKCB gene and increase in proapoptotic BAX and BBC3 genes. Further, Mer inhibition promoted chemosensitization, decreased colony-forming potential in clonogenic assays, and delayed disease onset in a mouse xenograft model of leukemia. Our results identify Mer as a potential therapeutic target in B-ALL and suggest that inhibitors of Mer may potentiate lymphoblast killing when used in combination with chemotherapy. This strategy could reduce minimal residual disease and/or allow for chemotherapy dose reduction, thereby leading to improved event-free survival and reduced therapy-associated toxicity for patients with B-ALL. Additionally, Mer is aberrantly expressed in numerous other malignancies suggesting that this approach may have broad applications.

Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia.

Receptor tyrosine kinases (RTKs) are cell surface proteins that tightly regulate a variety of downstream intra-cellular processes; ligand-receptor interactions result in cascades of signaling events leading to growth, proliferation, differentiation and migration. There are 58 described RTKs, which are further categorized into 20 different RTK families. When dysregulated or overexpressed, these RTKs are implicated in disordered growth, development, and oncogenesis. The TAM family of RTKs, consisting of Tyro3, Axl, and MerTK, is prominently expressed during the development and function of the central nervous system (CNS). Aberrant expression and dysregulated activation of TAM family members has been demonstrated in a variety of CNS-related disorders and diseases, including the most common but least treatable brain cancer in children and adults: glioblastoma multiforme.

TAM receptor tyrosine kinases: expression, disease and oncogenesis in the central nervous system.

Glioblastoma is an aggressive tumor that occurs in both adult and pediatric patients and is known for its invasive quality and high rate of recurrence. Current therapies for glioblastoma result in high morbidity and dismal outcomes. The TAM subfamily of receptor tyrosine kinases includes Tyro3, Axl, and MerTK. Axl and MerTK exhibit little to no expression in normal brain but are highly expressed in glioblastoma and contribute to the critical malignant phenotypes of survival, chemosensitivity and migration. We have found that Foretinib, a RTK inhibitor currently in clinical trial, inhibited phosphorylation of TAM receptors, with highest efficacy against MerTK, and blocked downstream activation of Akt and Erk in adult and pediatric glioblastoma cell lines, findings that are previously unreported. Survival, proliferation, migration, and collagen invasion were hindered in vitro. Foretinib treatment in vivo abolished MerTK phosphorylation and reduced tumor growth 3-4 fold in a subcutaneous mouse model. MerTK targeted shRNA completely prevented intracranial and subcutaneous glioma growth further delineating the impact of MerTK inhibition on glioblastoma. Our findings provide additional target validation for MerTK inhibition in glioblastoma and demonstrate that robust MerTK inhibition can be achieved with the multi-kinase inhibitor Foretinib as an innovative and translational therapeutic approach to glioblastoma.

Article	Year
Ectopic expression of the proto-oncogene Mer in pediatric T-cell acute lymphoblastic leukemia. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 16675557	2006
TAM receptor tyrosine kinases: biologic functions, signaling, and potential therapeutic targeting in human cancer. Advances in cancer research\| PubMed ID: 18620092	2008
Mer tyrosine kinase (MerTK) promotes macrophage survival following exposure to oxidative stress. Journal of leukocyte biology\| PubMed ID: 19386698	2009
Mer receptor tyrosine kinase is a novel therapeutic target in pediatric B-cell acute lymphoblastic leukemia. Blood\| PubMed ID: 19643988	2009
Thymoma in children: report of 2 cases and review of the literature. Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society\| PubMed ID: 20055684	2010
Inhibition of Mer and Axl receptor tyrosine kinases in astrocytoma cells leads to increased apoptosis and improved chemosensitivity. Molecular cancer therapeutics\| PubMed ID: 20423999	2010
Taking aim at Mer and Axl receptor tyrosine kinases as novel therapeutic targets in solid tumors. Expert opinion on therapeutic targets\| PubMed ID: 20809868	2010
Targeting paediatric acute lymphoblastic leukaemia: novel therapies currently in development. British journal of haematology\| PubMed ID: 20813012	2010
Constitutive induction of pro-inflammatory and chemotactic cytokines in cystathionine beta-synthase deficient homocystinuria. Molecular genetics and metabolism\| PubMed ID: 21601502	2011
Late effects of total body irradiation and hematopoietic stem cell transplant in children under 3 years of age. Pediatric blood & cancer\| PubMed ID: 22848000	2013
Mer receptor tyrosine kinase is a therapeutic target in pre-B-cell acute lymphoblastic leukemia. Blood\| PubMed ID: 23861246	2013
TAM receptor tyrosine kinases: expression, disease and oncogenesis in the central nervous system. Brain research\| PubMed ID: 24184575	2014
MerTK inhibition is a novel therapeutic approach for glioblastoma multiforme. Oncotarget\| PubMed ID: 24658326	2014

Amy K. Keating

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JoVE Journal Publications

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