An Embryonic Stem Cell–Like Signature Identifies Poorly Differentiated Lung Adenocarcinoma but not Squamous Cell Carcinoma

Purpose: An embryonic stem cell (ESC) profile correlates with poorly differentiated breast, bladder, and glioma cancers. In this article, we assess the correlation between the ESC profile and clinical variables in lung cancer. Experimental Design: Microarray gene expression analysis was done using Affymetrix Human Genome U133A on 443 samples of human lung adenocarcinoma and 130 samples of squamous cell carcinoma (SCC). To identify gene set enrichment patterns, we used the Genomica software. Results: Our analysis showed that an increased expression of the ESC gene set and a decreased expression of the Polycomb target gene set identified poorly differentiated lung adenocarcinoma. In addition, this gene expression signature was associated with markers of poor prognosis and worse overall survival in lung adenocarcinoma. However, there was no correlation between this ESC gene signature and any histologic or clinical variable assessed in lung SCC. Conclusions: This work suggests that not all poorly differentiated non–small cell lung cancers exhibit a gene expression profile similar to that of ESC, and that other characteristics may play a more important role in the determination of differentiation and survival in SCC of the lung. (Clin Cancer Res 2009;15(20):6386–90)

[1]  M. Biffoni,et al.  Identification and expansion of the tumorigenic lung cancer stem cell population , 2008, Cell Death and Differentiation.

[2]  A. Regev,et al.  An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors , 2008, Nature Genetics.

[3]  Michael F. Clarke,et al.  Applying the principles of stem-cell biology to cancer , 2003, Nature Reviews Cancer.

[4]  J. Nichols,et al.  Functional Expression Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells , 2003, Cell.

[5]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[6]  V. Pantesco,et al.  A Meta‐Analysis of Human Embryonic Stem Cells Transcriptome Integrated into a Web‐Based Expression Atlas , 2007, Stem cells.

[7]  H. Li,et al.  Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells , 2006, Oncogene.

[8]  Xianglin Shi,et al.  Constructing Molecular Classifiers for the Accurate Prognosis of Lung Adenocarcinoma , 2006, Clinical Cancer Research.

[9]  D. Elder,et al.  A tumorigenic subpopulation with stem cell properties in melanomas. , 2005, Cancer research.

[10]  Feng Jiang,et al.  Aldehyde Dehydrogenase 1 Is a Tumor Stem Cell-Associated Marker in Lung Cancer , 2009, Molecular Cancer Research.

[11]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[12]  J. Dick,et al.  Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell , 1997, Nature Medicine.

[13]  M. Surani,et al.  The Polycomb-Group GeneEzh2 Is Required for Early Mouse Development , 2001, Molecular and Cellular Biology.

[14]  L. Pevny,et al.  SOX2 Functions to Maintain Neural Progenitor Identity , 2003, Neuron.

[15]  Yi Zhang,et al.  Gene expression signatures for predicting prognosis of squamous cell and adenocarcinomas of the lung. , 2006, Cancer research.

[16]  Stephen Lam,et al.  Side population in human lung cancer cell lines and tumors is enriched with stem-like cancer cells. , 2007, Cancer research.

[17]  T. Jacks,et al.  Identification of Bronchioalveolar Stem Cells in Normal Lung and Lung Cancer , 2005, Cell.

[18]  Cynthia Hawkins,et al.  Identification of a cancer stem cell in human brain tumors. , 2003, Cancer research.

[19]  C. Shih,et al.  Identification of uPAR-positive Chemoresistant Cells in Small Cell Lung Cancer , 2007, PloS one.

[20]  P. Dalerba,et al.  Identification of pancreatic cancer stem cells. , 2006, Cancer research.

[21]  L. Ricci-Vitiani,et al.  Identification and expansion of human colon-cancer-initiating cells , 2007, Nature.

[22]  S. Morrison,et al.  Prospective identification of tumorigenic breast cancer cells , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[23]  J. Thomson,et al.  Embryonic stem cell lines derived from human blastocysts. , 1998, Science.

[24]  Giovanni Parmigiani,et al.  A Cross-Study Comparison of Gene Expression Studies for the Molecular Classification of Lung Cancer , 2004, Clinical Cancer Research.

[25]  T. Jacks,et al.  Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. , 2001, Genes & development.

[26]  Igor Jurisica,et al.  Gene expression–based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study , 2008, Nature Medicine.

[27]  J. Dick,et al.  A human colon cancer cell capable of initiating tumour growth in immunodeficient mice , 2007, Nature.