New York Researchers Find Signaling Link Between Pluripotent Stem Cells and Cancer

Stem cell researchers at Mount Sinai School of Medicine, the University of Manchester and the MD Anderson Cancer Center have discovered a new role for signaling pathways usually associated with cancer cells in embryonic stem cell self-renewal and in adult cells that are in the process of being reprogrammed into induced pluripotent stem cells (iPSCs).

Normal cells have several genes known as “proto-oncogenes” that stimulate cell growth and cell proliferation. When expressed, proto-oncogenes drive cells to grow, and mutations in proto-oncogenes that disrupt their regulation convert them into “oncogenes” that drive cells to grow uncontrollably. Oncogenes are commonly found in tumors and the accumulation of oncogenic mutations in cancer cells drive them to grow faster and faster and with less and less controls.

In this publication, a proto-oncogene called Aurka and its role in embryonic stem cell self-renewal was examined. Aurka is commonly amplified in several human cancers, which underscores its importance in driving growth.

By utilizing a functional genomics strategy, the research group identified the protein kinase Aurora A or Aurka as a vital component of embryonic stem cell function. Aurka is a protein kinase, which is a biochemical way of saying that it is an enzyme that places phosphate groups on proteins. By placing phosphate groups on proteins, Aurka regulates their function. One of the main targets is a well-known tumor suppressor gene product called p53. Tumor suppressor genes encode proteins that put the brakes on cell proliferation. Tumors tend to accumulate loss-of-function mutations in tumor suppressor genes and these mutations decrease the controls on cell proliferation. The p53 tumor suppressor protein is known as the “guardian of the genome.” Mutations in p53 are found in a very wide range of tumors and many oncologists think that inactivating mutations in the p53 gene are mandatory for the evolution of cancer.

In the absence of Aurka, p53 activity is up-regulated and up-regulation of p53 in embryonic stem cells causes them to differentiate and lose their undifferentiated state. However, If Aurka is active, it attaches a phosphate group to p53 and inhibits it, thus shifting the embryonic stem cell to a self-renewal state.

Ihor R. Lemischka, the Lillian and Henry M. Stratton Professor of Gene and Cell Medicine and Director of the Black Family Stem Cell Institute at Mount Sinai Medical Center in New York City, said: “These studies are exiting not only from a basic science point-of-view, but also because they suggest that stem cell research may impact the development of novel treatments for cancer. Conversely, cancer research may facilitate the realization of the biomedical potential of stem cells.”

Mature cells have low levels of p53, but embryonic stem cells and iPSCs show high levels of p53. The p53 protein also has a limited role in promoting programmed cell death. They also inhibit the cell cycle in pluripotent cells and these recent findings provide a possible explanation to my pluripotent stem cells have so much of this protein even though it is relatively inactive.

By developing Aurka inhibitors, these researchers hope to treat cancers more effectively, and also manipulate pluripotent stem cells more successfully.

See “Regulation of Embryonic and Induced Pluripotency by Aurora Kinase-p53 Signaling,” Dung-Fang Lee et al., Cell Stem Cell, Volume 11, Issue 2, 179-194, 3 August 2012 DOI:10.1016/j.stem.2012.05.020.

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Professor of Biochemistry at Spring Arbor University (SAU) in Spring Arbor, MI. Have been at SAU since 1999. Author of The Stem Cell Epistles. Before that I was a postdoctoral research fellow at the University of Pennsylvania in Philadelphia, PA (1997-1999), and Sussex University, Falmer, UK (1994-1997). I studied Cell and Developmental Biology at UC Irvine (PhD 1994), and Microbiology at UC Davis (MA 1986, BS 1984).

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