Effect of intra‐ and inter‐tumoral heterogeneity on molecular characteristics of primary IDH‐wild type glioblastoma revealed by single‐cell analysis

Xiong, Zujian; Yang, Qi; Li, Xuejun

doi:10.1111/cns.13396

Cited by 27 publications

(28 citation statements)

References 43 publications

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“…First, the current rat model of glioblastoma was produced by inoculation of the C6 cell line, which does not reflect the intra‐ and inter‐tumoral heterogeneity on molecular characteristics and sensitivities to therapies. 49 While it has been a considerable challenge in the field to inoculate primary glioblastoma cells into rodent brain, we will need to establish such models in the future to identify the optimal treatment paradigms for TEFT. Second, the side effects of TEFT were only partially studied in the current study, with a focus on local skin reactions.…”

Section: Discussionmentioning

confidence: 99%

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study

Yang

Liu

et al. 2021

CNS Neurosci Ther

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AimsTumor electric fields therapy (TTFields) is emerging as a novel anti‐cancer physiotherapy. Despite recent breakthroughs of TTFields in glioma treatment, the average survival time for glioblastoma patients with TTFields is <2 years, even when used in conjugation with traditional anti‐cancer therapies. To optimize TTFields‐afforded efficacy against glioblastoma, we investigated the cancer cell‐killing effects of various TTFields paradigms using in vitro and in vivo models of glioblastoma.MethodsFor in vitro studies, the U251 glioma cell line or primary cell cultures prepared from 20 glioblastoma patients were treated with the tumor electric field treatment (TEFT) system. Cell number, volume, and proliferation were measured after TEFT at different frequencies (100, 150, 180, 200, or 220 kHz), durations (24, 48, or 72 h), field strengths (1.0, 1.5, or 2.2V/cm), and output modes (fixed or random sequence output). A transwell system was used to evaluate the influence of TEFT on the invasiveness of primary glioblastoma cells. For in vivo studies, the therapeutic effect and safety profiles of random sequence electric field therapy in glioblastoma‐transplanted rats were assessed by calculating tumor size and survival time and evaluating peripheral immunobiological and blood parameters, respectively.ResultsIn the in vitro settings, TEFT was robustly effective in suppressing cell proliferation of both the U251 glioma cell line and primary glioblastoma cell cultures. The anti‐proliferation effects of TEFT were frequency‐ and “dose” (field strength and duration)‐dependent, and contingent on the field sequence output mode, with the random sequence mode (TEFT‐R) being more effective than the fixed sequence mode (TEFT‐F). Genetic tests were performed in 11 of 20 primary glioblastoma cultures, and 6 different genetic traits were identified them. However, TEFT exhibited comparable anti‐proliferation effects in all primary cultures regardless of their genetic traits. TEFT also inhibited the invasiveness of primary glioblastoma cells in transwell experiments. In the in vivo rat model of glioblastoma brain transplantation, treatment with TEFT‐F or TEFT‐R at frequency of 200 kHz and field strength of 2.2V/cm for 14 days significantly reduced tumor volume by 42.63% (TEFT‐F vs. control, p = 0.0002) and 63.60% (TEFT‐R vs. control, p < 0.0001), and prolonged animal survival time by 30.15% (TEFT‐F vs. control, p = 0.0415) and 69.85% (TEFT‐R vs. control, p = 0.0064), respectively. The tumor‐bearing rats appeared to be well tolerable to TEFT therapies, showing only moderate increases in blood levels of creatine and red blood cells. Adverse skin reactions were common for TEFT‐treated rats; however, skin reactions were curable by local treatment.ConclusionTumor electric field treatment at optimal frequency, strength, and output mode markedly inhibits the cell viability, proliferation, and invasiveness of primary glioblastoma cells in vitro independent of different genetic traits of the cells. Moreover, a random sequence electric field output confers considerable anti‐cancer effects against glioblastoma in vivo. Thus, TTFields are a promising physiotherapy for glioblastoma and warrants further investigation.

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Section: Discussionmentioning

confidence: 99%

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study

Yang

Liu

et al. 2021

CNS Neurosci Ther

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“…Single-cell RNA-Seq (scRNA-Seq) analysis has emerged as an important approach to dissect the cellular and molecular profile of complex tumors compared to bulk conventional analysis. scRNA-Seq has yielded insights into phenotypic and genotypic differences resulting from tumor cells, the relation with the neural lineages, and the tumor microenvironment, and subpopulations of transformed cells in these extremely heterogeneous tumors (63,(70)(71)(72). Analysis of scRNA-Seq suggested that GBM consist of a combination of tumor cells with different GBM subtype footprints (63).…”

Section: Hgg Intertumoral and Intratumoral Molecular Heterogeneitymentioning

confidence: 99%

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

et al. 2021

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Glioblastomas (GBM) are the most common and aggressive tumors of the central nervous system. Rapid tumor growth and diffuse infiltration into healthy brain tissue, along with high intratumoral heterogeneity, challenge therapeutic efficacy and prognosis. A better understanding of spatiotemporal tumor heterogeneity at the histological, cellular, molecular, and dynamic levels would accelerate the development of novel treatments for this devastating brain cancer. Histologically, GBM is characterized by nuclear atypia, cellular pleomorphism, necrosis, microvascular proliferation, and pseudopalisades. At the cellular level, the glioma microenvironment comprises a heterogeneous landscape of cell populations, including tumor cells, non-transformed/reactive glial and neural cells, immune cells, mesenchymal cells, and stem cells, which support tumor growth and invasion through complex network crosstalk. Genomic and transcriptomic analyses of gliomas have revealed significant inter and intratumoral heterogeneity and insights into their molecular pathogenesis. Moreover, recent evidence suggests that diverse dynamics of collective motion patterns exist in glioma tumors, which correlate with histological features. We hypothesize that glioma heterogeneity is not stochastic, but rather arises from organized and dynamic attributes, which favor glioma malignancy and influences treatment regimens. This review highlights the importance of an integrative approach of glioma histopathological features, single-cell and spatially resolved transcriptomic and cellular dynamics to understand tumor heterogeneity and maximize therapeutic effects.

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“… 34 , 35 Glioblastoma is viewed as an aggressive tumor with substantial heterogeneities. 36 Sottoriva et al performed a complete genomic analysis on biopsies of various parts of the tumors from 11 glioblastoma patients. The results revealed extensive intratumoral heterogeneities.…”

Section: Glioblastomamentioning

confidence: 99%

Prospects of antibodies targeting CD47 or CD24 in the treatment of glioblastoma

Liu

Wang

et al. 2021

CNS Neurosci Ther

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Glioblastoma has a sophisticated immune microenvironment that is different from other solid tumors. The central nervous system was once considered an immune exemption organ because of the lack dedicated lymphatic channels and the limited presentation of antigens derived from the brain to the peripheral immune cells.In 2015, Louveau et al. 1 defined a new lymphatic system. Most antigen-presenting cells that leave the brain may migrate into the deep cervical lymph nodes, where they activate T and B lymphocytes. Since then, immunotherapy for glioblastoma has attracted the interest of researchers. However, systemic immunity, especially the cellular immune function, is suppressed in patients with glioblastoma or in mouse models of glioblastoma. 2 Therefore, enhancing the patient's adaptive immunity, or turning "cold tumor" into "hot tumor," has become the primary goal for glioblastoma research.

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Effect of intra‐ and inter‐tumoral heterogeneity on molecular characteristics of primary IDH‐wild type glioblastoma revealed by single‐cell analysis

Cited by 27 publications

References 43 publications

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study

Exploring the efficacy of tumor electric field therapy against glioblastoma: An in vivo and in vitro study

Uncovering Spatiotemporal Heterogeneity of High-Grade Gliomas: From Disease Biology to Therapeutic Implications

Prospects of antibodies targeting CD47 or CD24 in the treatment of glioblastoma

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