The blood–tumour barrier in cancer biology and therapy

Nature Reviews Clinical Oncology, Год журнала: 2021, Номер 18(11), С. 696 - 714

Опубликована: Июль 12, 2021

Язык: Английский

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Macrophages and microglia: the cerberus of glioblastoma

Acta Neuropathologica Communications, Год журнала: 2021, Номер 9(1)

Опубликована: Март 25, 2021

Abstract Glioblastoma (GBM) is the most aggressive and deadliest of primary brain tumors, characterized by malignant growth, invasion into parenchyma, resistance to therapy. GBM a heterogeneous disease high degrees both inter- intra-tumor heterogeneity. Another layer complexity arises from unique microenvironment in which develops grows. The consists neoplastic non-neoplastic cells. abundant cells are those innate immune system, called tumor-associated macrophages (TAMs). TAMs constitute up 40% tumor mass consist brain-resident microglia bone marrow-derived myeloid periphery. Although genetically stable, can change their expression profiles based upon signals that they receive cells; therefore, heterogeneity creates TAMs. By interacting with other microenvironment, promote progression. Here, we review origin, heterogeneity, functional roles In addition, discuss prospects therapeutically targeting alone or combination standard newly-emerging therapies.

Язык: Английский

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Glioblastoma Microenvironment and Invasiveness: New Insights and Therapeutic Targets

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(8), С. 7047 - 7047

Опубликована: Апрель 11, 2023

Glioblastoma (GBM) is the most common and malignant primary brain cancer in adults. Without treatment mean patient survival approximately 6 months, which can be extended to 15 months with use of multimodal therapies. The low effectiveness GBM therapies mainly due tumor infiltration into healthy tissue, depends on cells’ interaction microenvironment (TME). cells TME involves cellular components such as stem-like cells, glia, endothelial non-cellular extracellular matrix, enhanced hypoxia, soluble factors adenosine, promote GBM’s invasiveness. However, here we highlight role 3D patient-derived glioblastoma organoids cultures a new platform for study modeling In this review, mechanisms involved GBM-microenvironment are described discussed, proposing potential prognosis biomarkers therapeutic targets.

Язык: Английский

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Mitochondrial malfunction and atrophy of astrocytes in the aged human cerebral cortex

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Дек. 16, 2023

How aging affects cells of the human brain active milieu remains largely unknown. Here, we analyze astrocytes and neurons in neocortical tissue younger (22-50 years) older (51-72 adults. Aging decreases amount reduced mitochondrial cytochromes but not neurons. The protein-to-lipid ratio increases Aged show morphological atrophy quantified by decreased length branches, volume fraction leaflets, shrinkage anatomical domain. Atrophy correlates with loss gap junction coupling between increased input resistance. is accompanied upregulation glial fibrillary acidic protein (GFAP) downregulation membrane-cytoskeleton linker ezrin associated leaflets. No significant changes neuronal excitability or spontaneous inhibitory postsynaptic signaling observed. Thus, impaired presence malfunction cortical astrocytes,

Язык: Английский

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The tumour microenvironment, treatment resistance and recurrence in glioblastoma

Journal of Translational Medicine, Год журнала: 2024, Номер 22(1)

Опубликована: Июнь 6, 2024

Abstract The adaptability of glioblastoma (GBM) cells, encouraged by complex interactions with the tumour microenvironment (TME), currently renders GBM an incurable cancer. Despite intensive research, many clinical trials, patients rely on standard treatments including surgery followed radiation and chemotherapy, which have been observed to induce a more aggressive phenotype in recurrent tumours. This failure improve is undoubtedly result insufficient models fail incorporate components human brain TME. Research has increasingly uncovered mechanisms tumour-TME that correlate worsened patient prognoses, tumour-associated astrocyte mitochondrial transfer, neuronal circuit remodelling immunosuppression. hijacked TME highly implicated driving therapy resistance, further alterations within resulting from exposure inducing increased growth invasion. Recent developments improving organoid models, aspects TME, are paving exciting future for research drug development GBM, hopes survival growing closer. review focuses GBMs their effect pathology treatment efficiency, look at challenges face sufficiently recapitulating this adaptive

Язык: Английский

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Glioblastoma heterogeneity and the tumour microenvironment: implications for preclinical research and development of new treatments

Biochemical Society Transactions, Год журнала: 2019, Номер 47(2), С. 625 - 638

Опубликована: Март 22, 2019

Abstract Glioblastoma is the deadliest form of brain cancer. Aside from inadequate treatment options, one main reasons glioblastoma so lethal rapid growth tumour cells coupled with continuous cell invasion into surrounding healthy tissue. Significant intra- and inter-tumour heterogeneity associated differences in corresponding microenvironments contributes greatly to progression. Within this microenvironment, extracellular matrix profoundly influences way cancer become invasive, changes (pH oxygen levels) metabolic (glucose lactate) components support growth. Furthermore, studies on clinical samples have revealed that microenvironment highly immunosuppressive which failure immunotherapy treatments. Although technically possible, many not yet been focus therapies, despite growing evidence its importance malignancy. Here, we review recent progress characterisation sources human material. We also discuss latest advances technologies for personalised vitro preclinical using organoid models better model interactions tissue, may play an essential role developing new more treatments aggressive type

Язык: Английский

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Dissecting and rebuilding the glioblastoma microenvironment with engineered materials

Nature Reviews Materials, Год журнала: 2019, Номер 4(10), С. 651 - 668

Опубликована: Авг. 16, 2019

Язык: Английский

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Biomaterials and 3D Bioprinting Strategies to Model Glioblastoma and the Blood–Brain Barrier

Advanced Materials, Год журнала: 2020, Номер 33(5)

Опубликована: Дек. 16, 2020

Abstract Glioblastoma (GBM) is the most prevalent and lethal adult primary central nervous system cancer. An immunosuppresive highly heterogeneous tumor microenvironment, restricted delivery of chemotherapy or immunotherapy through blood–brain barrier (BBB), together with brain's unique biochemical anatomical features result in its universal recurrence poor prognosis. As conventional models fail to predict therapeutic efficacy GBM, vitro 3D GBM BBB leveraging patient‐ healthy‐individual‐derived cells biomaterials bioprinting technologies potentially mimic essential physiological pathological BBB. 3D‐bioprinted constructs enable investigation cellular cell–extracellular matrix interactions a species‐matched, high‐throughput, reproducible manner, serving as screening drug platforms. Here, an overview current provided, elaborating on microenvironmental compositions BBB, relevant native tissues, strategies implement model fabrication. Collectively, are promising systems biomimetic alternatives traditional for more reliable mechanistic studies preclinical screenings that may eventually accelerate development process GBM.

Язык: Английский

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Breaking through the glioblastoma micro-environment via extracellular vesicles

Oncogene, Год журнала: 2020, Номер 39(23), С. 4477 - 4490

Опубликована: Май 4, 2020

Abstract Glioblastoma (GBM) is the most common and aggressive brain tumour. Prognosis remains poor, despite combined treatment of radio- chemotherapy following surgical removal. GBM cells coexist with normal non-neoplastic cells, including endothelial astrocytes immune constituting a complex dynamic tumour micro-environment (TME). Extracellular vesicles (EVs) provide critical means bidirectional inter-cellular communication in TME. Through delivery diverse range genomic, lipidomic proteomic cargo to neighbouring distant EVs can alter phenotype function recipient cell. As such, have demonstrated their role promoting angiogenesis, suppression, invasion, migration, drug resistance recurrence. Moreover, reflect within Thus, conjunction accessibility biofluids, they potentially serve as biomarker reservoir for patient prognosis, diagnosis predictive therapeutic response well follow-up. Furthermore, together ability cross blood–brain barrier undeterred through exploitation cargo, may an effective mean target site. Unveiling mechanisms by which TME are secreted offer indispensable understanding that holds potential better prognosis overall quality life patients.

Язык: Английский

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Convection-Enhanced Delivery: Connection to and Impact of Interstitial Fluid Flow

Frontiers in Oncology, Год журнала: 2019, Номер 9

Опубликована: Окт. 2, 2019

Convection enhanced delivery (CED) is a method used to increase transport of therapeutics in and around brain tumors. CED works through locally applying pressure differential drive fluid flow throughout the tumor, such that convective forces dominate over diffusive transport. This allows therapies bypass blood barrier would otherwise be too large or solely rely on passive diffusion. However, this also drives out tumor bulk into surrounding parenchyma, which results increased interstitial (IF) flow, within extracellular spaces tissue. Interstitial has been associated with altered molecules, matrix rearrangement, triggering cellular motility number mechanisms. Thus, simple drug may have unintended consequences tissue morphology. Clinically, prediction dispersal agents via convection important catheter design, placement, implementation optimize contact cells therapeutic agent. Prediction software can aid problem, yet we wonder if there better way predict distribution based simply pathways as determined from pre-intervention imaging. Overall, therapy seen limited success posit integration appreciation IF enhance outcomes. manuscript both review current state art mechanistic understanding relate these two elements each other clinical context.

Язык: Английский

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