"We found that the cells with p53 mutations are highly plastic. If a treatment blocks one path of action, they may learn other ways to grow," Zhu says. That helps explain why glioblastoma multiforme returns in drug-resistant forms.
Research details:
Zhu's team conducted a series of experiments using mice engineered to have a p53 mutation in the central nervous system. They found that a majority developed malignant brain tumors, and that a mutant form of p53 was present in the tumor cells, a phenomenon that is commonly found in human glioblastoma.
"Then we asked, does mutant p53 have any role in tumor initiation and progression? If so, we can use this as a marker for brain cancer in brain cells," says Yuan Wang, the study's first author and a U-M Ph.D. student in cell and developmental biology. The team found that mutant p53 was detectable in a minority of highly proliferative neural stem cells of p53-deficient mice two months after birth, and that the expansion of the mutant-p53-expressing cell population with features of transit-amplifying cells underlies the tumor initiation. The evidence supports the idea that mutant p53 can be a useful marker to trace the glioma cells at all stages.
What's next:
Before any treatments based on these discoveries can benefit people, scientists will need to do more animal studies and verify the animal findings in human studies.
Zhu and his team plan to continue experiments in mice to see if p53 function can be restored in tumor cells. They are also examining whether inhibiting neural stem cells in the SVZ has promise as a potential therapy. Given the plasticity of these cancer-initiating cells, targeting a single signaling pathway may not be sufficient, says Zhu. This trait adds to the complexity of cancer therapy.
Besides Zhu and Wang, other authors are Jiong Yang, Huarui Zheng, Gerald J. Tomasek, Peng Zhang, U-M Department of Internal Medicine, Division of Molecular Medicine and Genetics and Department of Cell and Developmental Biology; Paul E. McKeever, U-M Department of Pathology; and Eva Y-H. P. Lee, University of California, Irvine.
Citation: Cancer Cell, June 2, 2009 Ref: CC-D-08-00286R5
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