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Nature Reviews. Cancer Jan 2020For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the... (Review)
Review
For a blood-borne cancer therapeutic agent to be effective, it must cross the blood vessel wall to reach cancer cells in adequate quantities, and it must overcome the resistance conferred by the local microenvironment around cancer cells. The brain microenvironment can thwart the effectiveness of drugs against primary brain tumours as well as brain metastases. In this Review, we highlight the cellular and molecular components of the blood-brain barrier (BBB), a specialized neurovascular unit evolved to maintain brain homeostasis. Tumours are known to compromise the integrity of the BBB, resulting in a vasculature known as the blood-tumour barrier (BTB), which is highly heterogeneous and characterized by numerous distinct features, including non-uniform permeability and active efflux of molecules. We discuss the challenges posed by the BBB and BTB for drug delivery, how multiple cell types dictate BBB function and the role of the BTB in disease progression and treatment. Finally, we highlight emerging molecular, cellular and physical strategies to improve drug delivery across the BBB and BTB and discuss their impact on improving conventional as well as emerging treatments, such as immune checkpoint inhibitors and engineered T cells. A deeper understanding of the BBB and BTB through the application of single-cell sequencing and imaging techniques, and the development of biomarkers of BBB integrity along with systems biology approaches, should enable new personalized treatment strategies for primary brain malignancies and brain metastases.
Topics: Animals; Antineoplastic Agents; Biological Transport; Blood-Brain Barrier; Brain Neoplasms; Combined Modality Therapy; Drug Delivery Systems; Humans; Neoplasm Invasiveness; Neoplasm Metastasis; Precision Medicine; Tumor Microenvironment
PubMed: 31601988
DOI: 10.1038/s41568-019-0205-x -
Journal of Experimental & Clinical... Apr 2022Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor with an extremely poor prognosis. Given the poor survival with currently approved... (Review)
Review
Glioblastoma (GBM) is the most common high-grade primary malignant brain tumor with an extremely poor prognosis. Given the poor survival with currently approved treatments for GBM, new therapeutic strategies are urgently needed. Advances in decades of investment in basic science of glioblastoma are rapidly translated into innovative clinical trials, utilizing improved genetic and epigenetic profiling of glioblastoma as well as the brain microenvironment and immune system interactions. Following these encouraging findings, immunotherapy including immune checkpoint blockade, chimeric antigen receptor T (CAR T) cell therapy, oncolytic virotherapy, and vaccine therapy have offered new hope for improving GBM outcomes; ongoing studies are using combinatorial therapies with the aim of minimizing adverse side-effects and augmenting antitumor immune responses. In addition, techniques to overcome the blood-brain barrier (BBB) for targeted delivery are being tested in clinical trials in patients with recurrent GBM. Here, we set forth the rationales for these promising therapies in treating GBM, review the potential novel agents, the current status of preclinical and clinical trials, and discuss the challenges and future perspectives in glioblastoma immuno-oncology.
Topics: Brain Neoplasms; Glioblastoma; Humans; Immunotherapy; Immunotherapy, Adoptive; Neoplasm Recurrence, Local; Tumor Microenvironment
PubMed: 35428347
DOI: 10.1186/s13046-022-02349-7 -
CA: a Cancer Journal For Clinicians Jul 2020Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There... (Review)
Review
Glioblastoma is the most common malignant primary brain tumor. Overall, the prognosis for patients with this disease is poor, with a median survival of <2 years. There is a slight predominance in males, and incidence increases with age. The standard approach to therapy in the newly diagnosed setting includes surgery followed by concurrent radiotherapy with temozolomide and further adjuvant temozolomide. Tumor-treating fields, delivering low-intensity alternating electric fields, can also be given concurrently with adjuvant temozolomide. At recurrence, there is no standard of care; however, surgery, radiotherapy, and systemic therapy with chemotherapy or bevacizumab are all potential options, depending on the patient's circumstances. Supportive and palliative care remain important considerations throughout the disease course in the multimodality approach to management. The recently revised classification of glioblastoma based on molecular profiling, notably isocitrate dehydrogenase (IDH) mutation status, is a result of enhanced understanding of the underlying pathogenesis of disease. There is a clear need for better therapeutic options, and there have been substantial efforts exploring immunotherapy and precision oncology approaches. In contrast to other solid tumors, however, biological factors, such as the blood-brain barrier and the unique tumor and immune microenvironment, represent significant challenges in the development of novel therapies. Innovative clinical trial designs with biomarker-enrichment strategies are needed to ultimately improve the outcome of patients with glioblastoma.
Topics: Antineoplastic Agents; Bevacizumab; Brain; Brain Neoplasms; Chemoradiotherapy, Adjuvant; Glioblastoma; Humans; Immunotherapy; Incidence; Isocitrate Dehydrogenase; Magnetic Field Therapy; Magnetic Resonance Imaging; Mutation; Neoplasm Recurrence, Local; Precision Medicine; Prognosis; Review Literature as Topic; Survival Rate; Temozolomide; Treatment Outcome; Tumor Microenvironment; United States
PubMed: 32478924
DOI: 10.3322/caac.21613 -
International Journal of Molecular... Dec 2020Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms... (Review)
Review
Glioblastoma is the most common malignant primary brain tumor in adults and is almost invariably fatal. Despite our growing understanding of the various mechanisms underlying treatment failure, the standard-of-care therapy has not changed over the last two decades, signifying a great unmet need. The challenges of treating glioblastoma are many and include inadequate drug or agent delivery across the blood-brain barrier, abundant intra- and intertumoral heterogeneity, redundant signaling pathways, and an immunosuppressive microenvironment. Here, we review the innate and adaptive molecular mechanisms underlying glioblastoma's treatment resistance, emphasizing the intrinsic challenges therapeutic interventions must overcome-namely, the blood-brain barrier, tumoral heterogeneity, and microenvironment-and the mechanisms of resistance to conventional treatments, targeted therapy, and immunotherapy.
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Drug Resistance, Neoplasm; Glioblastoma; Humans; Molecular Targeted Therapy; Tumor Microenvironment
PubMed: 33396284
DOI: 10.3390/ijms22010351 -
Nature Dec 2020Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we...
Most deaths from cancer are explained by metastasis, and yet large-scale metastasis research has been impractical owing to the complexity of in vivo models. Here we introduce an in vivo barcoding strategy that is capable of determining the metastatic potential of human cancer cell lines in mouse xenografts at scale. We validated the robustness, scalability and reproducibility of the method and applied it to 500 cell lines spanning 21 types of solid tumour. We created a first-generation metastasis map (MetMap) that reveals organ-specific patterns of metastasis, enabling these patterns to be associated with clinical and genomic features. We demonstrate the utility of MetMap by investigating the molecular basis of breast cancers capable of metastasizing to the brain-a principal cause of death in patients with this type of cancer. Breast cancers capable of metastasizing to the brain showed evidence of altered lipid metabolism. Perturbation of lipid metabolism in these cells curbed brain metastasis development, suggesting a therapeutic strategy to combat the disease and demonstrating the utility of MetMap as a resource to support metastasis research.
Topics: Animals; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Cell Movement; Electronic Data Processing; Female; Heterografts; Humans; Lipid Metabolism; Mice; Molecular Typing; Mutation; Neoplasm Metastasis; Neoplasm Transplantation; Organ Specificity; Pilot Projects
PubMed: 33299191
DOI: 10.1038/s41586-020-2969-2 -
Cells Mar 2021Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic... (Review)
Review
Cancer stem cells (CSCs), known also as tumor-initiating cells, are quiescent, pluripotent, self-renewing neoplastic cells that were first identified in hematologic tumors and soon after in solid malignancies. CSCs have attracted remarkable research interest due to their role in tumor resistance to chemotherapy and radiation treatment as well as recurrence. Extensive research has been devoted to the role of CSCs in glioblastoma multiforme (GBM), the most common primary brain tumor in adults, which is characterized by a dismal prognosis because of its aggressive course and poor response to treatment. The aim of the current paper is to provide an overview of current knowledge on the role of cancer stem cells in the pathogenesis and treatment resistance of glioblastoma. The six regulatory mechanisms of glioma stem cells (GSCs)-tumor microenvironment, niche concept, metabolism, immunity, genetics, and epigenetics-are reviewed. The molecular markers used to identify GSCs are described. The role of GSCs in the treatment resistance of glioblastoma is reviewed, along with future treatment options targeting GSCs. Stem cells of glioblastoma thus represent both a driving mechanism of major treatment difficulties and a possible target for more effective future approaches.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Brain Neoplasms; Cell Lineage; Drug Resistance, Neoplasm; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Neoplastic Stem Cells; Phenotype; Radiation Tolerance; Tumor Microenvironment
PubMed: 33799798
DOI: 10.3390/cells10030621 -
Cancer Cell Dec 2020Brain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of mA...
Brain metastasis is a major cause of cancer mortality, but its molecular mechanisms are severely understudied. In addition, little is known regarding the role of mA reader YTHDF3 in human diseases. Here, we show that YTHDF3 overexpression clinically correlates with brain metastases in breast cancer patients. YTHDF3 promotes cancer cell interactions with brain endothelial cells and astrocytes, blood-brain barrier extravasation, angiogenesis, and outgrow. Mechanistically, YTHDF3 enhances the translation of mA-enriched transcripts for ST6GALNAC5, GJA1, and EGFR, all associated with brain metastasis. Furthermore, overexpression of YTHDF3 in brain metastases is attributed to increased gene copy number and the autoregulation of YTHDF3 cap-independent translation by binding to mA residues within its own 5' UTR. Our work uncovers an essential role of YTHDF3 in controlling the interaction between cancer cells and brain microenvironment, thereby inducing brain metastatic competence.
Topics: 5' Untranslated Regions; Adenosine; Animals; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Female; Gene Expression Regulation, Neoplastic; Gene Regulatory Networks; Humans; Mice; Neoplasm Transplantation; RNA-Binding Proteins; Survival Analysis; Up-Regulation
PubMed: 33125861
DOI: 10.1016/j.ccell.2020.10.004 -
Oncogene Jun 2023Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to... (Review)
Review
Glioblastoma (GBM) is one of the deadliest types of cancer and highly refractory to chemoradiation and immunotherapy. One of the main reasons for this resistance to therapy lies within the heterogeneity of the tumor and its associated microenvironment. The vast diversity of cell states, composition of cells, and phenotypical characteristics makes it difficult to accurately classify GBM into distinct subtypes and find effective therapies. The advancement of sequencing technologies in recent years has further corroborated the heterogeneity of GBM at the single cell level. Recent studies have only begun to elucidate the different cell states present in GBM and how they correlate with sensitivity to therapy. Furthermore, it has become clear that GBM heterogeneity not only depends on intrinsic factors but also strongly differs between new and recurrent GBM, and treatment naïve and experienced patients. Understanding and connecting the complex cellular network that underlies GBM heterogeneity will be indispensable in finding new ways to tackle this deadly disease. Here, we present an overview of the multiple layers of GBM heterogeneity and discuss novel findings in the age of single cell technologies.
Topics: Humans; Glioblastoma; Brain Neoplasms; Neoplasm Recurrence, Local; Immunotherapy; Tumor Microenvironment
PubMed: 37277603
DOI: 10.1038/s41388-023-02738-y -
Cancer Cell Aug 2023Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its...
Radiation therapy (RT) provides therapeutic benefits for patients with glioblastoma (GBM), but inevitably induces poorly understood global changes in GBM and its microenvironment (TME) that promote radio-resistance and recurrence. Through a cell surface marker screen, we identified that CD142 (tissue factor or F3) is robustly induced in the senescence-associated β-galactosidase (SA-βGal)-positive GBM cells after irradiation. F3 promotes clonal expansion of irradiated SA-βGal GBM cells and orchestrates oncogenic TME remodeling by activating both tumor-autonomous signaling and extrinsic coagulation pathways. Intratumoral F3 signaling induces a mesenchymal-like cell state transition and elevated chemokine secretion. Simultaneously, F3-mediated focal hypercoagulation states lead to activation of tumor-associated macrophages (TAMs) and extracellular matrix (ECM) remodeling. A newly developed F3-targeting agent potently inhibits the aforementioned oncogenic events and impedes tumor relapse in vivo. These findings support F3 as a critical regulator for therapeutic resistance and oncogenic senescence in GBM, opening potential therapeutic avenues.
Topics: Humans; Glioblastoma; Thromboplastin; Cell Line, Tumor; Neoplasm Recurrence, Local; Signal Transduction; Brain Neoplasms; Tumor Microenvironment
PubMed: 37451272
DOI: 10.1016/j.ccell.2023.06.007 -
Nature Sep 2019Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer...
Metastasis-the disseminated growth of tumours in distant organs-underlies cancer mortality. Breast-to-brain metastasis (B2BM) is a common and disruptive form of cancer and is prevalent in the aggressive basal-like subtype, but is also found at varying frequencies in all cancer subtypes. Previous studies revealed parameters of breast cancer metastasis to the brain, but its preference for this site remains an enigma. Here we show that B2BM cells co-opt a neuronal signalling pathway that was recently implicated in invasive tumour growth, involving activation by glutamate ligands of N-methyl-D-aspartate receptors (NMDARs), which is key in model systems for metastatic colonization of the brain and is associated with poor prognosis. Whereas NMDAR activation is autocrine in some primary tumour types, human and mouse B2BM cells express receptors but secrete insufficient glutamate to induce signalling, which is instead achieved by the formation of pseudo-tripartite synapses between cancer cells and glutamatergic neurons, presenting a rationale for brain metastasis.
Topics: Animals; Brain Neoplasms; Breast Neoplasms; Cell Line, Tumor; Female; Humans; Mice; Microscopy, Electron, Scanning; Microscopy, Electron, Transmission; Neoplasm Metastasis; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Synapses; Synaptic Transmission
PubMed: 31534217
DOI: 10.1038/s41586-019-1576-6