Abstract
BackgroundNeoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer. However, response to radiochemotherapy varies widely. Proton pump inhibitors (PPIs) have been demonstrated to impact on chemotherapy in a variety of other cancers. We analyzed the impact of PPI treatment on esophageal cancer cell lines, and investigated mechanisms that mediate the effect of PPI treatment in this tumour.MethodsWe investigated the effect of esomeprazole treatment on cancer cell survival, adhesion, migration and chemotherapy in human adeno-(OE19) and squamous-cell-carcinoma (KYSE410) cell lines. Furthermore, we investigated the effect of PPI treatment on intra-/extracellular pH and on expression of resistance-relevant miRNAs.ResultsEsomeprazole significantly inhibited tumour cell survival (in a dose-dependent manner), adhesion and migration in both tumour subtypes. Furthermore, esomeprazole augmented the cytotoxic effect of cisplatin and 5-FU in both tumour subtypes. Surprisingly, PPI treatment led to a significant increase of intracellular pH and a decrease of the extracellular pH. Finally, we found esomeprazole affected expression of resistance-relevant miRNAs. Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types.ConclusionOur study demonstrates for the first time that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapy in esophageal cancer cell lines. Furthermore, we observed that in this tumour entity, PPIs do not lead to intracellular acidification, but affect the expression of resistance-relevant miRNAs.
Highlights
Neoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer
Esomeprazole suppresses the metastatic potential of esophageal cancer cell lines Adhesion and migration are key determinants of the ability of tumour cells to metastasize into distant organs, as metastasis includes invasion of circulating tumour cells into distant organs where the tumour cells have to adhere and migrate through the endothelium of the vessels
Our results demonstrate for the first time that pump inhibitors (PPIs) such as esomeprazole have an effect on tumour cell survival, metastatic potential and sensitivity towards different chemotherapeutics in esophageal cancer cell lines, as has previously been reported in other tumour entities
Summary
Neoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer. Despite improvements in the management of esophageal cancer patients, the general outcome remains very poor for both histological subtypes, with an overall 5-year survival of approximately 10% and a 5year post-esophagectomy survival rate of approximately. In an attempt to improve outcome of patients after surgery, and to potentially increase the number of patients who qualify for surgery by reducing the size of the primary tumour, neoadjuvant therapy is used. Several recent meta-analyses have demonstrated the potential of neoadjuvant therapy in advancing overall survival for both histological subtypes, for therapy responders. In un-resectable disease, chemotherapy and irradiation showed good results, with complete tumour regression in up to 50% of patients and partial response in approximately 25% of patients. Cisplatin- and 5-fluorouracil (5-FU)-based chemotherapy in combination with irradiation has become part of standard treatment in neoadjuvant, definitive and palliative settings in most parts of the world [10,11,12]
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