Molecular profiling of prostate cancer derived exosomes may reveal a predictive signature for response to docetaxel.

Pedram Kharaziha,Kjell Hultenby,Pedro Fonseca,Anders Ullén,Jeffrey Yachnin,Theocharis Panaretakis,Sten Nilsson,George Baltatzis,Alireza Azimi,Dorothea Rutishauser,Roman Zubarev,Lena Lennartsson,Dimitris Chioureas

doi:10.18632/oncotarget.3226

Abstract

Docetaxel is a cornerstone treatment for metastatic, castration resistant prostate cancer (CRPC) which remains a leading cause of cancer-related deaths, worldwide. The clinical usage of docetaxel has resulted in modest gains in survival, primarily due to the development of resistance. There are currently no clinical biomarkers available that predict whether a CRPC patient will respond or acquire resistance to this therapy. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting. Importantly, we identified MDR-1, MDR-3, Endophilin-A2 and PABP4 that were enriched only in DU145 Tax-Res exosomes. We validated the presence of these proteins in the serum of a small cohort of patients. DU145 cells that have uptaken DU145 Tax-Res exosomes show properties of increased matrix degradation. In summary, exosomes derived from DU145 Tax-Res cells may be a valuable source of biomarkers for response to therapy.

Highlights

Prostate cancer (PCa) is the most frequent malignancy in men in western countries and it is the second cause of cancer mortality
We have generated DU145 cells that are stably resistant to 500 ng/ml docetaxel and extracellular vesicles (EV) were isolated from DU145 sensitive (DU145 TaxSen) and resistant (DU145 Tax-Res) cell supernatants
Nanoparticle tracking analysis (NTA) of the isolated exosomes revealed that the DU145 Tax-Res cells secrete about 2 to 3 times higher amounts of EVs compared to the DU145 Tax-Sen ones (Figure 1B)

Summary

Introduction

Prostate cancer (PCa) is the most frequent malignancy in men in western countries and it is the second cause of cancer mortality. Comparative proteomics analysis of exosomes secreted from DU145 prostate cancer cells that are sensitive (DU145 Tax-Sen) or have acquired resistance (DU145 Tax-Res) to docetaxel, demonstrated significant differences in the amount of exosomes secreted and in their molecular composition. A panel of proteins was identified by proteomics to be differentially enriched in DU145 Tax-Res compared to DU145 Tax-Sen exosomes and was validated by western blotting.

Results

Conclusion