Abstract
Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell–like phenotypes shown by many tumors.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Reya, T., Morrison, S.J., Clarke, M.F. & Weissman, I.L. Stem cells, cancer, and cancer stem cells. Nature 414, 105–111 (2001).
Beachy, P.A., Karhadkar, S.S. & Berman, D.M. Tissue repair and stem cell renewal in carcinogenesis. Nature 432, 324–331 (2004).
Stingl, J. & Caldas, C. Molecular heterogeneity of breast carcinomas and the cancer stem cell hypothesis. Nat. Rev. Cancer 7, 791–799 (2007).
Lobo, N.A., Shimono, Y., Qian, D. & Clarke, M.F. The biology of cancer stem cells. Annu. Rev. Cell Dev. Biol. 23, 675–699 (2007).
Andres, A.C. et al. Ha-ras and c-myc oncogene expression interferes with morphological and functional differentiation of mammary epithelial cells in single and double transgenic mice. Genes Dev. 2, 1486–1495 (1988).
Shachaf, C.M. et al. MYC inactivation uncovers pluripotent differentiation and tumour dormancy in hepatocellular cancer. Nature 431, 1112–1117 (2004).
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007).
Hochedlinger, K., Yamada, Y., Beard, C. & Jaenisch, R. Ectopic expression of Oct-4 blocks progenitor-cell differentiation and causes dysplasia in epithelial tissues. Cell 121, 465–477 (2005).
Valk-Lingbeek, M.E., Bruggeman, S.W. & van Lohuizen, M. Stem cells and cancer; the polycomb connection. Cell 118, 409–418 (2004).
Niwa, H. How is pluripotency determined and maintained? Development 134, 635–646 (2007).
Gidekel, S., Pizov, G., Bergman, Y. & Pikarsky, E. Oct-3/4 is a dose-dependent oncogenic fate determinant. Cancer Cell 4, 361–370 (2003).
Santagata, S., Ligon, K.L. & Hornick, J.L. Embryonic stem cell transcription factor signatures in the diagnosis of primary and metastatic germ cell tumors. Am. J. Surg. Pathol. 31, 836–845 (2007).
Li, X.L. et al. Expression of the SRY-related HMG box protein SOX2 in human gastric carcinoma. Int. J. Oncol. 24, 257–263 (2004).
Rodriguez-Pinilla, S.M. et al. Sox2: a possible driver of the basal-like phenotype in sporadic breast cancer. Mod. Pathol. 20, 474–481 (2007).
Rhodes, D.R. & Chinnaiyan, A.M. Integrative analysis of the cancer transcriptome. Nat. Genet. 37 (Suppl.), S31–S37 (2005).
Segal, E., Friedman, N., Kaminski, N., Regev, A. & Koller, D. From signatures to models: understanding cancer using microarrays. Nat. Genet. 37 (Suppl.), S38–S45 (2005).
Segal, E., Friedman, N., Koller, D. & Regev, A. A module map showing conditional activity of expression modules in cancer. Nat. Genet. 36, 1090–1098 (2004).
Mootha, V.K. et al. PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat. Genet. 34, 267–273 (2003).
Wei, C.L. et al. Transcriptome profiling of human and murine ESCs identifies divergent paths required to maintain the stem cell state. Stem Cells 23, 166–185 (2005).
Odom, D.T. et al. Tissue-specific transcriptional regulation has diverged significantly between human and mouse. Nat. Genet. 39, 730–732 (2007).
Assou, S. et al. A meta-analysis of human embryonic stem cells transcriptome integrated into a web-based expression atlas. Stem Cells 25, 961–973 (2007).
Boyer, L.A. et al. Core transcriptional regulatory circuitry in human embryonic stem cells. Cell 122, 947–956 (2005).
Lee, T.I. et al. Control of developmental regulators by Polycomb in human embryonic stem cells. Cell 125, 301–313 (2006).
Fernandez, P.C. et al. Genomic targets of the human c-Myc protein. Genes Dev. 17, 1115–1129 (2003).
Li, Z. et al. A global transcriptional regulatory role for c-Myc in Burkitt's lymphoma cells. Proc. Natl. Acad. Sci. USA 100, 8164–8169 (2003).
Sperger, J.M. et al. Gene expression patterns in human embryonic stem cells and human pluripotent germ cell tumors. Proc. Natl. Acad. Sci. USA 100, 13350–13355 (2003).
van de Vijver, M.J. et al. A gene-expression signature as a predictor of survival in breast cancer. N. Engl. J. Med. 347, 1999–2009 (2002).
Sotiriou, C. et al. Gene expression profiling in breast cancer: understanding the molecular basis of histologic grade to improve prognosis. J. Natl. Cancer Inst. 98, 262–272 (2006).
Miller, L.D. et al. An expression signature for p53 status in human breast cancer predicts mutation status, transcriptional effects, and patient survival. Proc. Natl. Acad. Sci. USA 102, 13550–13555 (2005).
Chin, K. et al. Genomic and transcriptional aberrations linked to breast cancer pathophysiologies. Cancer Cell 10, 529–541 (2006).
Wang, Y. et al. Gene-expression profiles to predict distant metastasis of lymph-node-negative primary breast cancer. Lancet 365, 671–679 (2005).
Desmedt, C. et al. Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series. Clin. Cancer Res. 13, 3207–3214 (2007).
Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl. Acad. Sci. USA 98, 10869–10874 (2001).
Hu, Z. et al. The molecular portraits of breast tumors are conserved across microarray platforms. BMC Genomics 7, 96 (2006).
Nielsen, T.O. et al. Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin. Cancer Res. 10, 5367–5374 (2004).
Livasy, C.A. et al. Phenotypic evaluation of the basal-like subtype of invasive breast carcinoma. Mod. Pathol. 19, 264–271 (2006).
Pawitan, Y. et al. Gene expression profiling spares early breast cancer patients from adjuvant therapy: derived and validated in two population-based cohorts. Breast Cancer Res. 7, R953–R964 (2005).
Orford, K.W. & Scadden, D.T. Deconstructing stem cell self-renewal: genetic insights into cell-cycle regulation. Nat. Rev. Genet. 9, 115–128 (2008).
Whitfield, M.L. et al. Identification of genes periodically expressed in the human cell cycle and their expression in tumors. Mol. Biol. Cell 13, 1977–2000 (2002).
Sun, L. et al. Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell 9, 287–300 (2006).
Sanchez-Carbayo, M., Socci, N.D., Lozano, J., Saint, F. & Cordon-Cardo, C. Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. J. Clin. Oncol. 24, 778–789 (2006).
Liu, R. et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356, 217–226 (2007).
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nat. Biotechnol. 26, 101–106 (2008).
Nguyen, H., Rendl, M. & Fuchs, E. Tcf3 governs stem cell features and represses cell fate determination in skin. Cell 127, 171–183 (2006).
Vassilev, A., Kaneko, K.J., Shu, H., Zhao, Y. & DePamphilis, M.L. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 15, 1229–1241 (2001).
Phillips, H.S. et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell 9, 157–173 (2006).
Fan, C. et al. Concordance among gene-expression-based predictors for breast cancer. N. Engl. J. Med. 355, 560–569 (2006).
DerSimonian, R. & Laird, N. Meta-analysis in clinical trials. Control. Clin. Trials 7, 177–188 (1986).
Suzuki, R. & Shimodaira, H. Pvclust: an R package for assessing the uncertainty in hierarchical clustering. Bioinformatics 22, 1540–1542 (2006).
Acknowledgements
We thank C. Fan and C. Perou for assistance with the intrinsic subtype classification and the proliferation cluster, J. Foekens for tumor data, K. Gurdziel and J. Rodriguez for bioinformatics assistance, and Y. Dor, T. Brummelkamp, W. Guo, H. Cedar, N. Friedman and E. Pikarsky for reviewing of the manuscript and helpful discussions. I.B.-P. is a Leukemia and Lymphoma Special Fellow; V.J.C. was supported in part by NIH P41 HG 004059 and in part by the Whitehead Institute Bioinformatics Department; A.R. is supported by the Burroughs Wellcome Career Award at the Scientific Interface; R.A.W. is supported by US National Institutes of Health/National Cancer Institute grant R01 CA078461, the Breast Cancer Research Foundation and the Ludwig Cancer Center for Molecular Oncology at the Massachusetts Institute of Technology.
Author information
Authors and Affiliations
Contributions
I.B.-P. conceived the study, collected and processed datasets, performed gene set expression analyses and wrote the manuscript. M.W.T. contributed to the design of the study, collected and processed many of the datasets and performed multiple analyses including gene set expression and nearest neighbor. V.J.C. supervised the statistical aspects of the study and performed the patient survival analyses. R.G. and G.W.B. processed datasets and performed various analyses, including transcription factor clustering and gene function assignment; G.W.B. set up the study website. A.R. designed the study together with I.B.-P., provided the analytical framework, supervised the analyses and reviewed the manuscript. R.A.W. contributed to the conception of the study, provided guidance and supervision of study design and goals and assisted in the writing of the manuscript.
Corresponding author
Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–4 (PDF 1419 kb)
Supplementary Table 1
ES-associated gene sets (XLS 525 kb)
Supplementary Table 2
Samples included in the breast cancer compendium (XLS 70 kb)
Supplementary Table 3
Proliferation-associated gene sets (XLS 132 kb)
Supplementary Table 4
The ES TFs set (XLS 12 kb)
Supplementary Table 5
Transcription regulators whose expression correlates with the Core 9 set (XLS 32 kb)
Rights and permissions
About this article
Cite this article
Ben-Porath, I., Thomson, M., Carey, V. et al. An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors. Nat Genet 40, 499–507 (2008). https://doi.org/10.1038/ng.127
Published:
Issue Date:
DOI: https://doi.org/10.1038/ng.127
This article is cited by
-
Malignant peripheral nerve sheath tumor (MPNST) and MPNST-like entities are defined by a specific DNA methylation profile in pediatric and juvenile population
Clinical Epigenetics (2024)
-
NCAPD2 is a favorable predictor of prognostic and immunotherapeutic biomarker for multiple cancer types including lung cancer
Genes and Environment (2024)
-
Identification of genes with oscillatory expression in glioblastoma: the paradigm of SOX2
Scientific Reports (2024)
-
Development of a stemness-related prognostic index to provide therapeutic strategies for bladder cancer
npj Precision Oncology (2024)
-
Compensatory cross-talk between autophagy and glycolysis regulates senescence and stemness in heterogeneous glioblastoma tumor subpopulations
Acta Neuropathologica Communications (2023)