Cancer stem cell-related marker expression in lung adenocarcinoma and relevance of histologic subtypes based on IASLC/ATS/ERS classification

Yoshihisa Shimada,¹ Hisashi Saji,³ Masaharu Nomura,^1,2 Jun Matsubayashi,² Koichi Yoshida,¹ Masatoshi Kakihana,¹ Naohiro Kajiwara,¹ Tatsuo Ohira,¹ Norihiko Ikeda<sup>1

1</sup>Department of Surgery I, ²Department of Anatomic Pathology, Tokyo Medical University Hospital, Tokyo, Japan; ³Department of Chest Surgery, St Marianna University School of Medicine, Kawasaki, Japan


Background: The cancer stem cell (CSC) theory has been proposed to explain tumor heterogeneity and the carcinogenesis of solid tumors. The aim of this study was to clarify the clinical role of CSC-related markers in patients with lung adenocarcinoma and to determine whether each CSC-related marker expression correlates with the histologic subtyping proposed by the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS), and the European Respiratory Society (ERS) classifications.
Methods: We reviewed data for all 103 patients in whom complete resection of adenocarcinoma had been performed. Expression of CSC-related markers, ie, aldehyde dehydrogenase 1A1 (ALDH1A1), aldo-keto reductase 1C family member 1 (AK1C1), and 1C family member 3 (AK1C3), was examined using immunostaining on whole-mount tissue slides, and the tumors were reclassified according to the IASLC/ATS/ERS classification.
Results: ALDH1A1 expression was observed in 66.0% of tumors, AK1C1 in 62.7%, and AK1C3 in 86.1%. Immunoreactivities with the frequency of mean expression of ALDH1A1 in papillary predominant adenocarcinoma were significantly higher than those of solid predominant adenocarcinoma (P<0.05). Papillary predominant adenocarcinoma had significantly lower expression of AK1C1 when compared with noninvasive or solid predominant adenocarcinomas (P<0.05). On multivariate analysis, larger tumor size (hazards ratio 1.899, P=0.044), lymph node metastasis (hazards ratio 2.702, P=0.005), and low expression of ALDH1A1 (hazards ratio 3.218, P<0.001) were shown to be independently associated with an unfavorable prognosis.
Conclusion: Immunohistochemistry of ALDH1A1 expression is strongly associated with prognosis. Expression of each CSC-related marker varies according to subtype, suggesting that a comprehensive histologic subtyping approach in the IASLC/ATS/ERS classification provides new molecular biology insights into the genesis of lung adenocarcinoma according to CSC theory.

Keywords: cancer stem cell marker, adenocarcinoma, ALDH1A1, AK1C1, AK1C3, prognosis