A program that pushes immature cells to grow up and fulfill their destiny as useful, dedicated cells is short-circuited in the most common and deadly form of brain tumor, scientists at The University of Texas MD Anderson Cancer Center report this week in the Early Edition of the Proceedings of the National Academy of Sciences (PNAS).
Stuck in what amounts to cellular adolescence, these precursor cells accumulate, contributing to the variability among glioblastoma multiforme (GBM) cells that make it so difficult to treat, said first author Jian Hu, Ph.D., instructor of Genomic Medicine.
"This arrested development is driven by the GBM cells' plasticity -- their stem-cell-like ability to produce many types of cells -- and the breakdown of the cellular maturation process known as terminal differentiation," said senior author and MD Anderson President Ronald DePinho, M.D.
By searching for genes missing from GBM cells, rather than mutated, Hu and colleagues discovered a key differentiation pathway whose absence fuels tumor growth. "If glioblastoma cells were to undergo differentiation, the tumor would stop growing," Hu said. "But we've shown that if the terminal differentiation circuitry is gone, they get stuck in the middle and produce many different cell types."
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.
The publication in PNAS is DePinho's Inaugural Paper, the first published in the journal by new members of the National Academy of Sciences. DePinho was elected to the prestigious academy in 2012. PNAS also published a question-and-answer interview with DePinho this week.
GBM cells appear locked in a stem-like state, which can lead to runaway division of undifferentiated cells.
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.Sifting genes involved in nervous system development
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.
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.Gene that turns on A2BP1 identified
They found Myt1L deleted in 5 percent of samples and its protein absent or greatly reduced in 80 percent of tumors. Expression or suppression of Myt1L had similar effects in stem cell lines and mice to those caused by the same actions in A2BP1.
Myt1L also is one of three genes known to trans-differentiate fibroblast cells into neurons, this research makes the first connection between Myt1L and A2BP1, 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.
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 GBM-suppressing chain of events
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.
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.
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.
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.
Scott Merville | EurekAlert!
Further reports about: > A2BP1 > Brain tumor cells > Cancer > Diabetes > Gates Foundation > M cells > PNAS > Science TV > blood malignancies > cell death > cell type > cellular adolescence > cellular diversity > genomic > glioblastoma cells > glioblastoma multiforme > glioblastoma multiforme reflects > heterogeneity machines > nervous system > psychiatric disorder > psychiatric disorders > stem cells > tumor formation
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