In recent years, studies have found that the incidence of primary malignant brain tumors has increased significantly, and the current prognosis is poor. Therefore, studying the mechanism of brain tumor recurrence, improving the prognosis of patients, and prolonging their survival time is an important research direction and a major problem faced by experts: due to the vague understanding of the source of brain tumor cells and its mechanism. Although a large number of related experimental studies have been done on the pathogenesis of malignant brain tumors, but no satisfactory results have been achieved.
Currently, only a small percentage of cells in surgical tissues of brain tumors have been found to have infinite proliferation, self-renewal, multi-directional differentiation potential, and tumorigenicity. These cells are called brain tumor stem cells (BTSCs), and others tumor cells have no or only short-term proliferation ability. Igntova and other scholars first reported that brain tumor stem cells (BTSC) existed in brain tumor surgical specimens, and isolated precursor neurons that can form neurospheres from glioblastomas, which are called neural stem cells in brain tumors. At present, each brain tumor stem cell has been successfully cultured and isolated from surgical specimens such as medulloblastoma, different grades of astrocytoma, ependymal tumor, and ganglioglioma.
Since Singh et al. First isolated CD133-positive tumor stem cells from malignant brain tumors, research on brain tumor stem cells has gradually become a hot topic in neuroscience and related fields. Preliminary studies have found that the occurrence, development, metastasis, and recurrence of brain tumors may be closely related to brain tumor stem cells. Therefore, further in-depth discussion of the biological characteristics of brain tumor stem cells and the mechanism in the occurrence and recurrence of malignant brain tumors will definitely be very important for the future of radical treatment and prevention of malignant brain tumors.
Here in this article, we will introduce three important biomarkers.
One of the most prominent one is TSGF, namely a group of tumor-related substances. It is a collective term for several internationally recognized carbohydrates and metabolites (lipoproteins, enzymes, amino acids) related to the growth of malignant tumors. TSGF is an effective, convenient and valuable tumor marker for the diagnosis and judgment of brain malignant tumors.
In addition, studies have shown that the expression specificity of tumor markers such as nestin, BEHAB, YKL-40, EphA2, glial fibrillary acidic protein, CD133, fatty acid binding protein, and MMP-9 is more obvious in gliomas.
There are many hypotheses about the source of BTSC, but currently they tend to be derived from mature neural stem cells (NSCs). The accumulation of multiple mutations leads to tumorigenicity and becomes BTSC. The source is discussed from the following two aspects: ① The origin of the tumor is consistent with the NSC distribution area. Studies have shown that the origin of brain tumors may originate in a part of the subventricular area, and BTSCs with high proliferation and differentiation potential are constantly produced in this area, which leads to tumorigenesis, and these areas coincide with the main locations of NSCs. ② BTSC and NSC have many similarities in genetics. The main manifestation is that BTSC does not express markers of differentiated cells, but instead has NSC markers, such as Nestin or CD133.
In summary, both theory and experiments support that BTSC is likely to be derived from mutant NSCs that are constantly dividing and proliferating. Although BTSC and NSC have many similarities, there are also obvious differences between them: first, BTSC has stronger self-renewal and proliferation capabilities than NSC, and the number of passages in vitro culture has increased significantly, with an immortalization trend. Its self-renewal and differentiation have become imbalanced; secondly, BTSC differentiates into the same phenotype as the parent tumor under the conditions that induce NSC differentiation and does not differentiate into neurons and glial cells in the same proportion as NSC. These differences provide new research directions and ideas on how to transform NSC into BTSC and whether the two are at the same level of differentiation.
2. CD133 protein, nestin, Sox2 protein
In recent years, Rath et al. have successfully cultured and isolated meningioma stem cell spheres with spherical focus growth through serum-free suspension culture. At present, most scholars use CD133 and Nestin as specific markers of brain tumor stem cells. CD133 is a transmembrane protein with a relative molecular weight of 120,000. Studies have shown that both solid tumors and brain tumor cell spheres obtained from in vitro cell line cultures show CD133 positive staining; and CD133 positive cells isolated from glioma cell lines in serum-free culture, they all grew spheroidally, had infinite proliferation, self-renewal, and multi-directional differentiation.
Singh et al. compared the biological characteristics of CD133-positive and negative tumor cells and found that the former has a strong ability to self-renew and proliferate, while the latter adheres to growth, does not divide, and does not proliferate. In vivo tumorigenicity tests showed that 100 CD133-positive tumor cells were tumorigenic, while 1 × 105 CD133-negative tumor cells formed only one glial scar at the transplant site.
For these reasons, CD133 is considered to be the most important marker of brain tumor stem cells. However, recent studies have shown that CD133-negative cells in some brain tumors also have the characteristics of tumor stem cells. Therefore, CD133 is not a reliable marker for brain tumor stem cells. Nestin, which belongs to the intermediate microfilament, is expressed in undifferentiated neural pluripotent stem cells and was once considered a marker of brain tumor stem cells. However, the study found that the same group of tumor cells, Nestin-positive ratio is much higher than CD133-positive ratio, which indicates that Nestin is also expressed in progenitor cells that have just begun to differentiate, and is not a reliable brain tumor stem cell marker.
Sox-2 belongs to the Sox (Sry-related HMG Box) gene family and is located at 3q26.3-q27 of the chromosome. It is a highly conserved transcription factor that can regulate the self-renewal of embryonic stem cells. It is the only Sox gene found in current research that plays an important role in maintaining the differentiation potential of embryonic stem cells. It is also a key to induce adult cells to become pluripotent stem cells.
3. Brain tumor stem cells
The research of brain tumor stem cells has become a new hot spot in the field of brain tumor research. Although great achievements have been made in the successful isolation and culture of brain tumor stem cells, no complete theoretical system has been formed so far. Therefore, it is of great significance to study the pathogenesis and biological behavior of brain tumors and to find new treatment options for malignant brain tumors that target tumor stem cells in the future. It can be imagined that the detection of tumor stem cells will become a new classification and judgment of brain tumors in the future. It is possible to use various treatment schemes for brain tumor stem cells to specifically kill brain tumor stem cells, instead of killing all tumor tissues, in order to achieve radical cure and prevent tumor recurrence and metastasis. With the continuous research on brain tumor stem cells, it will inevitably have a profound impact on the pathogenesis, pathological grading, prevention of recurrence and treatment options of brain tumors, making the radical cure of malignant brain tumors possible.