Original Paper

Cell Death and Differentiation (2008) 15, 504–514; doi:10.1038/sj.cdd.4402283; published online 30 November 2007

Identification and expansion of the tumorigenic lung cancer stem cell population

Edited by RA Knight

A Eramo1, F Lotti2, G Sette2, E Pilozzi3, M Biffoni1, A Di Virgilio4, C Conticello2, L Ruco3, C Peschle1 and R De Maria1

  1. 1Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
  2. 2Department of Experimental Oncology, Mediterranean Institute of Oncology, Catania, Italy
  3. 3Department of Experimental Medicine, Sant'Andrea Hospital, University ‘La Sapienza’, Rome, Italy
  4. 4Service for Biotechnology and Animal Welfare, Istituto Superiore di Sanità, Rome, Italy

Correspondence: R De Maria, Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, viale Regina Elena 299, Rome 00161, Italy. Tel: +39 0649903121; Fax: +39 0649387087; E-mail: demaria@iss.it

Received 3 May 2007; Revised 25 October 2007; Accepted 25 October 2007; Published online 30 November 2007.

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Abstract

Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133+ cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 104 lung cancer CD133+ cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133+ cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133+ cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.

Keywords:

cancer stem cells, stem cell markers, lung cancer, CD133, pulmonary stem cells, tumor sphere

Abbreviations:

AC, adenocarcinoma; APC, allophycocyanin; BCRP1, breast cancer resistance protein1; CC-10, Clara cell protein; CEA, carcinoembryonic antigen; ChrA, chromogranine A; CKs, cytokeratins; EGF, epidermal growth factor; Ep-CAM, epithelial cell adhesion molecule; FACS, fluorescence-activated cell sorting; FGF, fibroblast growth factor; FITC, fluorescein isothiocyanate; HMW-CKs, high molecular weight cytokeratins; LCC, large cell carcinoma; LCNEC, large cell neuroendocrine carcinoma; MTT, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl 2H-tetrazolium bromide; N-CAM, neural cell adhesion molecule; NSCLC, non-small cell lung cancer; PE, phycoerythrin; SCC, squamous cell carcinoma; SCID, severe combined immunodeficiency; SCLC, small cell lung cancer; SP-C, surfactant protein C