Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel <em>RIP-Tag; RIP-tva</em> Murine Model

Metastatic cancer accounts for 90% of deaths in patients with solid tumors. There is an urgent need to better understand the drivers of cancer metastasis ...

Weill Cornell Medicine

Immunoprecipitation of the origin recognition complex (ORC) from yeast extracts identified Yph1p, an essential protein containing a BRCT domain. Two Yph1p complexes were characterized. Besides ORC, MCM proteins, cell-cycle regulatory proteins, checkpoint proteins, 60S ribosomal proteins, and preribosome particle proteins were found to be associated with Yph1p. Yph1p is predominantly nucleolar and is required for 60S ribosomal subunit biogenesis and possibly for translation on polysomes. Proliferating cells depleted of Yph1p arrest in G(1) or G(2), with no cells in S phase, or significantly delay S phase progression after release from a hydroxyurea arrest. Yph1p levels decline as cells commit to exit the cell cycle, and levels vary depending on energy source. Yph1p may link cell proliferation control to DNA replication, ribosome biogenesis, and translation on polysomes.

Yph1p, an ORC-interacting protein: potential links between cell proliferation control, DNA replication, and ribosome biogenesis.

Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP) drives expression of both the SV40 T antigen (RIP-Tag) and the receptor for subgroup A avian leukosis virus (RIP-tva), are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by approximately 14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad) or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and invasion, as evaluated using two-chamber transwell assays. In addition, myosin Va was identified as a novel Bcl-xL-interacting protein that might mediate the effects of Bcl-xL on tumor cell migration and invasion.

Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion.

The acquisition of metastatic ability by tumor cells is considered a late event in the evolution of malignant tumors. We report that untransformed mouse mammary cells that have been engineered to express the inducible oncogenic transgenes MYC and Kras(D12), or polyoma middle T, and introduced into the systemic circulation of a mouse can bypass transformation at the primary site and develop into metastatic pulmonary lesions upon immediate or delayed oncogene induction. Therefore, previously untransformed mammary cells may establish residence in the lung once they have entered the bloodstream and may assume malignant growth upon oncogene activation. Mammary cells lacking oncogenic transgenes displayed a similar capacity for long-term residence in the lungs but did not form ectopic tumors.

Seeding and propagation of untransformed mouse mammary cells in the lung.

It is unclear whether the cellular origin of various forms of pancreatic cancer involves transformation or transdifferentiation of different target cells or whether tumors arise from common precursors, with tumor types determined by the specific genetic alterations. Previous studies suggested that pancreatic ductal carcinomas might be induced by polyoma middle T antigen (PyMT) expressed in non-ductal cells. To ask whether PyMT transforms and transdifferentiates endocrine cells toward exocrine tumor phenotypes, we generated transgenic mice that carry tetracycline-inducible PyMT and a linked luciferase reporter. Induction of PyMT in beta cells causes beta-cell hyperplastic lesions that do not progress to malignant neoplasms. When PyMT is de-induced, beta cell proliferation and growth cease; however, regression does not occur, suggesting that continued production of PyMT is not required to maintain the viable expanded beta cell population. In contrast, induction of PyMT in early pancreatic progenitor cells under the control of Pdx1 produces acinar cell carcinomas and beta-cell hyperplasia. The survival of acinar tumor cells is dependent on continued expression of PyMT. Our findings indicate that PyMT can induce exocrine tumors from pancreatic progenitor cells, but cells in the beta cell lineage are not transdifferentiated toward exocrine cell types by PyMT; instead, they undergo oncogene-dependent hyperplastic growth, but do not require PyMT for survival.

Activation of PyMT in beta cells induces irreversible hyperplasia, but oncogene-dependent acinar cell carcinomas when activated in pancreatic progenitors.

p53, apoptosis, and senescence are frequently activated in preneoplastic lesions and are barriers to progression to malignancy. These barriers have been suggested to result from an ATM-mediated DNA damage response (DDR), which may follow oncogene-induced hyperproliferation and ensuing DNA replication stress. To elucidate the currently untested role of DDR in breast cancer initiation, we examined the effect of oncogene expression in several murine models of breast cancer. We did not observe a detectable DDR in early hyperplastic lesions arising in transgenic mice expressing several different oncogenes. However, DDR signaling was strongly induced in preneoplastic lesions arising from individual mammary cells transduced in vivo by retroviruses expressing either PyMT or ErbB2. Thus, activation of an oncogene after normal tissue development causes a DDR. Furthermore, in this somatic ErbB2 tumor model, ATM, and thus DDR, is required for p53 stabilization, apoptosis, and senescence. In palpable tumors in this model, p53 stabilization and apoptosis are lost, but unexpectedly senescence remains in many tumor cells. Thus, this murine model fully recapitulates early DDR signaling; the eventual suppression of its endpoints in tumorigenesis provides compelling evidence that ErbB2-induced aberrant mammary cell proliferation leads to an ATM-mediated DDR that activates apoptosis and senescence, and at least the former must be overcome to progress to malignancy. This in vivo study also uncovers an unexpected effect of ErbB2 activation previously known for its prosurvival roles, and suggests that protection of the ATM-mediated DDR-p53 signaling pathway may be important in breast cancer prevention.

Defining the ATM-mediated barrier to tumorigenesis in somatic mammary cells following ErbB2 activation.

The gene encoding the receptor for hyaluronan-mediated motility (RHAMM) is overexpressed in many human cancers. However, it is unclear whether RHAMM plays a causal role in tumor initiation or progression. Using somatic gene transfer in a mouse model of islet cell tumorigenesis, we demonstrate that RHAMM isoform B (RHAMM(B)) promotes tumor growth and metastases to lymph nodes and the liver. The propensity of RHAMM(B)-expressing cells to metastasize to the liver was confirmed using an experimental metastasis assay in which cells were injected into the tail vein of immunodeficient mice. However, RHAMM(B) did not increase cell migration or proliferation in culture. In initial efforts to identify signaling pathways activated by RHAMM(B), we found that RHAMM(B) induced phosphorylation of epidermal growth factor receptor (EGFR), Erk1/2, and STAT3 and conferred susceptibility to apoptosis after treatment with an EGFR inhibitor, gefitinib. Taken together, the results indicate that RHAMM(B) promotes hepatic metastasis by islet tumor cells, perhaps through growth factor receptor-mediated signaling.

Receptor for hyaluronan-mediated motility isoform B promotes liver metastasis in a mouse model of multistep tumorigenesis and a tail vein assay for metastasis.

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&#x89C6;&#x7F51;&#x819C;&#x6BCD;&#x7EC6;&#x80DE;&#x7624;&#x8DEF;&#x5F84;&#x5728;&#x7531;&#x4E8E;&#x80F0;&#x817A;&#x795E;&#x7ECF;&#x5185;&#x5206;&#x6CCC;&#x80BF;&#x7624;&#x4E2D;&#x7684;&#x8870;&#x51CF;&#x589E;&#x52A0; Cdk4/Cdk6&#x3002;

PURPOSE: In mice, genetic changes that inactivate the retinoblastoma tumor suppressor pathway often result in pancreatic neuroendocrine tumors (Pan-NETs). Conversely, in humans with this disease, mutations in genes of the retinoblastoma pathway have rarely been detected, even in genome-wide sequencing studies. In this study, we took a closer look at the role of the retinoblastoma pathway in human Pan-NETs.EXPERIMENTAL DESIGN: Pan-NET tumors from 92 patients were subjected to immunohistochemical staining for markers of the retinoblastoma pathway. To search for amplifications of retinoblastoma pathway genes, genomic DNAs from 26 tumors were subjected to copy number analysis. Finally, a small-molecule activator of the retinoblastoma pathway was tested for effects on the growth of two Pan-NET cell lines.RESULTS: A majority of tumors expressed high amounts of Cdk4 or its partner protein cyclin D1. High amounts of phosphorylated Rb1 were present in tumors that expressed high levels of Cdk4 or cyclin D1. The copy numbers of Cdk4 or the analogous kinase gene Cdk6 were increased in 19% of the tumors. Growth of the human Pan-NET cell line QGP1 was inhibited in a xenograft mouse model by the Cdk4/6 inhibitor, PD 0332991, which reactivates the retinoblastoma pathway.CONCLUSIONS: Inactivation of the retinoblastoma pathway was indicated for most Pan-NETs. Gene amplification and overexpression of Cdk4 and Cdk6 suggests that patients with Pan-NETs may respond strongly to Cdk4/6 inhibitors that are entering clinical trials. Clin Cancer Res; 1-9. Â©2012 AACR.

Attenuation of the Retinoblastoma Pathway in Pancreatic Neuroendocrine Tumors Due to Increased Cdk4/Cdk6.

BUT : Chez la souris, des modifications g&eacute;n&eacute;tiques qui inactivent la voie de suppresseur de tumeur r&eacute;tinoblastome souvent provoquer des tumeurs neuroendocrines du pancr&eacute;as (Pan-NETs). &Agrave; l&#39;inverse, chez les humains atteints de cette maladie, les mutations dans les g&egrave;nes de la voie de r&eacute;tinoblastome rarement d&eacute;tect&eacute;es, m&ecirc;me dans les &eacute;tudes de s&eacute;quen&ccedil;age de g&eacute;nome. Dans cette &eacute;tude, nous avons pris le regarder de plus pr&egrave;s le r&ocirc;le de la voie de r&eacute;tinoblastome humaine Pan-NETs.EXPERIMENTAL Design : tumeurs Pan-NET de 92 patients ont &eacute;t&eacute; soumis &agrave; immunohistochemical souillant des marqueurs de la voie de r&eacute;tinoblastome. Pour rechercher des amplifications de g&egrave;nes de la voie r&eacute;tinoblastome, l&#39;ADN g&eacute;nomique du 26 tumeurs ont &eacute;t&eacute; soumis pour analyse nombre de copier. Enfin, un activateur de petites mol&eacute;cules de la voie de r&eacute;tinoblastome a &eacute;t&eacute; test&eacute; pour les effets sur la croissance de deux lign&eacute;es de cellules de Pan-NET.R&Eacute;SULTATS : Une majorit&eacute; des tumeurs exprim&eacute;s des quantit&eacute;s &eacute;lev&eacute;es de Cdk4 ou ses prot&eacute;ines partenaire cycline D1. Des quantit&eacute;s &eacute;lev&eacute;es de Rb1 phosphoryl&eacute;s &eacute;taient pr&eacute;sentes dans les tumeurs qui expriment des niveaux &eacute;lev&eacute;s de Cdk4 ou cycline D1. Le nombre de copies du Cdk4 ou du g&egrave;ne de la kinase analogue Cdk6 ont augment&eacute; de 19 % des tumeurs. La croissance d&#39;une lign&eacute;e cellulaire humaine Pan-NET QGP1 est inhib&eacute;e dans un mod&egrave;le de x&eacute;nogreffe de souris par l&#39;inhibiteur de la Cdk4/6, PD 0332991, ce qui r&eacute;active la voie du r&eacute;tinoblastome.CONCLUSIONS : L&#39;Inactivation de la voie de r&eacute;tinoblastome a &eacute;t&eacute; indiqu&eacute;e pour la plupart Pan-filets. Amplification du g&egrave;ne et surexpression de Cdk4 et Cdk6 sugg&egrave;re que les patients avec des Pan-filets peuvent r&eacute;agissent fortement aux inhibiteurs de la Cdk4/6 qui entrent dans les essais cliniques. Clin Cancer Res ; 1-9. &copy; 2012 AACR.

Att&eacute;nuation de la voie du r&eacute;tinoblastome dans les tumeurs neuroendocrines du pancr&eacute;as Due &agrave; augment&eacute; Cdk4/Cdk6.

Zweck: Bei M&auml;usen f&uuml;hren genetische Ver&auml;nderungen, die oft die Retinoblastom Tumor-Suppressor-Pathway inaktivieren pankreatischen neuroendokrinen Tumoren (Pan-NETs). Umgekehrt haben bei Menschen mit dieser Krankheit, Mutationen in Genen des Signalweges Retinoblastom selten, sogar in genomweiten Sequenzierung Studien nachgewiesen. In dieser Studie nahmen wir einen genaueren Blick auf die Rolle des Retinoblastom-Signalweges in menschlichen Pan-NETs.EXPERIMENTAL-DESIGN: Pan-NET-Tumoren von 92 Patienten wurden Immunohistochemical Beflecken f&uuml;r Marker des Signalweges Retinoblastom unterworfen. Zum Suchen Verst&auml;rkungen Retinoblastom Stoffwechselweg Gene, genomische DNA aus 26 wurden Tumoren unterzogen, um Anzahl Analyse zu kopieren. Schlie&szlig;lich wurde ein kleines Molek&uuml;l-Aktivator des Signalweges Retinoblastom f&uuml;r Auswirkungen auf das Wachstum von zwei Pan-NET-Zelllinien getestet.Ergebnis: Eine Mehrheit von Tumoren ausgedr&uuml;ckt hohe Mengen an Cdk4 oder sein Partner-Protein cyclin D1. Hohe Mengen an Phosphorylierte Rb1 waren in Tumoren, die hohe Konzentrationen von Cdk4 oder der cyclin D1 ausgedr&uuml;ckt. Kopie Zahlen Cdk4 oder das Analog-Kinase-gen Cdk6 wurden in 19 % der Tumoren erh&ouml;ht. Wachstum des menschlichen Pan-NET-Zelllinie QGP1 wurde in einem Mausmodell Xenograft-durch den Cdk4/6 wird, PD 0332991, gehemmt, die die Retinoblastom-Pathway reaktiviert.Schlussfolgerungen: Inaktivierung des Signalweges Retinoblastom war f&uuml;r die meisten Pan-Netze angezeigt. GENAMPLIFIKATION und eine &Uuml;berexpression von Cdk4 und Cdk6 legt nahe, dass Patienten mit Pan-Netze stark auf Cdk4/6 Inhibitoren reagieren k&ouml;nnen, die klinische Studien eingeben. Clin Cancer Res; 1-9. &copy; 2012 AACR.

D&auml;mpfung des Retinoblastom Biosyntheseweges in pankreatischen neuroendokrinen Tumoren aufgrund von erh&ouml;hten Cdk4/Cdk6.

SCOPO: Provocare cambiamenti genetici che inattivano il pathway di soppressore tumorale retinoblastoma spesso nei topi, tumori neuroendocrini pancreatici (Pan-NETs). Al contrario, negli esseri umani con questa malattia, mutazioni nei geni della via del retinoblastoma sono raramente state rilevate, anche in studi genome-wide sequenziamento. In questo studio, abbiamo preso uno sguardo pi&ugrave; da vicino il ruolo della via del retinoblastoma umano Pan-NETs.EXPERIMENTAL Design: tumori Pan-NET da 92 pazienti sono stati sottoposti ad immunoistochimica di colorazione per marcatori di via del retinoblastoma. Per la ricerca di amplificazioni di geni pathway di retinoblastoma, DNAs genomic da 26 tumori sono stati sottoposti per copiare numero analisi. Infine, un attivatore della piccolo-molecola di via del retinoblastoma &egrave; stato testato per gli effetti sulla crescita di due linee di cellule di Pan-NET.RISULTATI: La maggioranza dei tumori espressi in quantit&agrave; elevate di Cdk4 o suoi partner proteina chinasi ciclina D1. Quantit&agrave; elevate di Rb1 fosforilata erano presenti nei tumori che esprime alti livelli di Cdk4 o cyclin D1. Nel 19% dei tumori sono stati aumentati i numeri copia di Cdk4 o del gene della chinasi analoga Cdk6. Crescita della linea di cellule di Pan-NET QGP1 umana &egrave; stata inibita in un modello murino xenoinnesto da inibitore Cdk4/6, PD 0332991, che riattiva il pathway di retinoblastoma.CONCLUSIONI: Inattivazione della via del retinoblastoma &egrave; stato indicato per la maggior parte dei Pan-reti. Amplificazione del gene e iperespressione di Cdk4 e Cdk6 suggerisce che pazienti con Pan-reti possono rispondere fortemente agli inibitori Cdk4/6 che stanno entrando in studi clinici. Clin Cancer Res; 1-9. &copy; 2012 AACR.

Attenuazione del percorso Retinoblastoma in tumori neuroendocrini del pancreas dovuto aumentato Cdk4/Cdk6.

&#x76EE;&#x7684;: &#x30DE;&#x30A6;&#x30B9;&#x306E;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x306E;&#x816B;&#x760D;&#x6291;&#x5236;&#x56E0;&#x5B50;&#x306E;&#x7D4C;&#x8DEF;&#x3092;&#x3057;&#x3070;&#x3057;&#x3070;&#x4E0D;&#x6D3B;&#x5316;&#x907A;&#x4F1D;&#x7684;&#x5909;&#x5316;&#x81B5;&#x795E;&#x7D4C;&#x5185;&#x5206;&#x6CCC;&#x816B;&#x760D; (&#x30D1;&#x30F3;) &#x30CD;&#x30C3;&#x30C8;&#xFF09; &#x306E;&#x7D50;&#x679C;&#x3057;&#x307E;&#x3059;&#x3002;&#x9006;&#x306B;&#x3001;&#x3053;&#x306E;&#x75C5;&#x6C17;&#x306E;&#x4EBA;&#x9593;&#x3067;&#x306F;&#x3001;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x306E;&#x7A81;&#x7136;&#x5909;&#x7570;&#x306F;&#x307B;&#x3068;&#x3093;&#x3069;&#x3001;&#x30B2;&#x30CE;&#x30E0; &#x30B7;&#x30FC;&#x30B1;&#x30F3;&#x30B9;&#x306E;&#x7814;&#x7A76;&#x3067;&#x3042;&#x3063;&#x3066;&#x3082;&#x691C;&#x51FA;&#x3055;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x672C;&#x7814;&#x7A76;&#x3067;&#x306F;&#x3001;&#x6211;&#x3005; &#x4EBA;&#x9593;&#x306E;&#x30D1;&#x30F3; NETs.EXPERIMENTAL &#x30C7;&#x30B6;&#x30A4;&#x30F3;&#x3067;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x5F79;&#x5272;&#x3092;&#x8A73;&#x3057;&#x304F;&#x898B;&#x3066;&#x53D6;&#x3063;&#x305F;: &#x30D1;&#x30F3; NET &#x816B;&#x760D; 92 &#x60A3;&#x8005;&#x304B;&#x3089;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x30DE;&#x30FC;&#x30AB;&#x30FC;&#x306E;&#x67D3;&#x8272;&#x3092;&#x53D7;&#x3051;&#x308B;&#x3067;&#x3057;&#x305F;&#x3002;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x907A;&#x4F1D;&#x5B50;&#x3001;26 &#x304B;&#x3089;&#x306E;&#x30B2;&#x30CE;&#x30E0; Dna &#x306E;&#x5897;&#x5E45;&#x3092;&#x691C;&#x7D22;&#x3059;&#x308B;&#x306B;&#x306F;&#x3001;&#x816B;&#x760D;&#x6570;&#x89E3;&#x6790;&#x3092;&#x30B3;&#x30D4;&#x30FC;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x53D7;&#x3051;&#x305F;&#x3002;&#x6700;&#x5F8C;&#x306B;&#x3001;&#x5C0F;&#x5206;&#x5B50;&#x6D3B;&#x6027;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x30D1;&#x30F3; &#x30CD;&#x30C3;&#x30C8; &#x30BB;&#x30EB;&#x306E; 2 &#x884C;&#x306E;&#x751F;&#x80B2;&#x306B;&#x53CA;&#x307C;&#x3059;&#x5F71;&#x97FF;&#x306B;&#x3064;&#x3044;&#x3066;&#x8A66;&#x9A13;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x7D50;&#x679C;: &#x816B;&#x760D;&#x306E;&#x5927;&#x534A;&#x306F; Cdk4 &#x307E;&#x305F;&#x306F;&#x30B5;&#x30A4;&#x30AF;&#x30EA;&#x30F3; D1 &#x305D;&#x306E;&#x30D1;&#x30FC;&#x30C8;&#x30CA;&#x30FC;&#x86CB;&#x767D;&#x8CEA;&#x306E;&#x591A;&#x91CF;&#x3092;&#x8868;&#x660E;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;&#x591A;&#x91CF;&#x306E;&#x30EA;&#x30F3;&#x9178;&#x5316; Rb1 Cdk4 &#x307E;&#x305F;&#x306F;&#x30B5;&#x30A4;&#x30AF;&#x30EA;&#x30F3; D1 &#x306E;&#x9AD8;&#x30EC;&#x30D9;&#x30EB;&#x8868;&#x73FE;&#x306B;&#x304A;&#x3051;&#x308B;&#x816B;&#x760D;&#x5B58;&#x5728;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;Cdk4 &#x307E;&#x305F;&#x306F;&#x985E;&#x4F3C;&#x306E;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x907A;&#x4F1D;&#x5B50; Cdk6 &#x306E;&#x30B3;&#x30D4;&#x30FC;&#x6570;&#x306F;&#x3001;&#x816B;&#x760D;&#x306E; 19 &#xFF05; &#x306B;&#x5897;&#x52A0;&#x3057;&#x305F;.&#x6210;&#x9577;&#x30D1;&#x30F3; &#x30CD;&#x30C3;&#x30C8;&#x4EBA;&#x9593;&#x306E;&#x30BB;&#x30EB;&#x306E;&#x884C; QGP1 &#x306E;&#x7570;&#x7A2E;&#x79FB;&#x690D;&#x30DE;&#x30A6;&#x30B9; &#x30E2;&#x30C7;&#x30EB;&#x3067;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x3092;&#x518D;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D6;&#x5316; PD 0332991 Cdk4/6 &#x963B;&#x5BB3;&#x5264;&#x306B;&#x3088;&#x308B;&#x963B;&#x5BB3;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x7D50;&#x8AD6;: &#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x306E;&#x305F;&#x3081;&#x306E;&#x307B;&#x3068;&#x3093;&#x3069;&#x306E;&#x30D1;&#x30F3; &#x30CD;&#x30C3;&#x30C8;&#x3092;&#x793A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x907A;&#x4F1D;&#x5B50;&#x5897;&#x5E45;&#x3068;&#x904E;&#x5270;&#x767A;&#x73FE; Cdk4 &#x3068; Cdk6 &#x306E;&#x30D1;&#x30F3; &#x30CD;&#x30C3;&#x30C4;&#x306E;&#x60A3;&#x8005;&#x304C;&#x81E8;&#x5E8A;&#x8A66;&#x9A13;&#x306B;&#x5165;&#x3063;&#x3066;&#x3044;&#x308B; Cdk4/6 &#x963B;&#x5BB3;&#x5264;&#x306B;&#x5F37;&#x304F;&#x5FDC;&#x7B54;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;Clin &#x304C;&#x3093;&#x89E3;&#x50CF;&#x5EA6;;1 9. &copy; 2012 AACR&#x3002;

&#x305F;&#x3081;&#x306B;&#x81B5;&#x795E;&#x7D4C;&#x5185;&#x5206;&#x6CCC;&#x816B;&#x760D;&#x306B;&#x304A;&#x3051;&#x308B;&#x7DB2;&#x819C;&#x82BD;&#x7D30;&#x80DE;&#x816B;&#x7D4C;&#x8DEF;&#x306E;&#x6E1B;&#x8870; Cdk4/Cdk6 &#x5897;&#x52A0;&#x3057;&#x307E;&#x3057;&#x305F;&#x3002;

&#xC6A9;&#xB3C4;: &#xC950;, &#xC885;&#xC885; retinoblastoma &#xC885;&#xC591; &#xC5B5;&#xC81C;&#xAE30; &#xD1B5;&#xB85C; &#xBE44;&#xD65C;&#xC131;&#xD654; &#xD558;&#xB294; &#xC720;&#xC804;&#xC790; &#xBCC0;&#xD654; &#xCDCC; neuroendocrine &#xC885;&#xC591; (&#xD32C; &#xADF8;&#xBB3C;)&#xC5D0; &#xACB0;&#xACFC;. &#xBC18;&#xB300;&#xB85C;,&#xC774; &#xC9C8;&#xBCD1;&#xC73C;&#xB85C; &#xC778; &#xAC04;&#xC5D0; retinoblastoma &#xD1B5;&#xB85C;&#xC758; &#xC720;&#xC804;&#xC790;&#xC758; &#xBCC0;&#xC774; &#xAC70;&#xC758; &#xBC1C;&#xACAC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;, &#xAC8C;&#xB188; &#xC804;&#xCCB4; &#xC2DC;&#xD000;&#xC2F1; &#xC5F0;&#xAD6C;&#xC5D0;&#xB3C4;. &#xC774; &#xC5F0;&#xAD6C;&#xC5D0;&#xC11C; &#xC6B0;&#xB9AC; &#xC778;&#xAC04;&#xC758; &#xD32C; NETs.EXPERIMENTAL &#xB514;&#xC790;&#xC778;&#xC5D0; &#xBA74;&#xBC00; &#xD55C; retinoblastoma &#xD1B5;&#xB85C;&#xC758; &#xC5ED;&#xD560;&#xC744; &#xD588;&#xB2E4;: 92 &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xC885;&#xC591; &#xD32C; &#xADF8;&#xBB3C; immunohistochemical retinoblastoma &#xD1B5;&#xB85C;&#xC758; &#xD45C;&#xC2DD;&#xC5D0; &#xB300; &#xD55C; &#xC5BC;&#xB8E9;&#xC744; &#xBCF5;&#xC885; &#xB418;&#xC5C8;&#xB2E4;. Retinoblastoma &#xD1B5;&#xB85C; &#xC720;&#xC804;&#xC790;, &#xAC8C;&#xB188; DNAs 26&#xC5D0;&#xC11C;&#xC758; &#xD655;&#xB300;&#xC5D0; &#xB300; &#xD55C; &#xAC80;&#xC0C9; &#xC885;&#xC591; &#xBCF5;&#xC0AC; &#xBC88;&#xD638; &#xBD84;&#xC11D; &#xB300;&#xC0C1;&#xC774; &#xB418;&#xC5C8;&#xB2E4;. &#xB9C8;&#xC9C0;&#xB9C9;&#xC73C;&#xB85C;, retinoblastoma &#xD1B5;&#xB85C;&#xC758; &#xC791;&#xC740; &#xBD84;&#xC790; &#xD65C;&#xC131; &#xC81C; &#xB450; &#xD32C; &#xADF8;&#xBB3C; &#xC140; &#xB77C;&#xC778;&#xC758; &#xC131;&#xC7A5;&#xC5D0; &#xBBF8;&#xCE58;&#xB294; &#xC601;&#xD5A5;&#xC5D0; &#xB300; &#xD55C; &#xD14C;&#xC2A4;&#xD2B8; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4;.&#xACB0;&#xACFC;: &#xC885;&#xC591;&#xC758; &#xB300;&#xB2E4;&#xC218; Cdk4 &#xB610;&#xB294; D1 &#xF06C; &#xD30C;&#xD2B8;&#xB108; &#xB2E8;&#xBC31;&#xC9C8;&#xC758; &#xB192;&#xC740; &#xAE08;&#xC561;&#xC744; &#xD45C;&#xBA85; &#xD588;&#xB2E4;. Phosphorylated Rb1 &#xB192;&#xC740; &#xC591;&#xC758; Cdk4 &#xB610;&#xB294; cyclin d1&#xC758; &#xC0C1;&#xBD80;&#xB97C; &#xD45C;&#xD604; &#xD558;&#xB294; &#xC885;&#xC591;&#xC5D0; &#xC874;&#xC7AC; &#xD588;&#xB2E4;. &#xBCF5;&#xC0AC;&#xBCF8; &#xC218; Cdk4 &#xB610;&#xB294; &#xC720;&#xC0AC;&#xD55C; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xC720;&#xC804;&#xC790; cdk6&#xC758; &#xC885;&#xC591;&#xC758; 19% &#xC99D;&#xAC00; &#xD588;&#xB2E4;. &#xC778;&#xAC04;&#xC758; &#xD32C; &#xADF8;&#xBB3C; &#xC140; &#xB77C;&#xC778; qgp1&#xC758; &#xC131;&#xC7A5; retinoblastoma &#xD1B5;&#xB85C; &#xB2E4;&#xC2DC; &#xD65C;&#xC131;&#xD654; &#xD558;&#xBA74; PD 0332991 Cdk4/6 &#xC5B5;&#xC81C;&#xC81C;&#xC5D0; &#xC758;&#xD574; &#xB1CC;&#xC885;&#xC591; &#xB9C8;&#xC6B0;&#xC2A4; &#xBAA8;&#xB378;&#xC5D0; &#xC800;&#xD574; &#xD588;&#xB2E4;.&#xACB0;&#xB860;: &#xB300;&#xBD80;&#xBD84;&#xC758; &#xD32C; &#xADF8;&#xBB3C; retinoblastoma &#xD1B5;&#xB85C;&#xC758; &#xBE44;&#xD65C;&#xC131;&#xD654; &#xD45C;&#xC2DC; &#xD588;&#xB2E4;. &#xC720;&#xC804;&#xC790; &#xC99D;&#xD3ED; &#xBC0F; Cdk4 &#xADF8;&#xB9AC;&#xACE0; cdk6&#xC758; overexpression &#xD32C; &#xADF8;&#xBB3C;&#xACFC; &#xD658;&#xC790; Cdk4/6 &#xC5B5;&#xC81C;&#xC81C;&#xB294; &#xC784;&#xC0C1; &#xC2E4;&#xD5D8;&#xC744; &#xC785;&#xB825;&#xC744; &#xAC15;&#xB825; &#xD558; &#xAC8C; &#xC751;&#xB2F5;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xC81C;&#xC548; &#xD569;&#xB2C8;&#xB2E4;. Clin &#xC554; &#xD574;&#xC0C1;&#xB3C4;; 1-9. &copy; 2012 AACR.

&#xB85C; &#xC778;&#xD574; &#xCDCC; &#xC7A5; Neuroendocrine &#xC885;&#xC591;&#xC5D0;&#xC11C; Retinoblastoma &#xD1B5;&#xB85C;&#xC758; &#xAC10;&#xC1E0; &#xC99D;&#xAC00; Cdk4/Cdk6.

PROP&Oacute;SITO: En ratones, cambios gen&eacute;ticos que inactivan la v&iacute;a de supresor del tumor de retinoblastoma a menudo resultan en tumores neuroendocrinos pancre&aacute;ticos (Pan-redes). Por el contrario, en los seres humanos con esta enfermedad, las mutaciones en los genes de la v&iacute;a de retinoblastoma se raramente han detectado, incluso en estudios de secuenciaci&oacute;n del genoma. En este estudio, tomamos un vistazo m&aacute;s de cerca el papel de la v&iacute;a de retinoblastoma en dise&ntilde;o humano de Pan-NETs.EXPERIMENTAL: tumores de Pan-NET de 92 pacientes fueron sometidos a la coloraci&oacute;n immunohistochemical para marcadores de la v&iacute;a de retinoblastoma. Para buscar amplificaciones de genes v&iacute;a de retinoblastoma, ADN gen&oacute;mico de 26 tumores sometieron a an&aacute;lisis de n&uacute;mero de copia. Finalmente, se analiz&oacute; un activador de mol&eacute;culas peque&ntilde;as de la v&iacute;a de retinoblastoma efectos sobre el crecimiento de dos l&iacute;neas celulares de Pan-NET.Resultados: La mayor&iacute;a de los tumores expresa altas cantidades de Cdk4 o su socio de la prote&iacute;na ciclina D1. Altas cantidades de Rb1 fosforilada estaban presentes en los tumores que expresan altos niveles de Cdk4 o ciclina D1. Los n&uacute;meros de copia de Cdk4 o el gene de la cinasa an&aacute;loga Cdk6 aumentaron en 19% de los tumores. Crecimiento de la l&iacute;nea de c&eacute;lula humana de Pan-NET QGP1 fue inhibido en un modelo murino de xenoinjerto por el inhibidor de Cdk4/6, 0332991 PD, que reactiva la v&iacute;a de retinoblastoma.CONCLUSIONES: La inactivaci&oacute;n de la v&iacute;a de retinoblastoma fue indicada para redes Pan mayor&iacute;a. Amplificaci&oacute;n del gen y la sobreexpresi&oacute;n de Cdk4 y Cdk6 sugiere que los pacientes con Pan-redes pueden responder fuertemente a los inhibidores de Cdk4/6 que est&aacute;n entrando en ensayos cl&iacute;nicos. Clin Cancer Res; 1-9. &copy; 2012 AACR.

Atenuaci&oacute;n de la v&iacute;a de Retinoblastoma en tumores neuroendocrinos pancre&aacute;ticos debido a aumentado Cdk4/Cdk6.

Bcl-xL suppresses mitochondria-mediated apoptosis and is frequently overexpressed in cancer to promote cancer cell survival. Bcl-xL also promotes metastasis. However, it is unclear whether this metastatic function is dependent on its anti-apoptotic activity in the mitochondria. Here we demonstrate that Bcl-xL promotes metastasis independent of its anti-apoptotic activity. We show that apoptosis-defective Bcl-xL mutants and an engineered Bcl-xL targeted to the nucleus promote epithelial-mesenchymal transition, migration, invasion and stemness in pancreatic neuroendocrine tumour (panNET) and breast cancer cell lines. However, Bcl-xL proteins targeted to the mitochondria or outside of the nucleus do not have these functions. We confirm our findings in spontaneous and xenograft mouse models. Furthermore, Bcl-xL exerts metastatic function through epigenetic modification of the TGFβ promoter to increase TGFβ signalling. Consistent with these findings, we detect nuclear Bcl-xL in human metastatic panNETs. Taken together, the metastatic function of Bcl-xL is independent of its anti-apoptotic activity and its residence in the mitochondria.

Bcl-xL promotes metastasis independent of its anti-apoptotic activity.

The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various cancers, but its role in primary and metastatic non-small cell lung carcinoma (NSCLC) remains to be determined. Here, we investigate the clinical relevance of RHAMM expression in NSCLC. RHAMM protein expression correlates with histological differentiation stages and extent of the primary tumor (T stages) in 156 patients with primary NSCLC. Importantly, while focal RHAMM staining pattern is present in 57% of primary NSCLC, intense RHAMM protein expression is present in 96% of metastatic NSCLC cases. In a publicly available database, The Cancer Genome Atlas (TCGA), RHAMM mRNA expression is 12- and 10-fold higher in lung adenocarcinoma and squamous lung carcinoma than in matched normal lung tissues, respectively. RHAMM mRNA expression correlates with stages of differentiation and inferior survival in more than 400 cases of lung adenocarcinoma in the Director's Challenge cohort. Of 4 RHAMM splice variants, RHAMMv3 (also known as RHAMMB) is the dominant variant in NSCLC. Moreover, shRNA-mediated knockdown of RHAMM reduced the migratory ability of two lung adenocarcinoma cell lines, H1975 and H3255. Taken together, RHAMM, most likely RHAMMv3 (RHAMMB), can serve as a prognostic factor for lung adenocarcinomas and a potential therapeutic target in NSCLC to inhibit tumor migration.

Expression of the receptor for hyaluronic acid mediated motility (RHAMM) is associated with poor prognosis and metastasis in non-small cell lung carcinoma.

In human studies and mouse models, the contributions of p53 and p16(Ink4a)/p19(Arf) loss are well established in pancreatic ductal adenocarcinoma (PDAC). Although loss of functional p53 pathway and loss of Ink4a/Arf in human pancreatic acinar cell carcinoma (PACC) and pancreatic neuroendocrine tumor (PanNET) are identified, their direct roles in tumorigenesis of PACC and PanNET remain to be determined. Using transgenic mouse models expressing the viral oncogene polyoma middle T antigen (PyMT), we demonstrate that p53 loss in pancreatic Pdx1+ progenitor cells results in aggressive PACC, whereas Ink4a/Arf loss results in PanNETs. Concurrent loss of p53 and Ink4a/Arf resembles loss of p53 alone, suggesting that Ink4a/Arf loss has no additive effect to PACC progression. Our results show that specific tumor suppressor genotypes provocatively influence the tumor biological phenotypes in pancreatic progenitor cells. Additionally, in a mouse model of β-cell hyperplasia, we demonstrate that p53 and Ink4a/Arf play cooperative roles in constraining the progression of PanNETs.

Yi-Chieh Nancy Du

Department of Pathology and Laboratory Medicine

Weill Cornell Medicine

Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model

Yi-Chieh Nancy Du

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

Weill Cornell Medicine

Identification and Characterization of Metastatic Factors by Gene Transfer into the Novel RIP-Tag; RIP-tva Murine Model

Department of Pathology and Laboratory Medicine