Skip to main content
Log in

Signaling Pathways in Cancer and Embryonic Stem Cells

  • Published:
Stem Cell Reviews Aims and scope Submit manuscript

Abstract

Cancer cells have the ability to divide indefinitely and spread to different parts of the body during metastasis. Embryonic stem cells can self-renew and, through differentiation to somatic cells, provide the building blocks of the human body. Embryonic stem cells offer tremendous opportunities for regenerative medicine and serve as an excellent model system to study early human development. Many of the molecular mechanism underlying tumorigenesis in cancer and self-renewal in stem cells have been elucidated in the past decade. Here we present a systematic analysis of seven major signaling pathways implicated in both cancer and stem cells. We present on overview of the JAK/STAT, Notch, MAPK/ERK, PI3K/AKT, NF-kB, Wnt and TGF-β pathways and analyze their activation status in the context of cancer and stem cells. We focus on their role in stem cell self-renewal and development and identify key molecules, whose aberrant expression has been associated with malignant phenotypes. We conclude by presenting a map of the signaling networks involved in cancer and embryonic stem cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Harley, C. B., Futcher, A. B., & Greider, C. W. (1990). Telomeres shorten during ageing of human fibroblasts. Nature, 345, 458–460.

    Article  PubMed  CAS  Google Scholar 

  2. Campisi, J. (2005). Senescent cells, tumor suppression, and organismal aging: Good citizens, bad neighbors. Cell, 120, 513–522.

    Article  PubMed  CAS  Google Scholar 

  3. Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.

    Article  PubMed  CAS  Google Scholar 

  4. Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., et al. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282, 1145–1147.

    Article  PubMed  CAS  Google Scholar 

  5. Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292, 154–156.

    Article  PubMed  CAS  Google Scholar 

  6. Hahn, W. C., Counter, C. M., Lundberg, A. S., Beijersbergen, R. L., Brooks, M. W., & Weinberg, R. A. (1999). Creation of human tumour cells with defined genetic elements. Nature, 400, 464–468.

    Article  PubMed  CAS  Google Scholar 

  7. Gupta, G. P., & Massague, J. (2006). Cancer metastasis: Building a framework. Cell, 127, 679–695.

    Article  PubMed  CAS  Google Scholar 

  8. Wang, T. L., Rago, C., Silliman, N., Ptak, J., Markowitz, S., Willson, J. K., et al. (2002). Prevalence of somatic alterations in the colorectal cancer cell genome. Proceedings of the National Academy of Sciences of the United States of America, 99, 3076–3080.

    Article  PubMed  CAS  Google Scholar 

  9. Wang, J. C., & Dick, J. E. (2005). Cancer stem cells: lessons from leukemia. Trends in Cell Biology, 15, 494–501.

    Article  PubMed  CAS  Google Scholar 

  10. Al-Hajj, M., & Clarke, M. F. (2004). Self-renewal and solid tumor stem cells. Oncogene, 23, 7274–7282.

    Article  PubMed  CAS  Google Scholar 

  11. Tan, B. T., Park, C. Y., Ailles, L. E., & Weissman, I. L. (2006). The cancer stem cell hypothesis: A work in progress. Laboratory Investigation, 86, 1203–1207.

    Article  PubMed  CAS  Google Scholar 

  12. Brivanlou, A. H., & Darnell, J. E. Jr. (2002). Signal transduction and the control of gene expression. Science, 295, 813–818.

    Article  PubMed  CAS  Google Scholar 

  13. Darnell, J. E. Jr. (2002). Transcription factors as targets for cancer therapy. Nature Reviews. Cancer, 2, 740–749.

    Article  PubMed  CAS  Google Scholar 

  14. Darnell, J. E. (2005). Validating Stat3 in cancer therapy. Natural Medicines, 11, 595–596.

    Article  CAS  Google Scholar 

  15. Bromberg, J. (2002). Stat proteins and oncogenesis. Journal of Clinical Investigation, 109, 1139–1142.

    Article  PubMed  CAS  Google Scholar 

  16. Slamon, D. J., Clark, G. M., Wong, S. G., Levin, W. J., Ullrich, A., & McGuire, W. L. (1987). Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science, 235, 177–182.

    Article  PubMed  CAS  Google Scholar 

  17. Yarden, Y., & Ullrich, A. (1988). Growth factor receptor tyrosine kinases. Annual Review of Biochemistry, 57, 443–478.

    Article  PubMed  CAS  Google Scholar 

  18. Nichols, J., Chambers, I., Taga, T., & Smith, A. (2001). Physiological rationale for responsiveness of mouse embryonic stem cells to gp130 cytokines. Development, 128, 2333–2339.

    PubMed  CAS  Google Scholar 

  19. Sato, N., Meijer, L., Skaltsounis, L., Greengard, P., & Brivanlou, A. H. (2004). Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Natural Medicines, 10, 55–63.

    Article  CAS  Google Scholar 

  20. Noggle, S. A., James, D., & Brivanlou, A. H. (2005). A molecular basis for human embryonic stem cell pluripotency. Stem Cell Review, 1, 111–118.

    Article  CAS  Google Scholar 

  21. Ehebauer, M., Hayward, P., & Arias, A. M. (2006). Notch, a universal arbiter of cell fate decisions. Science, 314, 1414–1415.

    Article  PubMed  CAS  Google Scholar 

  22. Weng, A. P., Ferrando, A. A., Lee, W., Morris, J. Pt., Silverman, L. B., Sanchez-Irizarrym C., et al. (2004). Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 306, 269–271.

    Article  PubMed  CAS  Google Scholar 

  23. Roy, M., Pear, W. S., & Aster, J. C. (2007). The multifaceted role of Notch in cancer. Current Opinion in Genetics & Development, 17, 52–59.

    Article  CAS  Google Scholar 

  24. Stylianou, S., Clarke, R. B., & Brennan, K. (2006). Aberrant activation of notch signaling in human breast cancer. Cancer Research, 66, 1517–1525.

    Article  PubMed  CAS  Google Scholar 

  25. Noggle, S. A., Weiler, D., & Condie, B. G. (2006). Notch signaling is inactive but inducible in human embryonic stem cells. Stem Cells, 24, 1646–1653.

    Article  PubMed  CAS  Google Scholar 

  26. Lowell, S., Benchoua, A., Heavey, B., & Smith, A. G. (2006). Notch promotes neural lineage entry by pluripotent embryonic stem cells. PLoS Biol, 4, e121.

    Article  PubMed  CAS  Google Scholar 

  27. Katz, M., Amit, I., & Yarden, Y. (2007). Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochimica et Biophysica Acta.

  28. Sebolt-Leopold, J. S., & Herrera, R. (2004). Targeting the mitogen-activated protein kinase cascade to treat cancer. Nature Reviews. Cancer, 4, 937–947.

    Article  PubMed  CAS  Google Scholar 

  29. Armstrong, L., Hughes, O., Yung, S., Hyslop, L., Stewart, R., Wappler, I., et al. (2006). The role of PI3K/AKT, MAPK/ERK and NFkappabeta signalling in the maintenance of human embryonic stem cell pluripotency and viability highlighted by transcriptional profiling and functional analysis. Human Molecular Genetics, 15, 1894–1913.

    Article  PubMed  CAS  Google Scholar 

  30. Hennessy, B. T., Smith, D. L., Ram, P. T., Lu, Y., & Mills, G. B. (2005). Exploiting the PI3K/AKT pathway for cancer drug discovery. Nature Reviews Drug Discovery, 4, 988–1004.

    Article  PubMed  CAS  Google Scholar 

  31. Vivanco, I., & Sawyers, C. L. (2002). The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nature Reviews. Cancer, 2, 489–501.

    Article  PubMed  CAS  Google Scholar 

  32. Takahashi, K., Murakami, M., & Yamanaka, S. (2005). Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells. Biochemical Society Transactions, 33, 1522–1525.

    Article  PubMed  CAS  Google Scholar 

  33. Paling, N. R., Wheadon, H., Bone, H. K., & Welham, M. J. (2004). Regulation of embryonic stem cell self-renewal by phosphoinositide 3-kinase-dependent signaling. Journal of Biological Chemistry, 279, 48063–48070.

    Article  PubMed  CAS  Google Scholar 

  34. Courtois, G., & Gilmore, T. D. (2006). Mutations in the NF-kappaB signaling pathway: Implications for human disease. Oncogene, 25, 6831–6843.

    Article  PubMed  CAS  Google Scholar 

  35. Gilmore, T. D., Cormier, C., Jean-Jacques, J., & Gapuzan, M. E. (2001). Malignant transformation of primary chicken spleen cells by human transcription factor c-Rel. Oncogene, 20, 7098–7103.

    Article  PubMed  CAS  Google Scholar 

  36. Barth, T. F., Martin-Subero, J. I., Joos, S., Menz, C. K., Hasel, C., Mechtersheimer, G., et al. (2003). Gains of 2p involving the REL locus correlate with nuclear c-Rel protein accumulation in neoplastic cells of classical Hodgkin lymphoma. Blood, 101, 3681–3686.

    Article  PubMed  CAS  Google Scholar 

  37. Logan, C. Y., & Nusse, R. (2004). The Wnt signaling pathway in development and disease. Annual Review of Cell and Developmental Biology, 20, 781–810.

    Article  PubMed  CAS  Google Scholar 

  38. Tetsu, O., & McCormick, F. (1999). Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature, 398, 422–426.

    Article  PubMed  CAS  Google Scholar 

  39. Blanpain, C., Horsley, V., & Fuchs, E. (2007). Epithelial stem cells: Turning over new leaves. Cell, 128, 445–458.

    Article  PubMed  CAS  Google Scholar 

  40. Giles, R. H., van Es, J. H., & Clevers, H. (2003). Caught up in a Wnt storm: Wnt signaling in cancer. Biochimica et Biophysica Acta, 1653, 1–24.

    PubMed  CAS  Google Scholar 

  41. Reya, T., & Clevers, H. (2005). Wnt signalling in stem cells and cancer. Nature, 434, 843–850.

    Article  PubMed  CAS  Google Scholar 

  42. Jamieson, C. H., Ailles, L. E., Dylla, S. J., Muijtjens, M., Jones, C., Zehnder, J. L., et al. (2004). Granulocyte-macrophage progenitors as candidate leukemic stem cells in blast-crisis CML. New England Journal of Medicine, 351, 657–667.

    Article  PubMed  CAS  Google Scholar 

  43. Besser, D. (2004). Expression of nodal, lefty-a, and lefty-B in undifferentiated human embryonic stem cells requires activation of Smad2/3. Journal of Biological Chemistry, 279, 45076–45084.

    Article  PubMed  CAS  Google Scholar 

  44. Hansel, D. E., Kern, S. E., & Hruban, R. H. (2003). Molecular pathogenesis of pancreatic cancer. Annual Review of Genomics and Human Genetics, 4, 237–256.

    Article  PubMed  CAS  Google Scholar 

  45. Bardeesy, N., Cheng, K. H., Berger, J. H., Chu, G. C., Pahler, J., Olson, P., et al. (2006). Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes & Development, 20, 3130–3146.

    Article  CAS  Google Scholar 

  46. Langenfeld, E. M., Calvano, S. E., Abou-Nukta, F., Lowry, S. F., Amenta, P., & Langenfeld, J. (2003). The mature bone morphogenetic protein-2 is aberrantly expressed in non-small cell lung carcinomas and stimulates tumor growth of A549 cells. Carcinogenesis, 24, 1445–1454.

    Article  PubMed  CAS  Google Scholar 

  47. Langenfeld, E. M., Kong, Y., & Langenfeld, J. (2006). Bone morphogenetic protein 2 stimulation of tumor growth involves the activation of Smad-1/5. Oncogene, 25, 685–692.

    Article  PubMed  CAS  Google Scholar 

  48. Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial-mesenchymal transitions. Nature Reviews. Molecular Cell Biology, 7, 131–142.

    Article  PubMed  CAS  Google Scholar 

  49. Hartwell, K. A., Muir, B., Reinhardt, F., Carpenter, A. E., Sgroi, D. C., & Weinberg, R. A. (2006). The Spemann organizer gene, Goosecoid, promotes tumor metastasis. Proceedings of the National Academy of Sciences of the United States of America, 103, 18969–18974.

    Article  PubMed  CAS  Google Scholar 

  50. Zavadil, J., & Bottinger, E. P. (2005). TGF-beta and epithelial-to-mesenchymal transitions. Oncogene, 24, 5764–5774.

    Article  PubMed  CAS  Google Scholar 

  51. Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R. A., Come, C., et al. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117, 927–939.

    Article  PubMed  CAS  Google Scholar 

  52. Sato, N., Sanjuan, I. M., Heke, M., Uchida, M., Naef, F., & Brivanlou, A. H. (2003). Molecular signature of human embryonic stem cells and its comparison with the mouse. Developments in Biologicals, 260, 404–413.

    Article  CAS  Google Scholar 

  53. James, D., Levine, A. J., Besser, D., & Hemmati-Brivanlou, A. (2005). TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development, 132, 1273–1282.

    Article  PubMed  CAS  Google Scholar 

  54. Xu, R. H., Chen, X., Li, D. S., Li, R., Addicks, G. C., Glennon, C., et al. (2002). BMP4 initiates human embryonic stem cell differentiation to trophoblast. Nature Biotechnology, 20, 1261–1264.

    Article  PubMed  CAS  Google Scholar 

  55. Goumans, M. J., & Mummery, C. (2000). Functional analysis of the TGFbeta receptor/Smad pathway through gene ablation in mice. International Journal of Developmental Biology, 44, 253–265.

    PubMed  CAS  Google Scholar 

  56. Piccirillo, S. G., Reynolds, B. A., Zanetti, N., Lamorte, G., Binda, E., Broggi, G., et al. (2006). Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature, 444, 761–765.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We are grateful to the members of the Brivanlou lab, in particular Scott Noggle, Ariel Levine and Blaine Cooper for helpful discussions and assistance during the preparation of this manuscript. Andre Hoelz is acknowledged for inspiring discussions. This work was supported by NIH grant GM073370 to A.H. B. and a Zuckerman family postdoctoral fellowship to O.D.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Ali H. Brivanlou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dreesen, O., Brivanlou, A.H. Signaling Pathways in Cancer and Embryonic Stem Cells. Stem Cell Rev 3, 7–17 (2007). https://doi.org/10.1007/s12015-007-0004-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-007-0004-8

Keywords

Navigation