CD74: a potential mediator of resistance in the treatment of Glioblastoma

CD74 is a rapidly internalised transmembrane protein, highly expressed in a number of cancers and is associated with increased proliferation and invasion of tumour cells. CD74 is an attractive biomarker to monitor tumour progression and predict overall survival as expression levels have shown to be increased on the cell surface. Recent studies have suggested CD74 plays a potential role in tumour cell response to treatment, showing direct correlation between expression and response. The overall survival of patients with glioblastoma is poor, as treatment options are limited and not well defined. The standard options for the majority of patients is a combination of surgical resection, radiation and chemotherapy. The aim of this study is to investigate the association between CD74 expression and response to radiation and chemotherapy. A panel of murine and human glioblastoma cells lines were analysed by RT-PCR and Western blotting to examine CD74 expression. Results indicated murine MC38 and B16 cell lines and human LN229 and U87MG cells expressed CD74 and using shRNA constructs, CD74 expression was successfully knocked-down in these lines to enable further study. Interrogation of these CD74-depleted lines indicated a significant reduction in proliferation and migration compared to a non-targeting control. Human glioblastoma cell lines LN229 and U87MG were exposed to increasing doses of radiation, the results indicated the survival fraction of CD74 deficient cells was greater than that of the non-targeting control, suggesting an association between CD74 expression and sensitivity to radiation therapy in glioblastoma cell lines. However, when the same cells were exposed to increasing doses of Temozolomide there was a decrease in survival fraction of CD74-depleted cells compared to non-targeting controls, which showed no response to treatment. This study aims to further investigate the mechanism by which these change in sensitivity to treatment are mediated and determine if CD74 could not only be used as a marker for tumour progression, but to determine the most appropriate treatment option for patients