Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Embryonic Pathway Delivers Stem Cell Traits

19.05.2008
Cells that undergo an epithelial-to-mesenchymal transition (EMT) show properties of stem cells, including the ability to self-renew. In addition, stem cells exhibit properties of cells that undergo EMT. Strikingly, both normal and cancer stem cells can be generated from differentiated cells by EMT. Understanding the role of EMT in adult stem cell creation may lead toward the development of healthy stem cells for regenerative medicine and provide drug targets for cancer.

Studies of how cancer cells spread have led to a surprising discovery about the creation of cells with adult stem cell characteristics, offering potentially major implications for regenerative medicine and for cancer treatment.

Some cancer cells acquire the ability to migrate through the body by re-activating biological programs that have lain dormant since the embryo stage, as the lab of Whitehead Member Robert Weinberg has helped to demonstrate in recent years. Now scientists in the Weinberg lab have shown that both normal and cancer cells that are induced to follow one of these pathways may gain properties of adult stem cells, including the ability to self-renew.

In a paper published online by Cell on May 15, former postdoctoral researcher Sendurai Mani and his colleagues demonstrated in mice and in human cells that cells that have undergone an “epithelial-to-mesenchymal” (EMT) transition acquire several important characteristics of stem cells. Conversely, the researchers also showed that naturally existing normal stem cells as well as tumor-seeding cancer stem cells show characteristics of the post-EMT cells, including the acquisition of mesenchymal cell traits, which are usually associated with connective tissue cells.

... more about:
»EMT »FOXC2 »Mani »epithelial »mammary »metastasis »transition »undergo

Epithelial cells, which make up most of the human body, bind together in sheet-like structures. In embryonic development, the EMT process breaks up cell-cell adhesion in the epithelial layer, and converts epithelial cells into more loosely associated mesenchymal cells. In the context of cancer development, some cancer cells within a primary cancer may undergo an EMT, migrate through the body to their end destination, and there resume their epithelial form through a reverse process (the mesenchymal-to-epithelial transition).

Mani and his colleagues have identified FOXC2, one of the key genes involved in invasion and metastasis. In addition, FOXC2 appears to program the metastatic ability of some breast cancers.

Mani knew that during embryonic development, FOXC2 expression is restricted to mesoderm and mesoderm-derived cells when they are in an undifferentiated state, and its expression disappears once these cells differentiate. Similarly, his experiments showed that epithelial cells that undergo EMT express FOXC2, but that expression is lost when they revert back to an epithelial state.

In collaboration with Andrea Richardson and Jeffery Kutok, pathologists at Boston’s Brigham and Women’s Hospital, Mani went on to study FOXC2 expression in normal human breast tissue. It turned out that such cells were located precisely where researchers expect to find mammary epithelial stem cells.

As he pondered these findings and the earlier results about FOXC2’s role in metastasis, Mani wondered: Just what were these cells generated by EMT that expressed FOXC2?

Were they simply fibroblasts, the most common cells in normal connective tissue? Or were they actually stem cells?

“I asked Mai-Jing Liao, another postdoc in the Weinberg lab, to check whether the cells generated by EMT would have any stem cell properties,” recalls Mani, now an assistant professor in the department of molecular pathology at the University of Texas’s M. D. Anderson Cancer Center in Houston. “He said, ‘You must be out of your mind, but it won’t take more than half an hour to check.’”

Much to Liao’s surprise, when he examined cells that had undergo an EMT, his tests did highlight surface proteins that are key markers for stem cells.

The researchers found that the cells that underwent the EMT process were mesenchymal-like in appearance and demonstrated stem-cell surface markers. The cells also displayed an increased ability to grow in suspension, forming structures called mammospheres—another trait of mammary stem cells. Some cells in the resulting mammospheres showed, in turn, stem cell markers, indicating they could differentiate into two kinds of mammary cells. And cells in the mammospheres retained their stem cell properties even after the EMT induction process was stopped.

Furthermore, when the Weinberg lab scientists isolated stem-cell-like cells from cultured human mammary epithelial cells or from mouse breast tissue, their properties were very similar to the EMT-induced cells. Working with Kornelia Polyak of Dana-Farber Cancer Institute and Harvard Medical School, Mani found that this was also true with normal and tumor cells obtained from human patients.

“This for us is a very exciting discovery, not only because of its unexpectedness but because it offers a route by which one could in principle generate unlimited numbers of stem cells committed to create a specific cell type,” says Weinberg, who is also a professor of biology at Massachusetts Institute of Technology. “One could imagine, for example, that if one takes skin cells and induces them to undergo an EMT, they could become skin stem cells.”

Importantly, the researchers also demonstrated that inducing the EMT process can produce cells with many characteristics of cancer stem cells. (Beginning in 2003, scientists in various labs have identified these self-renewing, tumor-seeding cells in a number of solid tumors.)

This finding could help to answer a key question about metastasis: When tumor cells spread into different sites, how do they multiply enough to form a dangerous new tumor?

“If you take a population of human cancer cells that normally form a tumor very inefficiently and induce an EMT, their tumor-initiating abilities increase by about a hundred-fold, so that it takes about 10,000 cells rather than a million cells to form a tumor,” says Wenjun Guo, co-lead author on the paper and postdoctoral researcher in the Weinberg lab. “This suggests cancer stem cells are using pre-existing normal stem cell machinery to propagate their own self-renewal and therefore their tumor-initiating ability.”

Mani is continuing his research on the EMT/cancer stem cell connection and its role in cancer metastasis at the M. D. Anderson Cancer Center. Researchers in the Weinberg lab will investigate the EMT process with other cell lines. They also will attempt to give final proof in mice that the process creates completely defined stem cells, by taking cells from mouse mammary fat pads, inducing an EMT for some of the cells, returning the resulting cells to the fat pad, and seeing if they can regenerate the mammary gland.

This research was supported by the Breast Cancer Research Foundation, the MIT Ludwig Center for Molecular Oncology and the National Cancer Institute. Mani was supported by a Department of Defense postdoctoral fellowship.

Full citation:

Cell, online publication May 15, Print Edition, Volume 133 (4)

“The epithelial-mesenchymal transition generates cells with properties of stem cells”

Sendurai A. Mani (1,3,9,10), Wenjun Guo (1,9), Mai-Jing Liao (1,9), Elinor Ng Eaton (1), Ayyakkannu Ayyanan (4), Alicia Zhou (1), Mary Brooks (1), Ferenc Reinhard (1), Cheng Cheng Zhang (1), Michail Shipitsin (5,6), Lauren L. Campbell (5,7), Kornelia Polyak (5,6,7), Cathrin Brisken(4), Jing Yang (1,8), Robert A. Weinberg (1,2,).

1. Whitehead Institute for Biomedical Research, 9 Cambridge Center,
Cambridge, MA 02142
2. Department of Biology and MIT Ludwig Center for Molecular Oncology, Massachusetts Institute of Technology, Cambridge MA 02139
3. Department of Molecular Pathology, University of Texas M. D. Anderson
Cancer Center, 7435 Fannin St, Houston, TX 77054
4. Ecole polytechnique fédérale de Lausanne (EPFL) ISREC - Swiss Institute
for Experimental Cancer Research, CH-1066, Epalinges, Switzerland
5. Department of Medical Oncology, Dana-Farber Cancer Institute, Boston,
MA 02115
6. Department of Medicine, Harvard Medical School, Boston, MA 02115
7. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115
8. Department of Pharmacology, University of California, San Diego, School
of Medicine, 9500 Gilman Drive, La Jolla, CA 92093-0636
9. These authors contributed equally to this work

Eric Bender | newswise
Further information:
http://www.wi.mit.edu/news/

Further reports about: EMT FOXC2 Mani epithelial mammary metastasis transition undergo

More articles from Life Sciences:

nachricht Scientists unlock ability to generate new sensory hair cells
22.02.2017 | Brigham and Women's Hospital

nachricht New insights into the information processing of motor neurons
22.02.2017 | Max Planck Florida Institute for Neuroscience

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Microhotplates for a smart gas sensor

22.02.2017 | Power and Electrical Engineering

Scientists unlock ability to generate new sensory hair cells

22.02.2017 | Life Sciences

Prediction: More gas-giants will be found orbiting Sun-like stars

22.02.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>