Abstract
CD44, a surface marker for cancer stem cells, interacts with PKM2, a key regulator of aerobic glycolysis, and enhances the glycolytic phenotype of cancer cells leading to antioxidant protection and macromolecules’ synthesis. To clarify the clinical importance of this “cross-talk” as a mechanism of drug resistance, we assessed the expression both of PKM2 and of CD44 in cancer cells of patients with epithelial ovarian cancer (EOC) treated with platinum-based treatment. One hundred and seventy-one patients with EOC were assessed for PKM2mRNA expression and PKM2 and CD44 proteins detection. Associations with progression-free survival (PFS) and overall survival (OS) were assessed with Kaplan–Meier and adjusted Cox regression models. PKM2mRNA and protein as well as CD44 protein were detectable in the majority of patients. Positive correlation between PKM2 and CD44 protein expression was observed (Spearman rho = 0.2, p = 0.015). When we used the median to group patients into high versus low expression, high PKM2mRNA and protein levels were significantly associated with lower progression-free survival (PFS; p = 0.003 and p = 0.002, respectively) and shorter overall survival (OS; p ≤ 0.001 and p = 0.001, respectively). However, high CD44 protein expression was significantly correlated only with shorter OS (p = 0.004). Moreover, patients with both high PKM2 and CD44 protein levels experienced shorter PFS and OS (p = 0.007 and p = 0.003, respectively) compared to patients with low expression of both proteins. Finally, higher PKM2mRNA and protein expression as well as CD44 protein expression (HR: 2.16; HR: 1.82; HR: 1.01, respectively) were independent prognostic factors for decreased median OS (mOS), whereas only PKM2 protein expression (HR: 1.95) was an independent prognostic factor for decreased median PFS (mPFS). In conclusion, PKM2 expression is a negative prognostic factor in EOC patients, but the interaction between CD44 and PKM2 that may be implicated in EOC platinum-resistance needs further investigation.
Highlights
Ovarian cancer is the leading cause of death from gynecologic cancer in the developed world [1].High mortality rates can be attributed to the absence of symptoms at early stage and to the fact that more than 70% of patients present with advanced stage at the time of diagnosis [2,3]
We have recently investigated PKM2 and its potential predictive role in the outcome of non-small cell lung cancer (NSCLC) patients treated with cisplatin in first line setting
One hundred and eighty-seven specimens from patients with Epithelial ovarian cancer (EOC) were included in the study, but, 171 EOC formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed because only these patients had received front-line platinum-based treatment
Summary
Ovarian cancer is the leading cause of death from gynecologic cancer in the developed world [1]. High mortality rates can be attributed to the absence of symptoms at early stage and to the fact that more than 70% of patients present with advanced stage at the time of diagnosis [2,3]. Epithelial ovarian cancer (EOC) is the most common type, comprising 90% of all types of ovarian cancer. The standard treatment for EOC patients is cytoreductive surgery followed by platinum-based chemotherapy. Carboplatin in combination with paclitaxel is the standard of care that can improve overall survival of patients with previously untreated advanced ovarian cancer [4,5,6,7]. Despite advances made in first-line treatment options, the majority of patients will eventually relapse and develop resistance to platinum-based chemotherapy [2,8]
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