AbstractBackground and ObjectivesLung cancer is one of the leading causes of cancer‐related deaths in the world. Although the origin still remains to be resolved, a prevailing hypothesis implies the involvement of cancer stem cells (CSCs) responsible for tumor initiation, maintenance, and progression. Embryonic stem cell marker, OCT4, encoding the spliced variants OCT4A and OCT4B, has recently been shown to have a dual role; as a potential adult stem cell marker and as a CSC marker in germline and somatic tumors.MethodsWe investigated the expression and intracellular distribution of OCT4A and OCT4B using flow cytometry, Western blot and quantitative RT‐PCR analyses in normal and lung adenocarcinoma cell lines, primary cultures and tissue biopsies.ResultsWe demonstrate for the presence of rare OCT4A+ and OCT4B+ cells in normal lung. Notably, we observed higher levels of expression and atypical cytoplasmic distribution of OCT4A and not OCT4B, in the malignant setting, strongly indicating an oncogenic role in lung adenocarcinoma.ConclusionsWe postulate that OCT4A+ cells are involved in the oncogenesis of lung adenocarcinoma. Identification of these cells and the biological processes vital for their subsistence, will guide the development of diagnostic and therapeutic clinical approaches with the goal of eliminating lung adenocarcinoma. J. Surg. Oncol. 2010;102:689–698. © 2010 Wiley‐Liss, Inc.