Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL 32816, USA.
Orlando Neurosurgery, AdventHealth Neuroscience Institute, Orlando, FL 32803, USA.
Int J Mol Sci. 2023 Feb 7;24(4):3242. doi: 10.3390/ijms24043242.
Glioblastoma multiforme (GBM) possesses a small but significant population of cancer stem cells (CSCs) thought to play a role in its invasiveness, recurrence, and metastasis. The CSCs display transcriptional profiles for multipotency, self-renewal, tumorigenesis, and therapy resistance. There are two possible theories regarding the origin of CSCs in the context of neural stem cells (NSCs); i.e., NSCs modify cancer cells by conferring them with cancer-specific stemness, or NSCs themselves are transformed into CSCs due to the tumor environment created by cancer cells. To test the theories and to investigate the transcriptional regulation of the genes involved in CSC formation, we cocultured NSC and GBM cell lines together. Where genes related to cancer stemness, drug efflux, and DNA modification were upregulated in GBM, they were downregulated in NSCs upon coculture. These results indicate that cancer cells shift the transcriptional profile towards stemness and drug resistance in the presence of NSCs. Concurrently, GBM triggers NSCs differentiation. Because the cell lines were separated by a membrane (0.4 µm pore size) to prevent direct contact between GBM and NSCs, cell-secreted signaling molecules and extracellular vesicles (EVs) are likely involved in reciprocal communication between NSCs and GBM, causing transcription modification. Understanding the mechanism of CSC creation will aid in the identification of precise molecular targets within the CSCs to exterminate them, which, in turn, will increase the efficacy of chemo-radiation treatment.
多形性胶质母细胞瘤 (GBM) 存在一小部分但具有重要意义的癌症干细胞 (CSC)，被认为在其侵袭性、复发和转移中发挥作用。CSC 表现出多能性、自我更新、致瘤性和治疗耐药性的转录特征。关于 CSC 在神经干细胞 (NSC) 中的起源有两种可能的理论；即 NSC 通过赋予它们癌症特异性的干性来修饰癌细胞，或者由于癌细胞形成的肿瘤微环境，NSC 本身被转化为 CSC。为了验证这些理论并研究涉及 CSC 形成的基因的转录调控，我们将 NSC 和 GBM 细胞系共培养。在 GBM 中，与癌症干性、药物外排和 DNA 修饰相关的基因上调，而在共培养时 NSCs 中的基因下调。这些结果表明，在 NSCs 存在的情况下，癌细胞向干性和耐药性的转录特征转变。同时，GBM 触发 NSCs 分化。由于细胞系被膜（0.4 µm 孔径）隔开，以防止 GBM 和 NSCs 之间的直接接触，因此细胞分泌的信号分子和细胞外囊泡 (EV) 可能参与 NSCs 和 GBM 之间的相互交流，导致转录修饰。了解 CSC 形成的机制将有助于确定 CSC 内的精确分子靶点来消灭它们，这反过来又会提高化疗和放疗的疗效。
