Home | Pregnancy Timeline | News Alerts |News Archive Aug 13, 2013

Ectins project - human fetal neural stem cells. Human primary fetal brain stem cell, with stem cell nucleus stained blue. Picture by Prof. John Sinden Stem Cell Therapies for the Future, European Stem Cell Research http://ec.europa.eu/research/quality-of-life/stemcells/pressroom.html

Molecule needed in nerve-cell migration implicated in brain cancer

Brain-tumor cell invasion into surrounding tissue requires the same protein molecule that neurons need to migrate into position while differentiating and maturing.

In new research from the University of Illinois at Chicago College of Medicine and published August 7 in the online journal PLOS ONE, researchers investigated similarities between the transition of neural stem cells into neurons and the process by which cancer cells invade surrounding tissues.

"Both processes involve the mobilization of cells," says Anjen Chenn, director of clinical pathology and molecular diagnostics at UIC. "During embryonic development, stem cells that go on to become neurons must migrate long distances to other parts of the brain before they mature into adult neurons. We thought that this type of cell migration might have similarities with cancer cells that spread from tumors."

Chenn and colleagues analyzed the proteins expressed by embryonic mouse neural stem cells as they began their migration and found that one protein, cadherin11, was in especially high concentrations in transitioning cells.

Chenn believes the protein "regulates how the cells stick to each other and is also important in helping cells pull themselves along certain pathways as they travel to their final destinations."

When researchers overexpressed cadherin11 in embryonic mice, the neural stem cells began to migrate prematurely.

"This confirmed that cadherin11 was involved in the initiation of migration," said Chen.

To determine whether the protein was involved in the invasion of cancer cells into healthy tissues, researchers looked at its function in glioblastoma, the most common and aggressive type of adult brain cancer.

They examined survival data from patients with glioblastoma and noticed that patients whose tumors expressed elevated levels of the cadherin11 gene had the worst survival rates.

"We also saw that in our tissue samples, the tumor cells with high expression of cadherin11 tended to be located near blood vessels, suggesting that the protein could be involved in encouraging blood vessels to enervate tumors," Chenn said.

When Chenn and his colleagues mixed cells from blood vessel walls with human glioblastoma cells, the glioblastoma cells increased their expression of cadherin11.

"We have long known that tumors recruit their own blood supply, but this finding was particularly interesting because it suggests that blood vessels might actually be stimulating tumor cells to come to them," Chenn said. "Our results together indicate that cadherin11 is critical in inducing cell migration in cancer, and could be an important therapeutic target for preventing its spread."

Abstract
Metastasizing tumor cells undergo a transformation that resembles a process in normal development when non-migratory epithelial cells modulate the expression of cytoskeletal and adhesion proteins to promote cell motility. Here we find a mesenchymal cadherin, Cadherin-11 (CDH11), is increased in cells exiting the ventricular zone (VZ) neuroepithelium during normal cerebral cortical development. When overexpressed in cortical progenitors in vivo, CDH11 causes premature exit from the neuroepithelium and increased cell migration. CDH11 expression is elevated in human brain tumors, correlating with higher tumor grade and decreased patient survival. In glioblastoma, CDH11-expressing tumor cells can be found localized near tumor vasculature. Endothelial cells stimulate TGFβ signaling and CDH11 expression in glioblastoma cells. TGFβ promotes glioblastoma cell motility, and knockdown of CDH11 expression in primary human glioblastoma cells inhibits TGFβ-stimulated migration. Together, these findings show that Cadherin-11 can promote cell migration in neural precursors and glioblastoma cells and suggest that endothelial cells increase tumor aggressiveness by co-opting mechanisms that regulate normal neural development.

Jessica Schulte, Jianing Zhang, Lihui Yin, Maya Srikanth, Sunit Das and John Kessler of Northwestern University; Justin Lathia and Jeremy Rich of the Cleveland Clinic, and Eric Olson of the State University of New York, Syracuse, also contributed to this research.

This work was supported by March of Dimes Research Scholars Grant #1-FY10-504, the Wendy Will Case Fund (Chicago, IL), and a Brain Research Fund Seed Grant (Chicago, IL) to A. C., the Northwestern University Flow Cytometry Facility and the Northwestern University Cell Imaging Facility both supported by a Cancer Center Support Grant (NCI CA060553).

Original press release: http://www.eurekalert.org/pub_releases/2013-08/uoia-pii080713.php