Korean researchers have for the first time in the world identified the onset area of carcinogenesis in glioblastoma, a devastating and incurable brain cancer, which is expected to change the paradigm of cancer treatment.
The study, which overturns stereotypes about existing research and treatment, is a new turning point in therapy due to the revelation of the causation origin of glioblastoma. Researchers found that human glioblastomas arise from subventricular zone cells where the cancer is not present.
The findings are published in the latest issue of the world's most prominent journal Nature.
The Yonsei University Severance Hospital team, led by Professor Kang Seok-gu from the Department of Neurology, and the KAIST Graduate School of Medical Science and Engineering team directed by Professor Lee Jeong-ho conducted the study.
Glioblastoma is the most common brain tumor that can cause headaches due to elevated intracranial pressure, dysfunction due to brain tissue destruction such as cranial nerve paralysis, speech disorder, personality change, mental dysfunction, and seizures due to abnormal brain stimulation.
Although surgical treatment is the most important treatment for glioblastoma, and postoperative chemotherapy and radiotherapy are the standard treatment, the prognosis is poor. Precision cancer treatment approaches using targeted anticancer agents have also shown a poor response.
In the United States and Europe, studies on glioblastoma and clinical trials have been underway, but most focused only on the cancer tissue itself.
The research team took a different approach. Unlike conventional studies on a cancer tissue, researchers studied three different types of tissue - tumor tissues, healthy tissues and perineural tissues obtained during broad-spectrum resection – to investigate the mechanism of glioblastoma.
The research teams analyzed 30 cases of brain tumors that were operated on from 2013 to 2017. Researchers comprehensively combined and examined tumor tissues, healthy tissues, and perineural tissues.
As a result, tumor-induced mutant cells were found at low frequencies in the subventricular zone that did not have cancer cells. In fact, in about 56 percent of glioblastoma patients' tumors, researchers found the observed tumor-induced mutations were found in low frequency in the subventricular region where the tumor was absent. In particular, mutations were concentrated in the astrocytic ribbon region in the subventricular zone.
Researchers also confirmed through single-cell sequencing that tumor-induced mutant cells in the subventricular region migrate to other parts of the brain over time. Single cell sequencing is a state-of-the-art gene analyzing method capable of analyzing even small amounts of cells by providing spatial information on cell location.
Animal studies to verify the glioblastoma generation mechanism also produced the same results. According to the team, tumor-induced mutant cells such as P53, PTEN, and EGFR were generated in the subventricular region in the genetically modified animal model and migrated to other parts of the brain. Glioblastomas then developed over time.
The results of this study are expected to change the paradigm of cancer treatment and lead to clues for therapy not only glioblastoma but also other cancers.
"The study is a breakthrough regarding finding the development of cancer in which human glioblastomas begin to develop in the subventricular zone where normal neural stem cells are present, not where cancer originated," Professor Kang said. “We need to change the direction of cancer research from those that focus on cancer tissues to focus on tissues where cancer originates to solve the mystery of cancer treatment and open a new paradigm."
The team is working on an innovative treatment to prevent the process of tumor-induced mutations in the subventricular zone that evolves into glioblastomas.
The research was supported by the Korea Research Foundation, the Korea Health Industry Development Institute, the Suh Kyungbae Foundation, and the Ministry of Health and Welfare.