Navigation Links
Protein central to cancer stem cell formation provides new potential target

HOUSTON - Researchers have identified a pivotal protein in a cellular transformation that makes a cancer cell more resistant to treatment and more capable of growing and spreading, making it an inviting new target for drug development.

Additionally, the international team led by scientists at The University of Texas MD Anderson Cancer Center found the cancer drug sunitinib potentially has a new role in treating triple-negative, claudin-low breast cancer, a particularly resistant version of a type of cancer that is already difficult to treat.

"We found that FOXC2 lies at the crossroads of the cellular properties of cancer stem cells and cells that have undergone epithelial to mesenchymal transition (EMT), a process of cellular change associated with generating cancer stem cells," said senior author Sendurai Mani, Ph.D., assistant professor in MD Anderson's Department of Translational Molecular Pathology and co-director of the Metastasis Research Center.

Cancer stem cells are fewer in number than other tumor cells, yet research has tied them to cancer progression and resistance to treatment. Abnormal activation of the epithelial to mesenchymal transition can create cancer stem cells, Mani noted.

Sunitinib stifles growth of cancer stem cells

"There are multiple molecular pathways that activate EMT," Mani said. "We found many of these pathways also activate FOXC2 expression to launch this transition, making FOXC2 a potentially efficient check point to block EMT from occurring," Mani said.

Research uncovering this connection, published in the journal Cancer Research, focused on cell line and mouse model experiments. The next important step will be to assess the expression and activity of FOXC2 in human tumor samples, Mani said.

In the meantime, sunitinib, known commercially as Sutent and approved by the U.S. Food and Drug Administration for three other cancers, provides interesting, more immediate, potential.

"FOXC2 is a transcription factor, a protein that binds to DNA in the promoter region of genes to activate them. For a variety of reasons, transcription factors are hard to target with drugs," Mani said.

The team found that FOXC2 also regulates the platelet derived growth factor receptor (PDGFR-Beta). In cancer cell lines, they found that the PDGFR-Beta inhibitor sunitinib inhibited growth of cells with EMT or cancer stem cell properties that have active FOXC2.

Mice with triple-negative breast cancer treated with sunitinib had smaller primary tumors, longer survival, and fewer incidences of metastasis. There also was a steep drop in the cells' ability to form mammospheres, a hallmark of cancer stem cells.

EMT: an embryonic development process reactivated by cancer

Mani is an expert on EMT and cancer stem cells and was the first author on the original EMT study in Cell when he was with Robert Weinberg, Ph.D., at the Whitehead Institute/Massachusetts Institute of Technology.

Epithelial to mesenchymal transition is important to embryonic development, turning stationary epithelial cells into mobile mesenchymal cells to move them within the embryo. For example, a cell might be converted and then gather with other cells forming, for example, the kidney. Once there, it transitions back to an epithelial cell again and stays put.

Research has shown that carcinomas, tumors that form in the epithelium (lining) of organs are able to reactivate EMT. About 85 percent of all solid tumors are carcinomas.

The researchers focused on a recently discovered subtype of triple-negative breast cancer, so called because these cells lack receptors for three common treatments for breast cancer and thus are hard to treat. The claudin-low/basal B subtype is deficient in claudin, a membrane protein that binds epithelial cells together, and is particularly aggressive.

Building on an earlier paper that showed FOXC2 is expressed more heavily in cells after EMT is induced by a variety of factors, Mani and colleagues followed up first by using short hairpin RNA to suppress FOXC2 in breast cancer cells.

Blocking FOXC2 had no effect on cell growth, but it altered both the physical appearance of the cells, increased their ability to cluster like epithelial cells, reduced protein biomarkers of mesenchymal cells and increased levels of E-cadherin, an important epithelial cell marker.

Additional experiments showed that FOXC2 did not regulate three proteins known to separately launch EMT. They also found that breast cancer cells primed to undergo EMT became less invasive when FOXC2 was knocked down.

Impact on cancer stem cells

Knocking down FOXC2 in mammary epithelial cell lines with stem cell properties caused:

  • A reversal of expression of two cell surface cancer stem cell markers, CD44 and CD24.

  • A reduction in their ability to form mammospheres.

  • Heightened sensitivity to the chemotherapy drug paclitaxel. Chemo resistance is a hallmark of cancer stem cells.

They also found FOXC2 elevated in cancer cells with stem cell properties.

Examining cell lines in malignant human mammary epithelial cells showed:

  • Forced expression of FOXC2 alone is sufficient to induce EMT resulting in cancer stem cells.

  • Overexpression of the FOXC2 protein led to more efficient tumor formation.

  • Aggressive growth and metastasis in mice, with FOXC2-enhanced cells spreading to the lungs, liver, hind leg bone and to the brain, while unenhanced cancer cells did not spread at all.

FOXC2 boosts claudin-low breast cancer cells

FOXC2 was found overexpressed in metastatic tumors compared to primary tumors in two claudin-low human breast cancer xenografts. A second experiment showed all six claudin-low cell lines overexpressed FOXC2 compared to none of the other 7 cell lines. FOXC2 is required both for mesenchymal and invasive capacity of three claudin-low breast cancer cell lines. Blocking FOXC2 increased the cells' epithelial properties and decreased mesenchymal characteristics.

Mani and colleagues had earlier found increased expression of PDGFR-B in cells forced to undergo EMT. "We thought PDGFR-B might be a druggable target in these FOXC2-expressing cells," Mani said. They found suppressing FOXC2 reduced the ability of three cancer cell lines to migrate towards PDGF-B.

Mani said the team believes that targeting FOXC2 pathway using either PDGFR-beta inhibitors or other yet-to-be-known small-molecule inhibitors will be an effective therapeutic strategy for inhibiting EMT and consequently reducing EMT/cancer stem cell-associated metastasis, relapse and therapy resistance.

MD Anderson has filed a patent application connected to this study.


Contact: Scott Merville
University of Texas M. D. Anderson Cancer Center

Related medicine news :

1. Novel protein may help detect Lou Gehrigs disease and dementia, Mayo Clinic finds
2. Protein paves the way for correct stem cell differentiation
3. Excess protein linked to development of Parkinsons disease
4. Muscular Development Store Comments on Efficacy of Protein Blends
5. Scientists discover protein that allows safe recycling of iron from old red blood cells
6. The Muscular Development Store Comments on How Optimum Nutrition’s Protein Supplements Fit Into Your Workout
7. DNA-repairing protein may be key to preventing recurrence of some cancers
8. A blend of soy and dairy proteins promotes muscle protein synthesis when consumed after exercise
9. UT MD Anderson scientists find protein that reins in runaway network
10. Lack of protein Sp2 disrupts neuron creation in brain
11. Protein identified that can disrupt embryonic brain development and neuron migration
Post Your Comments:
Related Image:
Protein central to cancer stem cell formation provides new potential target
(Date:11/27/2015)... ... November 27, 2015 , ... MPWH, the No.1 Herpes-only dating community in the world, revealed ... 1-1 ). More than 3.7 billion people under the age of 50 – or ... to WHO's first global estimates of HSV-1 infection . , "The data shocks us ...
(Date:11/27/2015)... ... November 27, 2015 , ... ... Microsoft Dynamics SL User Group (MSDSLUG). Recognized as Microsoft’s official group for end ... Microsoft Dynamics SL software users, partners, industry experts and representatives. Intellitec Solutions’ membership ...
(Date:11/27/2015)... ... November 27, 2015 , ... The ... prided itself for not only fulfilling the needs of advisers and clients but ... affordable price and providing top-tier customer service. However, there's always room for improvement, ...
(Date:11/27/2015)... (PRWEB) , ... November 27, 2015 , ... CBD ... Accreditation of Allied Health Education Programs (CAAHEP) awarded accreditation to its Diagnostic Medical Sonography ... CAAHEP accredited colleges, as only one of twelve colleges and universities in the state ...
(Date:11/27/2015)... CA (PRWEB) , ... November 27, 2015 , ... ... California Medical Associates, Inc. and Dr. Tucker Bierbaum with Emergency Medicine at ... They observed that both STEMI and Sepsis conditions present in similar ways and require ...
Breaking Medicine News(10 mins):
(Date:11/26/2015)... November 26, 2015 ... the "2016 Future Horizons and Growth ... Testing Market: Supplier Shares, Country Segment Forecasts, ... their offering. --> ) ... "2016 Future Horizons and Growth Strategies in ...
(Date:11/26/2015)... 2015 Research and Markets ( ) ... Care Market by Type (Dressings, Therapy Devices, Active Wound ... Out-Patient Facility), and Geography - Global Forecast to 2020" ... --> --> The purpose of this ... of the global advanced wound care market. It involves ...
(Date:11/26/2015)... , Nov. 26, 2015 Research and ... of the "2016 Future Horizons and Growth ... Market: Supplier Shares, Country Segment Forecasts, Competitive Intelligence, ... --> --> ... of the Italian therapeutic drug monitoring market, including ...
Breaking Medicine Technology: