Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria

Aichler, Michaela; Elsner, Mareike; Ludyga, Natalie; Feuchtinger, Annette; Zangen, Verena; Maier, Stefan K.; Balluff, Benjamin; Schöne, Cédrik; Hierber, Ludwig; Braselmann, Herbert; Meding, Stephan; Rauser, Sandra; Zischka, Hans; Aubele, Michaela; Schmitt, Manfred; Feith, Marcus; Hauck, Stefanie M; Ueffing, Marius; Langer, Rupert; Kuster, Bernhard; ... (2013). Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria. Journal of pathology, 230(4), pp. 410-419. Wiley 10.1002/path.4199

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Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pretherapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Pathology
UniBE Contributor:	Langer, Rupert
Subjects:	500 Science > 570 Life sciences; biology 600 Technology > 610 Medicine & health
ISSN:	0022-3417
Publisher:	Wiley
Language:	English
Submitter:	Andrea Arnold
Date Deposited:	02 Apr 2014 16:22
Last Modified:	05 Dec 2022 14:31
Publisher DOI:	10.1002/path.4199
PubMed ID:	23592244
Uncontrolled Keywords:	COX7A2, MALDI imaging mass spectrometry, chemotherapy, oesophageal adenocarcinoma, tumour response
URI:	https://boris.unibe.ch/id/eprint/45920