RESUMEN
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response (AU9
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Asunto(s)
Humanos , Masculino , Femenino , Glioblastoma/diagnóstico , Glioblastoma/radioterapia , Fosfohidrolasa PTEN/administración & dosificación , Fosfohidrolasa PTEN/análisis , Biomarcadores/análisis , Biomarcadores de Tumor/análisis , Quimioradioterapia Adyuvante/métodos , Fosfohidrolasa PTEN/efectos de la radiación , Tolerancia a Radiación/efectos de la radiación , Fosfatidilinositol 4,5-Difosfato/análisis , Fosfatidilinositol 4,5-Difosfato/efectos de la radiación , Adenosina Difosfato Ribosa/análisis , Adenosina Difosfato Ribosa/efectos de la radiaciónRESUMEN
Glioblastoma (GBM) is fatal. The standard radiotherapy and chemotherapy (temozolomide) followed by an adjuvant phase of temozolomide provide patients with, on average, a 2.5 months benefit. New treatments that can improve sensitivity to the standard treatment are urgently needed. Herein, we review the mechanisms and utility of poly (ADP-ribose) polymerase inhibitors in combination with radiation therapy as a treatment option for GBM patients and the role of phosphatase and tensin homologue mutations as a biomarker of response.
Asunto(s)
Neoplasias Encefálicas/genética , Quimioradioterapia , Glioblastoma/genética , Mutación/genética , Fosfohidrolasa PTEN/genética , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Humanos , PronósticoRESUMEN
OBJECTIVE: Aberrant Wnt signalling has previously been associated with gynaecological cancers, and the aim of this study was to investigate the expression of Wnt5a in epithelial ovarian cancer, and clarify its role in activating or inhibiting ß-catenin dependent and independent Wnt signalling pathways. METHOD: Wnt5a expression was investigated in a large cohort of epithelial ovarian cancer patient samples using immunohistochemistry and correlated with clinicopathological variables. Wnt5a function was investigated in vitro in ovarian cell lines. RESULTS: Wnt5a expression was found to be upregulated in all major subtypes (serous, endometrioid, clear cell and mucinous) of epithelial ovarian cancer compared to borderline tumours and benign controls. Treatment of ovarian surface epithelial cells with recombinant Wnt5a decreased cell adhesion and was associated with increased epithelial to mesenchymal transition (EMT). In addition, downstream targets of ß-catenin dependent Wnt signalling were inhibited, and ß-catenin independent targets increased following Wnt5a upregulation. Knockdown of Wnt5a in ovarian cancer cells was associated with a mesenchymal to epithelial transition (MET), but had no significant effect on cell migration or proliferation. CONCLUSION: This study adds to the increasing evidence that Wnt signalling may play an important role in ovarian cancer development. Utilising an unparalleled large cohort of 623 patients, Wnt5a protein expression was shown to be significantly higher in ovarian cancer patients when compared to benign and borderline ovarian tumours and healthy control patients. In addition, we have utilised in vitro models to show for the first time in ovarian cancer that Wnt5a driven non-canonical pathways can alter epithelial to mesenchymal transition (EMT).
