Análisis de la expresión génica relativa de las vías Notch, Wnt y Hedgehog en cancer stem cells en cáncer de pulmón no microcítico

Abstract

[ES] En Cáncer de Pulmón, la supervivencia global no supera el 15% a los cinco años. Incluso disponiendo de terapias individualizadas, la adquisición de resistencias a los tratamientos es una de las causas principales de su elevada mortalidad. Actualmente, se postula que las responsables de las recurrencias/ resistencias que ocurren en estos pacientes son las Células Madre Tumorales (CSCs). Por tanto, el objetivo de este proyecto es la identificación de marcadores de CSCs en muestras de cáncer de pulmón no-microcítico que nos permitan su aislamiento y la correlación con variables clínicopatológicas, y pronósticas de los pacientes. Además, a partir de las CSC aisladas realizaremos estudios de cribado farmacológico,con la finalidad de poder diseñar estrategias terapéuticas más racionales destinadas a lograr la eliminación de la población de CSCs, y poder trasladar nuestros hallazgos a la clínica con el fin de individualizar los tratamientos y mejorar el curso clínico de los pacientes afectado

[EN] Non-small cell lung cancer (NSCLC) presents a high incidence and mortality rates (1,4 millions of new cases per year and 1,6 millions of deaths annually). In spite of the efforts invested in research and de improvements of treatments, NSCLC still present a high recurrence rate. Nowadays it is believe that a small cell population found in tumor, cancer stem cells (CSC), are responsible of the resistance against treatments and the recurrence in NSCLC. CSC exhibit stem properties such as unlimited proliferation and self-renewal capacities, being capable of regenerate all tumor cell types. There are evidences of the important role in the proliferation and maintenance of CSC of some signaling pathways such as Notch, Wnt and Hedgehog. Therefore, the aim of this study is to analyze relative gene expression of Notch, Wnt and Hedgehog related genes, and also of several specific biomarkers of a CSC phenotype, in a cohort of resectable NSCLC in order to establish relationships between patient’s prognoses. So, 178 samples of tumor tissue and lung parenchyma were obtained from each patient. ARN isolated from those samples was used to perform expression analysis of 17 genes by real time PCR (RTqPCR). Statistical analysis demonstrate differences in expression levels between normal and tumor tissue in some genes: NOTCH3 (x2.24), WNT5A (x1.53), GLI1 (x1.75), SMO (x2.59), EPCAM1 (x1.51), SHH (x0.34) and ABCG2 (x0.23). Talking about the prognostic value, we have found that a major expression in tumor tissue of HEY1 and NOTCH1 (Notch’s related genes) is associated with a worse outcome. Moreover, the subgroup of patients who showed a high expression level of SMO and a lower expression level of PTCH1 (Hedgehog’s related genes) correlated also with a poor outcome. In addition, regarding our results, MYC and also CCND1 and WNT5A could be used as response biomarkers in the group of patients who received chemotherapy treatment after surgery. Multivariable analysis data revealed that HEY1, PTCH1 and MYC could be used as independent prognostic biomarkers. In conclusion, our results demonstrate the putative implication of the signaling pathways studied with de prognostic of NSCLC, opening the doors to the possibility of using some of the genes studied as biomarkers of this disease.