Multidrug resistance transporter profile reveals MDR3 as a marker for stratification of blastemal Wilms tumour patients.

Lourdes Hontecillas-Prieto,Enrique De Álava,Daniel J Garcia-Dominguez,Rosa Garcia-Mejias,Diego Pascual Vaca,Carmen Saez,Gema L Ramirez-Villar,David Marcilla

doi:10.18632/oncotarget.14491

Abstract

Wilms tumour (WT) is the most common renal tumour in children. Most WT patients respond to chemotherapy, but subsets of tumours develop resistance to chemotherapeutic agents, which is a major obstacle in their successful treatment. Multidrug resistance transporters play a crucial role in the development of resistance in cancer due to the efflux of anticancer agents out of cells. The aim of this study was to explore several human multidrug resistance transporters in 46 WT and 40 non-neoplastic control tissues (normal kidney) from patients selected after chemotherapy treatment SIOP 93–01, SIOP 2001. Our data showed that the majority of the studied multidrug resistance transporters were downregulated or unchanged between tumours and control tissues. However, BCRP1, MDR3 and MRP1 were upregulated in tumours versus control tissues. MDR3 and MRP1 overexpression correlated with high-risk tumours (SIOP classification) (p = 0.0022 and p < 0.0001, respectively) and the time of disease-free survival was significantly shorter in patients with high transcript levels of MDR3 (p = 0.0359). MDR3 and MRP1 play a role in drug resistance in WT treatment, probably by alteration of an unspecific drug excretion system. Besides, within the blastemal subtype, we observed patients with low MDR3 expression were significantly associated with a better outcome than patients with high MDR3 expression. We could define two types of blastemal WT associated with different disease outcomes, enabling the stratification of blastemal WT patients based on the expression levels of the multidrug resistance transporter MDR3.

Highlights

Wilms tumour (WT), called nephroblastoma, is an embryonal malignant neoplasm of the kidney accounting for 6–7% of all childhood cancers [1,2,3]
BCRP1, MDR3 and MRP1 were upregulated in tumours versus control tissues
We found that expression of BCRP1, MDR3 (Multidrug resistance 3) and MRP1 (Multidrug resistanceassociated protein 1) were significantly higher in WT patient samples than in control samples

Summary

Introduction

Wilms tumour (WT), called nephroblastoma, is an embryonal malignant neoplasm of the kidney accounting for 6–7% of all childhood cancers [1,2,3]. Children’s Oncology Group (COG) and the International Society of Paediatric Oncology (SIOP) are the two major groups which have great contributions in the management of WT Both develop two different approaches or protocols of the diagnosis and treatment www.impactjournals.com/oncotarget of WT [6, 8,9]. In Europe, SIOP delays nephrectomy 4–6 weeks favoring upfront chemotherapy and reducing complications of surgery and tumour spillage [3, 11]. Both collaborative groups have proven valuable in predicting outcomes and the different approaches of treatment have shown almost equivalent clinical outcomes [10, 12,13]

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