Main Category: Cancer / Oncology
Also Included In: Neurology / Neuroscience; Stem Cell Research
Article Date: 10 Aug 2013 – 0:00 PDT
University of Texas M. D. Anderson Cancer Center
Other co-authors are Allen Ho, Liang Yuan, Baoli Hu, Ph.D., Sujun Hua, Ph.D., Soyoon Sarah Hwang and Yaoqui Alan Wang, Ph.D., of both Cancer Biology and Genomic Medicine; Jianhua Zhang, Ph.D., of Genomic Medicine and the Institute of Applied Cancer Science; Lynda Chin, M.D., Genomic Medicine; Boyi Gan, Ph.D., of Experimental Radiation Oncology; Tianyi Hu of Trinity College of Arts and Sciences at Duke University; Hongwu Zheng, Ph.D., of Cold Spring Harbor Laboratory in New York, and Gongxiong Wu, M.D., of Joslin Diabetes Center, Harvard Medical School.
To explain the difference between A2BP1′s deletion in only 10 percent of tumors but the absence or reduction of its protein in 90 percent of tumors, the team searched for transcription factors that turn on A2BP1 that might also be deleted or suppressed.
TPM1 proteins come in two forms, one found to have much higher cancer-blocking activity than the other. Splicing of TPM1 by A2BP1 increased levels of the version greater tumor-suppressing activity. Subsequent experiments showed that this version of TPM1 protein significantly reduced glioblastoma formation, invasion and migration in cell cultures and stymied tumor formation in mice.
A microarray analysis of 71 human glioblastoma samples revealed high levels of stem cell and precursor cell markers for neurons and supportive cells. Fewer cells expressed markers of terminal differentiation. Overall, there were high levels of cellular heterogeneity dominated by immature cells. Higher-grade gliomas had greater heterogeneity.
In addition to discovering the deletion and suppression of A2BP1 in GBM, the team established that Myt1L switches on A2BP1, which splices TPM1 into a cell-differentiating, tumor-suppressing mode. “This is probably not the only way that A2BP1 suppresses tumors, but it’s a key mechanism,” Hu said.
Gene that turns on A2BP1 identified
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Some therapies, mainly in blood malignancies, work by forcing immature cells to differentiate. There’s been some hope that differentiation therapy might work on glioblastoma, but Hu notes that it’s likely to be less effective if the cell’s differentiation machinery is missing.
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Their research could lead to biomarkers that indicate whether differentiation therapy will work against a given tumor. A combination of drugs that block stemness pathways and activate Myt1L-A2PB1 differentiation might provide an effective treatment for GBM, the authors noted.
Please note: If no author information is provided, the source is cited instead.
University of Texas M. D. Anderson Cancer Center. “In glioblastoma multiforme, cell maturity pathway is deleted or weak.” Medical News Today. MediLexicon, Intl., 10 Aug. 2013. Web.
10 Aug. 2013. <http://www.medicalnewstoday.com/releases/264588.php>
“When a normal neural stem cell divides, it makes one copy of itself and one copy of a precursor cell destined to differentiate into a neuron, an astrocyte or an oligodendrocyte,” Hu said.
A multistep analysis of RNAs that interact with A2BP1 pointed to the known tumor-suppressor TPM1 as a key gene in mediating A2BP1′s differentiation and cancer-blocking activity.
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GBM cells appear locked in a stem-like state, which can lead to runaway division of undifferentiated cells.
Such cellular diversity, or heterogeneity, is a hallmark of cancer that helps it survive and progress. The “multiforme” in glioblastoma multiforme reflects the heterogeneity among and inside tumors.
MLA
By profiling 430 TCGA GBM samples, the researchers found A2BP1 deleted in 10 percent of tumors. However, additional analysis showed that its protein is absent or steeply reduced in 90 percent of samples. The gene also is deleted in other nervous system tumors, and in 48 percent of colon cancer samples and 18 percent of sarcomas, suggesting a major tumor-suppressing role across cancers.
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In glioblastoma multiforme, cell maturity pathway is deleted or weak
A GBM-suppressing chain of events
Silencing A2BP1 in GBM-prone premalignant neural stem cells led to tumor formation in mouse brains after 15 weeks, while control mice were tumor-free through 25 weeks. Forcing expression of the gene in mouse and human glioma stem cell lines impaired tumor formation by causing immature cells to try to differentiate into neurons, which subsequently died from apoptosis.
This research was funded by grants from the National Cancer Institute of the National Institutes of Health (5K99CA172700, PO1 5PO1CA095616 and UO1 5UO1CA084313); the Leukemia and Lymphoma Society; the U.S. Department of Defense; Helen Hay Whitney Foundation, Juvenile Diabetes Research Foundation and an Exploration-Hypothesis Development Grant.
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