Detection of oesophageal cancer biomarkers by plasma proteomic profiling of human cell line xenografts in response to chemotherapy

Abstract

Background:The incidence of oesophageal adenocarcinoma is increasing worldwide but survival remains poor. Neoadjuvant chemotherapy may improve survival, but targeting treatment to patients who respond to chemotherapy could be improved by the availability of markers of response. This study sought proteomic markers of therapeutic response using an adenocarcinoma xenograft model.Methods:Epirubicin, cisplatin or 5-fluorouracil was administered to severe combined immune-deficient mice bearing OE19 oesophageal adenocarcinoma xenografts. Murine plasma samples from treated and untreated xenografts were analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectroscopy, and panels of peaks were found using class prediction models that distinguished treatment groups. Proteins in these peaks were identified by mass spectroscopy in tryptic digests of purified fractions. Five paired samples from oesophageal cancer patients before and after chemotherapy were analysed using the same methodology.Results:Plasma protein peaks were identified that differed significantly (P<0.05, ANOVA) between the treated xenograft and control groups. Marker panels predicted treated vs untreated xenografts with sensitivities of 100%, specificities of 86–100% and test efficiencies of 89–100%. Three of the proteins identified in these panels, apolipoprotein A-I, serum amyloid A and transthyretin were confirmed in the clinical samples.Conclusion:Plasma protein markers can be detected in response to chemotherapy in oesophageal adenocarcinoma xenografts and in clinical samples, and have the potential to monitor response and guide chemotherapy in oesophageal adenocarcinoma.

Current advances in esophageal cancer proteomics

“…Apolipoprotein A-I, serum amyloid A, and transthyretin in pre-treatment plasma samples were found to be associated with disease-free survival and overall survival. The authors also reported the correlation of these three proteins with response to chemotherapy in a mouse xenograft model [55]. These data suggest that plasma apolipoprotein A-I, serum amyloid A, and transthyretin are promising candidate prognostic biomarkers that should be validated in EC clinical studies.…”

“…Plasma protein profiling in mice with OE19 EAC xenografts that were treated with clinically relevant chemotherapeutic agents epirubicin, cisplatin, or 5-fluorouracil resulted in the identification of apolipoprotein A-1, serum amyloid A, and transthyretin as candidate biomarkers of response to chemotherapy [55]. However, although the results were confirmed in clinical samples, the number of patients with evident pathological response was relatively small; the biomarker pattern could not be compared with other indicators of clinical response and required further validation.…”

Proteomics for identifying mechanisms and biomarkers of drug resistance in cancer

“…To search serum predictive biomarkers for therapeutic response of esophageal adenocarcinoma, proteomes of serum samples from esophageal adenocarcinoma xenografts with chemotherapy (epirubicin, cisplatin or 5-fluorouracil) and controls were analyzed by SELD-TOF MS. A panel of biomarkers predicted treated vs untreated xenografts with sensitivities of 100%, specificities of 86-100% and test efficiencies of 89-100%. Among those biomarkers, apolipoprotein A-I, serum amyloid A (SAA) and transthyretin were confirmed in the clinical samples, and have the potential to monitor response and guide chemotherapy in esophageal adenocarcinoma [50]. Nasopharyngeal cancer (NPC) relapse occurs frequently after therapy.…”

Identification of the up-regulation of TP-alpha, collagen alpha-1(VI) chain, and S100A9 in esophageal squamous cell carcinoma by a proteomic method

“…The discovery of new markers for distinguishing normal cells from tumorous ones is critical for early detection and may yield potential biomarkers for understanding tumor formation and ESCC progression. High-throughput and high-sensitivity proteomics technology provides an effective approach for screening novel cancerspecific biomarkers [9][10][11]. The technique is based on differential isotopic labeling of proteins or peptides and is derived from two cell states (e.g., healthy and tumor cells) with either light or heavy tags.…”