Glioma stem cells, the “root cause” of glioma

  The term glioma, initially used only by professionals, has become notorious, even infamous, in recent years, not only because of the increasing medical science knowledge available to the general public, but also because it indicates that the incidence of this tumor is rising dramatically. Under the guidance of Academician Wang Loyal, he himself has been engaged in clinical and research work on glioma for many years, and although some achievements have been made, some key issues are still not completely clarified. For example, why does glioma recur after surgery? Why adjuvant radiotherapy and chemotherapy still cannot stop tumor recurrence? Why there is a long and short period of recurrence after treatment, and so on. With the intensive research in recent years, I have now finally confirmed the root cause of the refractory and recurrent nature of glioma, which is the root cause of its disease, and that is glioma stem cells.  Recent studies have shown that human tumors are mainly derived from tumor stem cells, and it has also been shown that glioma stem cells are also the source of glioma. The fundamental difference between glioma stem cells and normal glial cells is that glioma stem cells have the potential to increase in value indefinitely, renew themselves, and differentiate in multiple directions, which means that they can differentiate into multiple cells under certain conditions and have the ability to proliferate indefinitely. The mechanism of glioma stem cell tumorigenesis lies in the presence of a small number of neural stem cells in the brain tissue under normal conditions. These cells differentiate into corresponding tissue cells as needed when the brain tissue is damaged, and play a role in repairing the damaged tissue, similar to the hematopoietic function of hematopoietic stem cells in the bone marrow. Under the influence of various adverse factors or tumorigenic factors, the gene expression of neural stem cells gradually undergoes mutation, leading to their unlimited proliferation and differentiation. It is not only able to differentiate into abnormal glial cells, but also into vascular endothelial cells under the condition of hypoxia, and under the condition of insufficient immunity of the body, the body cannot clear away these abnormal cells in time, and eventually they evolve into tumors, at which time the Neural stem cells also become glioma stem cells.  After a lot of clinical observation and experimental research, we found that not only can glioma stem cells be isolated and cultured in glioma tissues, but also the number of such stem cells is closely related to the malignancy of the tumor, i.e., the number of glioma stem cells in gliomas with high malignancy is more, while the number of stem cells in gliomas with low malignancy is less. I have now been able to find 100% of typical glioma stem cells during glioma surgery based on my experience, which has been repeatedly verified in the laboratory. Combining the characteristics of infiltrative glioma growth with my personal clinical experience, I suspect that in a specific glioma there is probably a tumor germinal center composed of glioma stem cells and neovascularization, and that the tumor begins to infiltrate distantly along the less resistant nerve fiber interstices and extravascular interstices in the process of continuous growth. If we can excise the tumor germinal center more thoroughly, it is likely that we can greatly improve the effectiveness of surgical treatment and prolong the time of tumor recurrence. This suspicion has been gradually confirmed, and the time to tumor recurrence in my operated glioma patients is much longer than the average reported in China and abroad.  In recent years, my students and I have also started to study the mechanism of glioma stem cell resistance to chemotherapy, and our findings have finally led to a new discovery: that is, glioma cells are easily killed under the same concentration of chemotherapeutic drugs, while glioma stem cells exhibit extreme drug resistance, and under the repeated action of chemotherapeutic drugs Under the repeated action of chemotherapeutic drugs, glioma stem cells gradually showed some changes in gene and protein expression levels, such as abnormal expression of certain genes in the DNA mismatch repair system and abnormal expression of DNA repair genes, suggesting that glioma stem cells have increased their ability to repair damage caused by chemotherapeutic drugs, i.e., increased drug resistance, and glioma cells differentiated from such stem cells have become resistant to chemotherapy. The results of this study can satisfactorily explain the mechanism of glioma recurrence after chemotherapy, that is, most of the glioma cells were killed in the early stage of chemotherapy, but the glioma stem cells survived, and as the drug continued to act, the glioma stem cells adjusted by their own molecular level changes, so that the new glioma cells became resistant to chemotherapy, and if the glioma stem cells continued to differentiate and proliferate, the tumor recurred. As a result, it leads to the recurrence of the tumor. This may also explain why the dose and type of chemotherapeutic agents need to be constantly adjusted for recurrent gliomas.  Although our study only partially illustrates the mechanism of chemoresistance and recurrence of glioma after chemotherapy, it can also be inferred that the mechanism of glioma recurrence after radiotherapy, which needs to be further demonstrated by future studies.  In conclusion, our work has further demonstrated that the “root cause” of glioma lies in glioma stem cells, and that glioma stem cells are the root cause of drug resistance, radiation therapy resistance, and recurrence of glioma. There is still a long way to go to overcome this problem, but I believe that when we can solve the root cause of glioma stem cells, it is likely to be the time when glioma will be cured.