Protein expression profiling in esophageal adenocarcinoma patients indicates association of heat-shock protein 27 expression and chemotherapy response.
OBJECTIVE
To identify pretherapeutic predictive biomarkers in tumor biopsies of patients with locally advanced esophageal adenocarcinomas treated with neoadjuvant chemotherapy, we used an explorative proteomic approach to correlate pretherapeutic protein expression profiles with tumor response to neoadjuvant chemotherapy.


METHODS
Thirty-four patients with locally advanced esophageal adenocarcinomas who received neoadjuvant platin/5-fluorouracil-based chemotherapy before surgical resection were enrolled in this study. Response to chemotherapy was determined (a) by the amount of decline of [18F]fluorodeoxyglucose tumor uptake 2 weeks after the start of chemotherapy measured by positron emission tomography and (b) by histopathologic evaluation of tumor regression after surgical resection. Explorative quantitative and qualitative protein expression analysis was done through a quantitative differential protein expression analysis that used dual-isotope radioactive labeling of protein extracts. Selected identified biomarkers were validated by immunohistochemistry and quantitative real time reverse transcription-PCR.


RESULTS
Proteomic analysis revealed four cellular stress response-associated proteins [heat-shock protein (HSP) 27, HSP60, glucose-regulated protein (GRP) 94, GRP78] and a number of cytoskeletal proteins whose pretherapeutic abundance was significantly different (P < 0.001) between responders and nonresponders. Immunohistochemistry and gene expression analysis confirmed these data, showing a significant association between low HSP27 expression and nonresponse to neoadjuvant chemotherapy (P = 0.049 and P = 0.032, respectively).


CONCLUSIONS
Albeit preliminary, our encouraging data suggest that protein expression profiling may distinguish cancers with a different response to chemotherapy. Our results suggest that response to chemotherapy may be related to a different activation of stress response and inflammatory biology in general. Moreover, the potential of HSPs and GRPs as biomarkers of chemotherapy response warrants further validation.
Langer
Rupert
R
Institute of Pathology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany. rupert.langer@lrz.tu-muenchen.de
Ott
Katja
K
Specht
Katja
K
Becker
Karen
K
Lordick
Florian
F
Burian
Maria
M
Herrmann
Ken
K
Schrattenholz
Andre
A
Cahill
Michael A
MA
Schwaiger
Markus
M
Hofler
Heinz
H
Wester
Hans-Jurgen
HJ
D000230:Adenocarcinoma / Q000737:chemistry* / Q000188:drug therapy; D000328:Adult; D000368:Aged; D000091342:Endoplasmic Reticulum Chaperone BiP; D004938:Esophageal Neoplasms / Q000737:chemistry* / Q000188:drug therapy; D005260:Female; D020869:Gene Expression Profiling; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis* / Q000235:genetics; D006360:Heat-Shock Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D008875:Middle Aged; D018832:Molecular Chaperones / Q000032:analysis / Q000235:genetics; D040901:Proteomics
D000091342:Endoplasmic Reticulum Chaperone BiP; D055551:HSP27 Heat-Shock Proteins; C000717247:HSPA5 protein, human; C057725:HSPB1 protein, human; D006360:Heat-Shock Proteins; D008562:Membrane Glycoproteins; D018832:Molecular Chaperones; C053387:endoplasmin