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ES2627011T3 - Variantes de corte y empalme específicas de metástasis de Mena y usos de las mismas en el diagnóstico, pronóstico y tratamiento de tumores - Google Patents

Variantes de corte y empalme específicas de metástasis de Mena y usos de las mismas en el diagnóstico, pronóstico y tratamiento de tumores Download PDF

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ES2627011T3
ES2627011T3 ES08713370.8T ES08713370T ES2627011T3 ES 2627011 T3 ES2627011 T3 ES 2627011T3 ES 08713370 T ES08713370 T ES 08713370T ES 2627011 T3 ES2627011 T3 ES 2627011T3
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mena
cells
tumors
seq
metastases
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John S. Condeelis
Sumanta Goswami
Frank Gertler
Paola Nistico
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Istituti Fisioterapici Ospitalieri IFO
Albert Einstein College of Medicine
Massachusetts Institute of Technology
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Abstract

Un método para determinar si un sujeto tiene un tumor metastásico, que comprende analizar una muestra de sangre, tejido y/o tumor del sujeto en busca de la expresión de la variante ++ y/o +++ de Mena, en el que la expresión de la variante ++ y/o +++ de Mena se compara con la expresión de Mena 11a, y en el que la sobreexpresión de la variante ++ y/o +++ de Mena indica la presencia de un tumor metastásico.

Description

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se llevó a cabo mediante el uso del programa informático ABI Prism 2.0 (Applied Biosystems, Foster City, CA). Se proporciona una estrategia para el diseño de las secuencias de los cebadores en la Figura 5.
RACE, Clonación y Secuenciación: El RACE de 3' y 5' se llevó a cabo mediante el uso del kit Invitrogen RACE Ready cDNA (las secuencias se proporcionan en la Tabla 1, y la estrategia de diseño de cebadores de RACE se proporciona en la Figura 5), y se clonaron mediante el uso del kit de clonación de Invitrogen TOPO TA, siguiendo el protocolo del fabricante. Brevemente, la PCR se llevó a cabo mediante el uso de dos cebadores internos para las secuencias ++ y +++ (Tabla 1) y un cebador de oligo dT para el extremo 5', y un cebador de poli G para el extremo 3'. Los productos de PCR se eluyeron del gel y se clonaron en el vector pCR-TOPO. El vector ligado se transformó en células químicamente competentes; los clones seleccionados se secuenciaron mediante el uso de cebadores M13. La alineación de secuencias se llevó a cabo mediante el uso del programa informático DNASTAR.
Tabla 1. Secuencias de Cebadores
Secuencias de cebadores de Mena
1.
AGAGGATGCCAATGTCTTCG (SEQ ID Nº:5)
2.
TGTCTAGGCAATGTTGGCC (SEQ ID Nº:6)
3.
GATTCAAGACCATCAGGTTGTG (SEQ ID Nº:7)
4.
CAATGTTGGCCCTAAATAGAA (SEQ ID Nº:8) d4. TTCTATTTAGGGCCAACATTG (SEQ ID Nº:9)
5.
TACATCGCAAATTAGTGCTGTC (SEQ ID Nº:10) d5. GACAGCACTAATTTGCGATGT (SEQ ID Nº:11)
6.
CCAACCAGAAAACCTTGGG (SEQ ID Nº:12)
7.
TGCTTCAGCCTCTCATAGTCA (SEQ ID Nº:13)
8.
GAGCGAGAGAGGCAGAG (SEQ ID Nº:14)
9.
GCTCGGAAGCAGAGGAGTCT (SEQ ID Nº:15) Cebador Pan Mena Directo: CGGCAGTAAGTCACCTGTCA (SEQ ID Nº:16) Inverso: CTTCAGCTTTGCCAGCTCTT (SEQ ID Nº:17) Cebadores Smart Oligonucleótido SMART II™ A AAGCAGTGGTATCAACGCAGAGTACGCGGG (SEQ ID Nº:18) Cebador A de CDS de 3'-RACE AAGCAGTGGTATCAACGCAGAGTAC (T) 30V N (SEQ ID Nº:19) (N = A, C, G, o T; V = A, G, o C) Cebador A de CDS de 5'-RACE (T) 25V N (SEQ ID Nº:20) (N = A, C, G, o T; V = A, G, o C) Largo: CTAATACGACTCACTATAGGGCAAGCAGTGGTATCAACGCAGAGT (SEQ ID Nº:21) Corto: CTAATACGACTCACTATAGGGC (SEQ ID Nº:22)
Resultados y Discusión
En este estudio se han identificado isoformas específicas de Mena que están elevadas en las células de cáncer de mama invasivo. Se utilizaron tres modelos en este informe, es decir, el modelo de aloinjerto de adenocarcinoma de ratas MTLn3, el modelo de cáncer de mama transgénico de ratones PyMT y varias líneas celulares de cáncer de mama humano. La expresión de Mena está elevada 3-4 veces en las células de cáncer de mama primarias invasivas (Wang et al., 2004). Los controles realizados para determinar los efectos de las manipulaciones usadas para recoger las células tumorales invasivas del tumor mamario primario demuestran que la expresión de la isoforma de invasión
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de Mena no se induce por la recogida de las células. Solamente el microambiente del tumor induce la expresión de estas isoformas. En este estudio se determinó la estabilidad de esta sobreexpresión, es decir, las células invasivas recogidas mediante un análisis de invasión in vivo mostraron una elevación de 3-4 veces de la expresión de Mena en comparación con APTCs. Por lo tanto, las células se siguieron y se separaron de la sangre y de la metástasis pulmonar. Mediante el uso del modelo MTLn3 y del modelo transgénico PyMT de ratón, se recogieron las células invasivas y se separaron mediante un análisis de invasión in vivo, y las APTCs mediante clasificación por FACS. El análisis mediante RT-PCR de las células invasivas mostró que hubo amplicones específicos de los exones ++ y +++ elevados en ambos modelos. También se detectó un amplicón específico para el exón +. Sin embargo, no mostró ningún cambio entre las células invasivas y las APTCs. Los estudios mediante QRT-PCR confirmaron el hallazgo de la RT-PCR, y mostraron una elevación de los exones ++ y +++ en las células invasivas para el modelo de MTLn3 (Figura 1A) y para el modelo de PyMT de ratón (Figura 1B). La Figura 2 muestra que la variante de corte y empalme ++ y +++ del ARN mensajero de Mena permanece elevada en las células que se han intravasado a la sangre y en las células que han formado metástasis eficaces en el pulmón. Esto indica que el cambio del nivel de expresión se debe a un cambio genético estable en las células metastásicas.
Los resultados de la RT-PCR y la QRT-PCR mostraron que ambos exones ++ y +++ están elevados en las células invasivas. Sin embargo, no estuvo claro si los exones están presentes en un único transcrito o en transcritos diferentes. Para abordar esta cuestión, se clonaron y se secuenciaron los transcritos que albergaban ++ y +++ de los tumores transgénicos de ratón PyMT invasivos. Se seleccionó el análisis RACE para identificar los transcritos que contenían los exones ++ y +++. Los resultados proporcionan una secuencia consenso de al menos 10 clones para cada transcrito. Los resultados muestran un 100% de coincidencia con las secuencias publicadas de ratón, y demostraron que los exones ++ y +++ están en transcritos diferentes. Las alineaciones para las secuencias ++ y +++ se muestran en la Figura 4.
Las Figuras 6 y 7 muestran que las dos variantes 2+ y 3+ permanecen elevadas a nivel de mARN en las células tumorales circulantes en la sangre, lo que hace posible un análisis de sangre para estas variantes. Así, se puede usar una PCR, sondas de ácidos nucleicos y/o tinción con anticuerpos para diagnosticar una enfermedad metastásica mediante el uso de una muestra de sangre.
Basándose en los datos de alineación de secuencias anteriores, una sonda molecular, ácido nucleico o anticuerpo, o ambos, hacia cada variante ++ o +++ proporcionaría una herramienta de diagnóstico/pronóstico importante. Debido a que la estimulación de la expresión de los exones ++ y +++ observada aquí es un cambio estable en las células tumorales mamarias invasivas y metastásicas, las sondas dirigidas de manera específica hacia estos exones serían marcadores de diagnóstico potentes con respecto a la presencia de células metastásicas, y por lo tanto con respecto a la posibilidad de enfermedad metastásica.
La Figura 8 muestra el aumento de la migración de células tumorales cuando se expresa Mena 3+. De manera importante, como se muestra en la Figura 9, la inhibición de la migración de células tumorales metastásicas se da cuando se inhibe Mena, en este caso mediante el uso de mito, una molécula que redirige a Mena hacia un lugar erróneo en la célula. Este resultado establece que la inhibición de la función de Mena inhibe la migración de las células metastásicas, y por lo tanto es una buena estrategia para inhibir la metástasis.
Todos los adenocarcinomas humanos derivan de órganos epiteliales que pueden compartir una estrategia morfogenética común a nivel molecular (Condeelis y Pollard, 2006; Wang et al., 2004, 2005). La característica distintiva de la invasión, de la que Mena 2+ y 3+ son isoformas de invasión, predice que se usa la misma estrategia morfogenética para la morfogénesis normal de órganos y la metástasis tumoral. Esto sugiere que Mena 2+ y 3+ serán objetivos útiles para el diagnóstico y la terapia de todos los adenocarcinomas comunes en seres humanos adultos. En particular, la invención descrita en la presente memoria será aplicable a tumores tales como tumores de mama, próstata, páncreas, colon, cerebro e hígado.
Referencias
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Brinkman BM. Splice variants as cancer biomarkers. Clin Biochem. julio de 2004; 37(7):584-94.
Condeelis y Pollard (2006) Macrophages: Obligate partners for tumor cell migration, invasion, and metastasis. Cell
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Condeelis J, Singer RH, Segall JE. The great escape: when cancer cells hijack the genes for chemotaxis and motility. Annu Rev Cell Dev Biol. 2005;21: 695-718.
Di Modugno F, Bronzi G, Scanlan MJ et al. Human Mena protein, a serex-defined antigen overexpressed in breast cancer eliciting both humoral and CD8+ T-cell immune response. Int J Cancer. 10 de mayo de 2004; 109(6):909-18.
Gertler FB, Niebuhr K, Reinhard M et al. Mena, a relative of VASP and Drosophila Enabled, is implicated in the control of microfilament dynamics. Cell. 18 de oct. de 1996; 87(2):227-39.
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Kamai T, Tsujii T, Arai K, Takagi K, Asami H, Ito Y, Oshima H. Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res. julio de 2003; 9(7):2632-41.
Kuhnel K, Jarchau T, Wolf E et al. The VASP tetramerization domain is a right-handed coiled coil based on a 15residue repeat. Proc Natl Acad Sci USA. 7 de dic. de 2004; 101(49):17027-32.
5 Loureiro JJ, Rubinson DA, Bear JE et al. Critical roles of phosphorylation and actin binding motifs, but not the central proline-rich region, for Ena/vasodilator-stimulated phosphoprotein (VASP) function during cell migration. Mol Biol Cell. julio de 2002; 13 (7):2533-46.
Otsubo T, Iwaya K, Mukai Y, Mizokami Y, Serizawa H, Matsuoka T, Mukai K. Involvement of Arp2/3 complex in the process of colorectal carcinogenesis. Mod Pathol. abril de 2004; 17(4):461-7.
10 Prehoda KE, Lee DJ, Lim WA. Structure of the enabled/VASP homology 1 domain-peptide complex: a key component in the spatial control of actin assembly. Cell. 14 de mayo de 1999; 97(4):471-80.
Sambrook J y Russell DW. Molecular Cloning. A Laboratory Manual, tercera edición, Cold Spring Harbor Laboratory Press, 2001.
Scott JA, Shewan AM, den Elzen NR et al. Ena/VASP proteins can regulate distinct modes of actin organization at 15 cadherin-adhesive contacts. Mol Biol Cell. marzo de 2006; 17(3):1085-95.
Urbanelli L, Massini C, Emiliani C et al. Characterization of human Enah gene. Biochim Biophys Acta. ene.-feb. de 2006; 1759(1-2):99-107.
Venables JP. Unbalanced alternative splicing and its significance in cancer. Bioessays. abril de 2006; 28(4):378-86.
Wang W, Goswami S, Lapidus K, et al. Identification and testing of a gene expression signature of invasive 20 carcinoma cells within primary mammary tumors. Cancer Res. 1 de dic. de 2004; 64(23):8585-94.
Wang, Goswami, Sahai, Wyckoff, Segall, Condeelis (2005) Tumor Cells caught in the act of invading: their strategy for enhanced cell motility. Trends Cell Biol. 15:138-145.
Wang W, Mouneimne G, Sidani M et al., The activity status of cofilin is directly related to invasion, intravasation, and metastasis of mammary tumors. J Cell Biol. 8 de mayo de 2006; 173(3):395-404.
25 Wyckoff JB, Segall JE, Condeelis JS. The collection of the motile population of cells from a living tumor. Cancer Res. 1 de oct. de 2000; 60(19):5401-4.
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