Affiliations 

  • 1 Department of Basic Medicine, Tsinghua University
  • 2 Tsinghua University
  • 3 Department of Thoracic Surgery, Peking Union Medical College Hospital
  • 4 Medical Microbiology, University Malaya
  • 5 Department of Cancer Biotherapy Center, The Third Affiliated Hospital of Kunming Medical University (Tumor Hospital of Yunnan Province)
  • 6 Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences
  • 7 Department of Thoracic Surgery, China-Japan Friendship Hospital
  • 8 Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute
  • 9 Fudan University
  • 10 Pharmacology, Nanjing Medical University
  • 11 Department of Basic Medicine, Tsinghua University weiguo@tsinghua.edu.cn
Cancer Res, 2017 Apr 17.
PMID: 28416482 DOI: 10.1158/0008-5472.CAN-16-1633

Abstract

Cancer stem-like cells (CSC) are thought to drive tumor initiation, metastasis, relapse and therapeutic resistance, but their specific pathogenic characters in many cancers including non-small cell lung cancer (NSCLC) have yet to be well defined. Here we develop findings that the growth factor HGF promotes CSC sphere formation in NSCLC cell populations. In patient-derived sphere-forming assays (PD-SFA) with HGF, CD49f and CD104 were defined as novel markers of lung CSC (LCSC). In particular, we isolated a subpopulation of CD166(+)CD49f(hi)CD104(-)Lin(-) LCSC present in all human specimens of NSCLC examined, regardless of their histological subtypes or genetic driver mutations. This specific cell population was tumorigenic and capable of self-renewal, giving rise to tumor spheres in vitro and orthotopic lung tumors in immune-compromised mice. Mechanistic investigations established that NOTCH1 was preferentially expressed in this cell subpopulation and required for self-renewal via the transcription factor HES1. Through a distinct HES1-independent pathway, NOTCH1 also protected LCSCs from cisplatin-induced cell death. Notably, treatment with a γ-secretase inhibitor that blunts NOTCH1 function ablated self-renewing LCSC activity and restored platinum sensitivity in vitro and in vivo Overall, our results define the pathogenic characters of a cancer stem-like subpopulation in lung cancer, the targeting of which may relieve platinum resistance in this disease.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.