Gene expression profiling of glioblastoma cell lines depending on TP53 status after tumor-treating fields (TTFields) treatment

Abstract

Glioblastoma is frequently associated with TP53 mutation, which is linked to a worse prognosis and response to conventional treatments (chemoradiotherapy). Therefore, targeting TP53 is a promising strategy to overcome this poor therapeutic response. Tumor-treating fields (TTFields) are a recently approved treatment for newly diagnosed glioblastoma, which involves direct application of lowintensity, intermediate-frequency alternating electric fields to the tumor, thereby offering a local tumor-killing effect. However, the influence of TP53 mutation status on the effectiveness of TTFields is controversial. Here, we identified the key gene signatures and pathways associated with TTFields in four glioblastoma cell lines varying in TP53 mutation status using gene profiling and functional annotation. Overall, genes associated with the cell cycle, cell death, and immune response were significantly altered by TTFields regardless of TP53 status. TTFields appeared to exert enhanced anticancer effects by altering the immune system in the inflammatory environment and regulating cell cycle-and cell death-related genes, but the precise genes influenced vary according to TP53 status. These results should facilitate detailed mechanistic studies on the molecular basis of TTFields to further develop this modality as combination therapy, which can improve the therapeutic effect and minimize side effects of chemoradiotherapy. Glioblastoma (GBM) a histological subtype of glioma in which most patients survive for an average of 12-15 months 1. In primary and secondary GBM, TP53 mutation is observed in up to 30% and 70% of cases, respectively, which results in a common molecular abnormality 2. TP53 is a major tumor suppressor that selectively eliminates mutated or damaged cells 3 , reduces the proliferation of cancer cells, and prevents the malignant transformation of normal cells 4. Moreover, TP53 regulates transcriptional target genes involved in many cellular responses including apoptosis 5 , senescence 6 , DNA repair 7 , and cell cycle 8 , among others. Several decades of research of glioma has shown that not only does TP53 serve a central role in the regulatory network of tumorigenesis, but also that the TP53 status is closely associated with the disease progression and survival of patients with GBM during radio-and chemotherapy 9,10. Several researchers have suggested that TP53-based targeted therapy is a promising approach for treating GBM, but its value as a prognostic marker in the clinical field is unclear. Microarray analysis is a useful method for evaluating therapies for GBM to detect differential expression between normal and cancer cells following treatment with specific drugs or physical procedures 11,12. TP53 has functional effects on the transcriptional profiles of genes in several cancer cell lines 13 , but the impact of tumortreating fields (TTFields) on GBM according to the TP53 status remains unknown. TTFields has been proposed as an effective cancer treatment in combination with other therapies 14. Alternating ele...

Molecular alterations associated with improved outcome in patients with glioblastoma treated with Tumor-Treating Fields

“…In a GB study, 4 cell lines were used with varying TP53 status to influence TTFields treatment. 14 Genes associated with cell cycle, cell death, and immune response were analyzed after TTFields application and were altered despite TP53 status. 14 In our study, there was no difference detected in TTFields response between tumors that were TP53 wild-type vs mutant.…”

“… 14 Genes associated with cell cycle, cell death, and immune response were analyzed after TTFields application and were altered despite TP53 status. 14 In our study, there was no difference detected in TTFields response between tumors that were TP53 wild-type vs mutant. TP53 is a ubiquitous tumor suppressor marker so it may not be surprising that no differences were found.…”

Impact of General Factors on Glioma Immunotherapy

“… 81 82 Its tumor-killing effect can also be enhanced by regulating genes related to the cell cycle and cell death in glioma. 83 Immunogenic cell death can activate robust innate immunity such as by activating the STING pathway and releasing proinflammatory cytokines and chemokines. 84 There is also evidence that TTFields promotes the eradication of cancer cells by DCs and DC maturation in vitro and the recruitment of immune cells in vivo.…”

Zika Virus: A New Therapeutic Candidate for Glioblastoma Treatment

“…This therapy represents a valuable clinical approach for treating GBM. TTF induces the expression of genes involved in the cell cycle, cell death, and the immune response, regardless of TP53 status [53], suppressing angiogenesis by downregulating pro-angiogenic factors, including VEGF [54], and might also target vascular niche-associated GSCs [55].…”