Análisis de la expresión de CXCR3 y su ligando CXCL10 en cáncer papilar de tiroides
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Fecha
2010
Autores
Bohmwald Prieto, Karen
Profesor/a Guía
Facultad/escuela
Idioma
es
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Editor
Universidad Andrés Bello
Nombre de Curso
Licencia CC
Licencia CC
Resumen
El cáncer de tiroides es la patología más común del sistema endocrino y el cáncer
papilar de tiroides (CPT) es la manifestación más frecuente, dentro del cáncer tiroideo, con
una incidencia entre el 75 al 80%. Si bien el CPT presenta un crecimiento lento y los
pacientes que lo padecen tienen una alta sobrevida, éste presenta una alta frecuencia de
metástasis a los nódulos linfáticos cervicales, característica que lo sitúa en un tipo de cáncer
agresivo. Los factores moleculares involucrados en los procesos que conllevan a la
metástasis del CPT a los nódulos linfáticos, se desconocen. Se ha propuesto que existen
moléculas con capacidad quimioatractante, que estarían involucradas en conferir la
capacidad proliferativa, migratoria e invasiva de las células tumorales hacia los nódulos
linfáticos. Existen evidencias que sugieren a las quimioquinas y sus receptores, como
aquellas señales específicas en el proceso de metástasis. Entre estas moléculas se
encuentran el receptor CXCR3 y su quimioquina CXCL10. Se ha demostrado que CXCR3
y CXCL10 participarían en metástasis a los nódulos linfáticos en cáncer de colon y de
mama. Estudios recientes muestran que tanto CXCR3 y CXCL10 se encuentran presentes
en el infiltrado linfocitario en enfermedades inflamatorias de la tiroides. Con estos
antecedentes planteo la siguiente hipótesis: "El receptor de quimioquinas CXCR3 y su
quimioquina CXCL10, se encuentran sobreexpresados en el CPT. Éste aumento en la
expresión se correlacionaría con factores clínicos de agresividad tumoral ". Para evaluar
esta hipótesis se analizó, mediante PCR en tiempo real, el contenido de ARNrn de CXCR3
en muestras de CPT y tejido control correspondiente a la zona contralateral al tumor
.Mediante inmunohistoquírnica se analizó el contenido y localización de las proteínas
CXCR3 y CXCL10 en muestras control y con CPT. Se realizó un estudio de correlación
entre los parámetros clínicos de agresividad y el contenido de CXCR3. Finalmente se
evaluó, en una línea celular de CPT llamada TPC-1, el rol de CXCR3 y CXCL10 en la
proliferación tumoral. Los resultados de esta tesis, apoyan parte de nuestra hipótesis,
debido a que indican que el ARNm de CXCR3 aumenta 1 ,5 veces en CPT en comparación
al tejido control. Este resultado se correlacionó con el aumento del 20% del contenido de
CXCR3 y CXCL10 en muestras con CPT en comparación al tejido control. Los parámetros
clínicos de agresividad no mostraron relación con respecto al contenido de CXCR3.
CXCL10 no estimuló la proliferación de las células TPC-1 a las 24 hrs. de incubación en
forma significativa. Basado en estos hallazgos, podemos concluir que en el CPT hay un
aumento en la expresión de CXCR3 y su ligando CXCL10. La expresión aumentada de
CXCL10 muestra una tendencia a conferir a las células de CPT una mayor capacidad de
proliferación, proceso que es de gran importancia en la progresión tumoral.
Thyroid cancer is the most common pathology of the endocrine system and the papillary thyroid cancer (PTC) it's the most frequent type of Cancer with an incidence of 75 to 80%. Even though, that PTC has a low growth and the patients that suffer PTC have high survival this type of PTC has a high tendency to develop cervical lymph node metastases. This features makes this type of cancer an aggressive one. The molecular players involved in the processes that lead to metastasis of PTC to the lymph nodes are unknown. It has been proposed that molecules with chemoattractant capacity, could confer to tumor cells the proliferative, migratory and invasive capacity to make metastasis to the lymph nodes. There are evidences in the literature that support that chemokines and their receptors could play this role in metastasis. It has been shown that in colon and breast cancer the receptor CXCR3 and its ligand CXCL10 participate in the metastasis to the lymph nodes. Recent studies have shown that both CXCR3 and CXCL10 are present in the infiltrating lymphocytes in inflammatory diseases of the thyroid gland. Base on this evidences I propose the following hypothesis: "The chemokine receptor CXCR3 and its chemokine CXCL10, are overexpressed in PTC. This overexpression would correlate with clinical factors of tumor aggressiveness ". To test this hypothesis we analyzed by real time PCR the content of CXCR3 mRNA in PTC and control samples that are from the contralateral of side of the tumor tissue from patients with PTC. Immunohistochemistry analysis was done control and PTC samples to study the localization and content of CXCR3 and CXCL10. A correlation analysis was done among the content of CXCR3 in PTC and clinical parameters of aggressiveness. Finally, the role of CXCR3 and CXCL10 in tumor proliferation was evaluted in vitro in the PTC cell line named TPC-I. An increase of 1.5 times CXCR3 mRNA in samples with PTC compared with control tissue. This result correlates with the 20% higher expression of CXCR3 and CXCL10 proteins in PTC compared with control samples. This results support our hypothesis. The clinical parameters of aggressiveness did not correlate with CXCR3 content in PTC. CXCL10 did not increased the proliferation of TPC-I cells at 24 hrs of incubation significantly. Based on these findings, we conclude that exist an increase in the expression of CXCR3 and its ligand CXCL10 in CPT . The increased expression of CXCL10 in CPT has a tendency to confer to CPT the capacity of proliferate, a process that is of great importance in tumor progression.
Thyroid cancer is the most common pathology of the endocrine system and the papillary thyroid cancer (PTC) it's the most frequent type of Cancer with an incidence of 75 to 80%. Even though, that PTC has a low growth and the patients that suffer PTC have high survival this type of PTC has a high tendency to develop cervical lymph node metastases. This features makes this type of cancer an aggressive one. The molecular players involved in the processes that lead to metastasis of PTC to the lymph nodes are unknown. It has been proposed that molecules with chemoattractant capacity, could confer to tumor cells the proliferative, migratory and invasive capacity to make metastasis to the lymph nodes. There are evidences in the literature that support that chemokines and their receptors could play this role in metastasis. It has been shown that in colon and breast cancer the receptor CXCR3 and its ligand CXCL10 participate in the metastasis to the lymph nodes. Recent studies have shown that both CXCR3 and CXCL10 are present in the infiltrating lymphocytes in inflammatory diseases of the thyroid gland. Base on this evidences I propose the following hypothesis: "The chemokine receptor CXCR3 and its chemokine CXCL10, are overexpressed in PTC. This overexpression would correlate with clinical factors of tumor aggressiveness ". To test this hypothesis we analyzed by real time PCR the content of CXCR3 mRNA in PTC and control samples that are from the contralateral of side of the tumor tissue from patients with PTC. Immunohistochemistry analysis was done control and PTC samples to study the localization and content of CXCR3 and CXCL10. A correlation analysis was done among the content of CXCR3 in PTC and clinical parameters of aggressiveness. Finally, the role of CXCR3 and CXCL10 in tumor proliferation was evaluted in vitro in the PTC cell line named TPC-I. An increase of 1.5 times CXCR3 mRNA in samples with PTC compared with control tissue. This result correlates with the 20% higher expression of CXCR3 and CXCL10 proteins in PTC compared with control samples. This results support our hypothesis. The clinical parameters of aggressiveness did not correlate with CXCR3 content in PTC. CXCL10 did not increased the proliferation of TPC-I cells at 24 hrs of incubation significantly. Based on these findings, we conclude that exist an increase in the expression of CXCR3 and its ligand CXCL10 in CPT . The increased expression of CXCL10 in CPT has a tendency to confer to CPT the capacity of proliferate, a process that is of great importance in tumor progression.
Notas
Tesis (Bioquímico, Magíster en Bioquímica)
Esta tesis se realizó en el laboratorio de Biología Celular y Farmacología de la Universidad Andrés Bello y fue financiada por el proyecto CONSORCIO TECNÓLOGICO EN BIOMEDICINA CTU06 ÁREA 2
Esta tesis se realizó en el laboratorio de Biología Celular y Farmacología de la Universidad Andrés Bello y fue financiada por el proyecto CONSORCIO TECNÓLOGICO EN BIOMEDICINA CTU06 ÁREA 2
Palabras clave
Cáncer de Tiroides, Receptor CXCR3, Quimiocinas