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Cell surface protein reveals and imperils breast cancer stem cells

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Cancer stem cells, a small subgroup of hard-core tumor cells capable of both self-renewal and tumor generation, are hard to find, let alone kill.

Scientists at MD Anderson have discovered a cell surface protein that both identifies breast cancer stem cells and provides a target for their destruction.

In findings reported this week in the Journal of Clinical Investigation, the team reported that the ganglioside GD2 is a marker for breast cancer stem cells and vulnerable to an experimental drug called triptolide.

"This is the first targetable marker for breast cancer stem cells," says co-senior author Michael Andreeff, M.D., Ph.D., professor in MD Anderson's departments of Leukemia and Stem Cell Transplantation and Cellular Therapy.

Cancer stem cells are thought to be crucial to resistance to treatment, disease progression and metastasis.  Triptolide stymied cancer growth in cell lines and and prolonged survival in mouse experiments.

Human clinical trials are several years away.

120517sendurai-a_-manifinal.jpgThe breast cancer findings grew from the team's research in mesenchymal stem cells (MSC), which can divide into one copy of themselves and one differentiated copy of a bone, muscle, fat or cartilage cell. Andreeff has shown these mobile mesenchymal stem cells home to wounds, including tumors, making them potential carriers of cancer therapy.
 
"GD2 is one of the markers for mesenchymal stem cells," says study first author Venkata Lokesh Battula, Ph.D., instructor in MD Anderson's Department of Leukemia. "Our previous report that epithelial-to-mesenchymal transition-derived stem cells are functionally similar to MSCs  prompted us to test several MSC markers on breast cancer stem cells.
 
About 85% of solid tumors start in the lining of an organ, called the epithelium. These cells can change into mesenchymal cells.

"In cancer, this change from stationary epithelial cells to the mobile mesenchymal stem cells is an important step in metastasis," says co-senior author Sendurai Mani, Ph.D., assistant professor MD Anderson's Department of Molecular Pathology and co-director of  the Metastasis Research Center.
 
The researchers found GD2 expression divided breast cancer cell lines into two distinct groups: About 4.5% were GD2-positive and 92.7% were GD2-negative.

GD2-positive breast cancer cells:
  • Formed more and larger mammospheres, a clumping of cells used as an indicator of tumor-generating capacity, than GD2-negative cells.
  • Migrated faster in cell culture
  • Generated five times as many tumors when just 10 cells of each type were transplanted into mice.  
  • Were 85-95 % correlated with another combination stem cell marker.
  • Expressed genes involved in migration, invasion and epithelial-to-mesenchymal transition. 
  • Had nine-times the levels of GD3 synthase, an enzyme important to creation of GD2.
Mice injected with 1 million breast cancer cells having a small interfering RNA that blocked GD3 synthase never developed tumors over eight weeks, while all of those with active GD3S developed tumors.

Half of mice treated with triptolide, a known inhibitor of GD3 synthase, did not develop breast cancer while the other half had tumors that were much smaller than untreated mice.  Treated mice lived longer, too.

Drug development continues, as well as efforts to understand the role of GD2 in cancer stem cells. Andreeff noted that the protein is an immune suppressor, which may allow the tumor and its metastases to evade detection and destruction by the immune system.

MD Anderson news release

Journal of Clinical Investigation study

Earlier study in the journal Stem Cells.

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