Open AccessALDH‐1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients
Author(s) -
Ajani J.A.,
Wang X.,
Song S.,
Suzuki A.,
Taketa T.,
Sudo K.,
Wadhwa R.,
Hofstetter W.L.,
Komaki R.,
Maru D.M.,
Lee J.H.,
Bhutani M.S.,
Weston B.,
Baladandayuthapani V.,
Yao Y.,
Honjo S.,
Scott A.W.,
Skinner H.D.,
Johnson R.L.,
Berry D.
Publication year - 2014
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1016/j.molonc.2013.10.007
Subject(s) - aldehyde dehydrogenase , medicine , univariate analysis , immunohistochemistry , cancer , esophageal cancer , oncology , cancer research , pathology , gastroenterology , biology , gene , multivariate analysis , biochemistry
Purpose Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase‐1 (ALDH‐1) could be associated with response. Methods The labeling indices (LIs) of ALDH‐1 by immunohistochemistry in untreated tumor specimens were established in EC patients who had chemoradiation and surgery. Univariate logistic regression and 3‐fold cross validation were carried out for the training (67% of patients) and validation (33%) sets. Non‐clinical experiments in EC cells were performed to generate complimentary data. Results Of 167 EC patients analyzed, 40 (24%) had a pathologic complete response (pathCR) and 27 (16%) had an extremely resistant (exCRTR) cancer. The median ALDH‐1 LI was 0.2 (range, 0.01–0.85). There was a significant association between pathCR and low ALDH‐1 LI (p ≤ 0.001; odds‐ratio [OR] = 0.432). The 3‐fold cross validation led to a concordance index (C‐index) of 0.798 for the fitted model. There was a significant association between exCRTR and high ALDH‐1 LI (p ≤ 0.001; OR = 3.782). The 3‐fold cross validation led to the C‐index of 0.960 for the fitted model. In several cell lines, higher ALDH‐1 LIs correlated with resistant/aggressive phenotype. Cells with induced chemotherapy resistance upregulated ALDH‐1 and resistance conferring genes (SOX9 and YAP1). Sorted ALDH‐1+ cells were more resistant and had an aggressive phenotype in tumor spheres than ALDH‐1− cells. Conclusions Our clinical and non‐clinical data demonstrate that ALDH‐1 LIs are predictive of response to therapy and further research could lead to individualized therapeutic strategies and novel therapeutic targets for EC patients.