Unique proteome signature of post-chemotherapy ovarian cancer ascites-derived tumor cells.

Nuzhat Ahmed,Ruth M Escalona,Maoshan Chen,Jock K Findlay,George Kannourakis,Chantel Samardzija,David Greening

doi:10.1038/srep30061

Abstract

Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients.

Highlights

In the past several years, studies have reported proteomic analyses of ascites fluid in an attempt to identify biomarkers for ovarian cancer[7,8,9]
As previously described[6], two distinct populations of cells were observed; (i) non-adherent cellular aggregates that floated as three-dimensional structures in the growth medium without attachment to the plates (Fig. 1A), and (ii) spindle shaped fibroblast-like single cells that adhered to the low attachment plates[5]
As described previously[5], high expression of cancer antigen 125 (CA125) and cytokeratin 7 (CK7) was observed in the cells dispersed from non-adherent spheroids, while no significant expression of fibroblast surface protein (FSP) was evident

Summary

Introduction

In the past several years, studies have reported proteomic analyses of ascites fluid in an attempt to identify biomarkers for ovarian cancer[7,8,9]. Isolated tumor cells in the ascites of cancer patients that have survived chemotherapy treatments and re-emerged as recurrent tumors are likely to experience in vivo proteome changes that would allow them to withstand the cytotoxic pressure of chemotherapy. Ascites were collected from patients at the time of surgery prior to chemotherapy treatment (CN) and at recurrence (CR) In this preliminary study, label-free quantitative proteomics was used to identify and monitor protein expression changes associated with chemoresistance and recurrence, utilising a set of unmatched CN (n = 4) and CR (n = 4) patient-derived samples. Our data identified novel and differentially expressed proteins and associated pathways which will provide better understanding of the intraperitoneal spread of recurrent ovarian cancer To our knowledge, this is the first study using comparative proteomic analysis to describe the unique protein signature between ascites-derived tumor cells from CN and CR patients

Methods

Results

Conclusion