Cancer Stem Cell Regulatory Gene Identified
Cancer stem cells have many of the same characteristics as regular stem cells - and are thought to be directly responsible for tumor formation and growth. Tufts University researchers have recently identified that the STAT3 gene regulates cancer stem cells in the aggressive brain cancer, Glioblastoma multiforme (GBM) - offering a promising new option in the fight against such cancers.
With current treatment options - radiation, chemotherapy and surgery - patients with Glioblastoma multiforme typically only survive 12 to 14 months. However; “when STAT3 is inhibited, cancer stem cells in glioblastomas lose their stem-cell characteristics permanently, suggesting that STAT3 regulates growth and self-renewal of stem cells within glioblastomas. Strikingly, a single, acute treatment with STAT3 inhibitors was effective, implying that a STAT3 inhibitor could stop tumor formation,” said senior author Brent Cochran, PhD, a professor at Tufts University School of Medicine and a member of the cellular and molecular physiology program faculty at the Sackler School of Biomedical Sciences at Tufts.
“STAT3 has been shown to be activated in a number of human tumors. This study is one of the first to show, however, that STAT3 regulates cancer stem cells. It is one of the few genes linked to the propagation of cancer stem cells, and it appears to regulate processes involved in the six hallmarks of cancer: growth, metastasis, angiogenesis, evasion of apoptosis, tissue invasion, and cell immortalization,” he continued.
The researchers worked with cancer stem cells isolated from surgically removed glioblastoma tumors. They treated the cancer cell cultures with small-molecule STAT3 inhibitors - STA-21 and S3I-201. After several days of treatment, cell growth in the STAT3-inhibited cultures was significantly less than that in the control samples. Additionally, in the STAT3-inhibited samples it was discovered that key proteins that help maintain stem-cell characteristics had been turned off. These findings suggests that STAT3 plays an important and distinct role in cancer stem cells - and may make it an excellent target for cancer therapy.
“Current cancer therapies that prolong life do not specifically target cancer stem cells, and these cells are often resistant to traditional radiation and chemotherapies. STAT3 appears to govern the propagation of cancer stem cells in Glioblastoma multiforme. Targeted inhibition of STAT3 in GBM cancer stem cells gives us a new approach to treating this devastating brain cancer,” said Julian Wu, MD, associate chairman of neurosurgery and chief of the division of neurosurgical oncology at Tufts Medical Center. He is also a professor at Tufts University School of Medicine. Dr. Wu is known for his expertise in gene therapy for brain tumors and the molecular genetics of primary and metastatic brain tumors.
“We are encouraged by the potential of STAT3 in our study,” said Cochran. “Research has already demonstrated that STAT3 and cancer go hand in hand, but, until this study, we did not know that STAT3 regulates cancer stem cells, which are extremely resistant to conventional therapy. Given these findings, I hope that our future research investigating the mechanisms involved in inhibiting STAT3 will contribute to more effective and less invasive cancer therapies.”
Sherry MM, Reeves A, Wu JK, and Cochran BH. 2009. Stem Cells. “STAT3 is required for proliferation and maintenance of multipotency in glioblastoma stem cells.” Published online August 5, 2009, doi: 10.1002/stem.185
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