Acquisition of tumorigenic potential and enhancement of angiogenesis in pulmonary stem/progenitor cells through Oct-4 hyperexpression

// Sing-Yi Gu 1, 2 , Choa-Chi Ho 3 , Yung-Kang Huang 2 , Huei-Wen Chen 1 , Yu-Chi Wang 2 , Chia-Yu Kuo 2 , Shu-Chun Teng 4 , Wen-Mei Fu 2 , Pan-Chyr Yang 3 , Cheng-Wen Wu 5 , Fu-Chuo Peng 1 , Thai-Yen Ling 2, 6 1 Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan 2 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan 3 Department of Internal Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan 4 Department of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan 5 Institute of Biomedical Science, Academia Sinica, Taipei, Taiwan 6 Research Center for Developmental Biology and Regenerative Medicine, National Taiwan University, Taipei, Taiwan Correspondence to: Thai-Yen Ling, e-mail: tyling@ntu.edu.tw Fu-Chuo Peng, e-mail: fcpeng@ntu.edu.tw Keywords: pulmonary stem/progenitor cells, cancer initiating cells, Oct-4, angiogenesis, angiopoietins/Tie2 Received: November 01, 2015      Accepted: January 28, 2016      Published: February 9, 2016 ABSTRACT Cancer stem cells, also known as cancer initiating cells (CICs), are considered to be responsible for tumor growth and chemoresistance. Different hypotheses have been proposed to explain the origin of CICs, including mutations in adult stem/progenitor cells or the acquisition of stem-like characteristics in differentiated cells; however, studies have yielded conflicting identification for CICs and have little information for the origin to generate CICs. Part of the difficulty in identifying CICs may stem from the fact that the CICs studied have been largely derived from cancer cell lines or well-developed tumors. In previous studies, we have reported the enrichment of mouse pulmonary stem/progenitor cells (mPSCs) by using serum-free primary selection culture followed by FACS isolation using the coxsackievirus/adenovirus receptor (CAR) as the positive selection marker. Here, we demonstrated that overexpression of the pluripotent transcription factor Oct-4 is sufficient to induce CAR + /mPSCs transformation, which we name CAR + /mPSCs Oct-4_hi . These transformed cells possess cancer initiating and chemoresistance potential, as well as exhibiting remarkable expression of certain proangiogenic factors, including angiopoietins (ANGs) and VEGF, and enhanced angiogenic potential. Moreover, CAR + /mPSCs Oct-4_hi actively participated in tumor blood vessel formation and triggered a novel angiogenic mechanism, the angiopoietins/Tie2 signaling pathway. These study provide critical evidence supporting the possible origin to generate CICs, and help elucidate the pathways responsible for CICs-mediated blood vessel formation.