Astrocytes Protect Medulloblastoma Cells From Radiotherapy Or Chemotherapy

Object: Medulloblastoma(MB)is a common posterior cranial fossa tumor originated in the primitive neuroectodermal layer,is the most common pediatric central nervous system tumor.It mainly happens on the inferior crest of the cerebellum.and often occurs through the dissemination of cerebrospinal fluid.The treatments of medulloblastoma are mainly surgery supplemented by radiotherapy and chemotherapy.However,it is not easy to complete removal of MB by surgery.Radiotherapy and chemotherapy also have serious side effects,causing varying degrees of decline in IQ and cognitive impairment,hearing impairment,endocrine disorders,nervous system development disorders,growth retardation,secondary tumors,Cardiopulmonary toxicity and reproductive toxicity,etc..MB's long-term survival rate is poor.The children's normal growth and quality of life are seriously affected.Reducing the dose of radiotherapy and chemotherapy is difficult to control the tumor cells and even trigger the treatment resistance and recurrence problems.Through recent studies,many strategies have been proposed to overcome the radiotherapy and chemotherapy resistance of tumor cells,but little attention is paid to the mechanisms mediated by the tumor microenvironment and how to avoid them.With the continuous development of tumor molecular biology technology and the deep understanding of tumor pathogenesis at the molecular level,the tumor microenvironment is the biological key to tumorigenesis,progression and metastasis.Astrocytes are specialized glial cells that are widely distributed in the brain,provide energy metabolites to neurons,and maintain homeostasis of extracellular ions and neurotransmitters.They play an important role in microcirculation.It is also an important component of the medulloblastoma microenvironment.In addition,astrocytes release a large number of growth factors and cytokines that may provide a supportive microenvironment for tumor growth and metastasis.Studies have been shown that astrocytes play an integral role in the occurrence and development of SHH medulloblastoma,which highlights the importance of astrocytes in the medulloblastoma microenvironment.However,for the time being,the effects of astrocytes on the radiotherapy and chemotherapy of medulloblastoma are still lacking.Therefore,this study objects to show the effects of astrocytes,an important component of the tumor microenvironment on medulloblastoma radiotherapy and chemotherapy,and provide clinical treatment and resistance to medulloblastoma and offer new train of thought for the research on drug resistance.Methods: Medulloblastomas and astrocytes were co-cultured at a 1:10 concentration in vitro to mimic the conditions of the simulated tumor microenvironment after extracted from primary medulloblastoma cells and astrocytes.After radiotherapy or chemotherapy treatment,the effects of astrocytes on the radiotherapy and chemotherapy injury of medulloblastoma were studied by comparing the survival state of medulloblastoma cells cultured and co-cultured.The mechanisms of radiation and chemotherapy injury protection was studied through a comparative study of astrocytoma on medulloblastoma which was conducted by comparing the differences in proliferative capacity,apoptosis and DNA damage between medulloblastoma cultured alone and astrocytic cells during radiotherapy and chemotherapy.Results: The results are summarized as following.1.The cultured medulloblastomas died in large numbers in the case of 1Gy radiotherapy,while the medulloblastomas co-cultured with astrocytes survived,and at 2?M cisplatin chemotherapy,a lot of medulloblastomas cultured died,and the co-cultured medulloblastoma dead number is small.2.Through labeling of the DNA damage-specific antibody ?H2AX and the apoptosis-specific antibody Cleaved-caspase3,the degree of DNA damage and apoptosis in the case of 1Gy radiotherapy for medulloblastoma co-cultured with astrocytes were found.Both were lower than those of medulloblastoma cultured alone;at 2?M cisplatin chemotherapy,the degree of DNA damage and apoptosis of cultured medulloblastoma was higher than that of co-cultured medulloblastoma.It has been demonstrated that co-culture with astrocytes can increase the resistance of medulloblastoma to DNA damage,thereby reducing its apoptosis in radiotherapy and chemotherapy.3.Quantitative analysis of q PCR revealed that the medulloblastoma is higher while medulloblastoma co-cultured with astrocytes showed significantly more expression of Interferon-Related DNA Damage Resistance Signature(IRDS)than that cultured alone in the presence of 1Gy radiotherapy or 2?M cisplatin chemotherapy.Conclusion: Astrocytes have a protective effect against medulloblastoma radiotherapy and chemotherapy.In the course of radiotherapy and chemotherapy of medulloblastoma,astrocytes could depress the apoptosis of medulloblastoma by increasing the resistance of medulloblastoma to DNA damage.Further studies have found that the protective effect of astrocytes on radiotherapy and chemotherapy injury of medulloblastoma may be related to the enhancement of interferon-related DNA damage resistance gene(IRDS)expression in medulloblastoma.