The role of the neural niche in brain metastasis

Hoshide, Reid; Jandial, Rahul

doi:10.1007/s10585-017-9857-7

Cited by 25 publications

(20 citation statements)

References 24 publications

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“…2A, B). It was recently reported that a complex reciprocal communication between metastatic tumor cells and other brain stoma cells primed the successful outgrowth of overt brain metastases, which was dependent on the release of some factors, including secreted soluble proteins or small vesicles (such as exosomes) (20,21). To establish the existence of the exosomes in HBMECconditioned medium, the medium was collected from the coculture system in which the HBMECs were labeled by Syto fluorescence in advance.…”

Section: Resultsmentioning

confidence: 99%

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Miao

Jiang

et al. 2018

FASEB j.

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Small cell lung cancer (SCLC) is the most aggressive histologic subtype of lung cancer, with a strong predilection for early brain metastases. Despite efforts and advances in new therapeutics for SCLC, the prognosis of patients with SCLC with brain metastases is consistently poor. Therefore, a better understanding of the mechanisms of SCLC brain metastasis is important in improving current treatments. In this study, elevated S100A16 levels were associated with SCLC brain metastases, which was a possible secondary event arising from the brain metastatic microenvironment. Using an in vitro cell coculture system, we found that the coculturing of SCLC cells with human brain microvascular endothelial cells (HBMECs) led to an increased expression of S100A16 in SCLC cells. Conversely, treatment of HBMECs with GW4869, an inhibitor of exosome release, significantly blocked this effect in the cocultured SCLC cells. Alternatively, the results from Western blot analyses and immunofluorescence indicated that the HBMEC exosomes purified by ultracentrifugation also induced the elevation and translocation from the cytoplasm to the nucleus of S100A16 in the recipient SCLC cells. The inhibition experiments demonstrated that elevated S100A16 contributed a benefit of HBMEC exosomes for the survival of the recipient SCLC cells under stress. Moreover, the elevation of S100A16 in SCLC cells prevented the loss of mitochondrial membrane potential (Δψm) and enhanced resistance to apoptosis under stressful conditions, which were determined by Annexin V/propidium iodide and JC-1 assay. Further results showed that the S100A16-mediated protective effect was caused by the presence of an important element in Δψm, prohibitin (PHB)-1, a protein in the mitochondrial inner membrane. Conversely, the delivery of PHB-1 siRNAs into S100A16 overexpressing SCLC cells weakened these protective effects. Our findings suggest that elevated S100A16 plays an active role in facilitating the survival of SCLC cells through modulating the mitochondrial function, identifying S100A16 as an important potential target in SCLC brain metastasis.-Xu, Z.-H., Miao, Z.-W., Jiang, Q.-Z., Gan, D.-X., Wei, X.-G., Xue, X.-Z., Li, J.-Q., Zheng, F., Qin, X.-X., Fang, W.-G., Chen, Y.-H., Li. B. Brain microvascular endothelial cell exosome-mediated S100A16 up-regulation confers small cell lung cancer cell survival in brain.

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Section: Resultsmentioning

confidence: 99%

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Miao

Jiang

et al. 2018

FASEB j.

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“…Metastasis is a process rather than a simple endpoint, wherein the arrest of the cancer cells occurs at vascular branch points, cancer cells have to remain close to microvessels, and perivascular growth by early angiogenesis is predominant in lung cancer and by vessel co-option in melanoma [77]. In comparison, breast cancer cells that reach the brain exhibit a GABAergic phenotype similar to neuronal cells, They can use GABA as an energy metabolite and increase cell survival [79, 80].…”

Section: The Tumor Microenvironment In Brain Metastasesmentioning

confidence: 99%

Tumor microenvironment differences between primary tumor and brain metastases

et al. 2020

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The present review aimed to discuss contemporary scientific literature involving differences between the tumor microenvironment (TME) in melanoma, lung cancer, and breast cancer in their primary site and TME in brain metastases (BM). TME plays a fundamental role in the behavior of cancer. In the process of carcinogenesis, cells such as fibroblasts, macrophages, endothelial cells, natural killer cells, and other cells can perpetuate and progress carcinogenesis via the secretion of molecules. Oxygen concentration, growth factors, and receptors in TME initiate angiogenesis and are examples of the importance of microenvironmental conditions in the performance of neoplastic cells. The most frequent malignant brain tumors are metastatic in origin and primarily originate from lung cancer, breast cancer, and melanoma. Metastatic cancer cells have to adhere to and penetrate the blood–brain barrier (BBB). After traversing BBB, these cells have to survive by producing various cytokines, chemokines, and mediators to modify their new TME. The microenvironment of these metastases is currently being studied owing to the discovery of new therapeutic targets. In these three types of tumors, treatment is more effective in the primary tumor than in BM due to several factors, including BBB. Understanding the differences in the characteristics of the microenvironment surrounding the primary tumor and their respective metastasis might help improve strategies to comprehend cancer.

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“…These factors activate astrocytes to produce growth factors (IL-6, IL-1B, and tumor necrosis factor), resulting in a perpetuation of cancer cell growth in the neural niche ( 18 ). Activation of VEGF, Notch pathways and secretion of BMP-2 (a growth factor that differentiates neuronal stem cells into astrocytes) sustain neoangiogenesis in BMs and tumor–astrocyte interactions ( 19 ).…”

Section: Biology and Pathophysiology Of Bmsmentioning

confidence: 99%

Mechanisms and Therapy for Cancer Metastasis to the Brain

2018

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Advances in chemotherapy and targeted therapies have improved survival in cancer patients with an increase of the incidence of newly diagnosed brain metastases (BMs). Intracranial metastases are symptomatic in 60–70% of patients. Magnetic resonance imaging (MRI) with gadolinium is more sensitive than computed tomography and advanced neuroimaging techniques have been increasingly used in the detection, treatment planning, and follow-up of BM. Apart from the morphological analysis, the most effective tool for characterizing BM is immunohistochemistry. Molecular alterations not always reflect those of the primary tumor. More sophisticated methods of tumor analysis detecting circulating biomarkers in fluids (liquid biopsy), including circulating DNA, circulating tumor cells, and extracellular vesicles, containing tumor DNA and macromolecules (microRNA), have shown promise regarding tumor treatment response and progression. The choice of therapeutic approaches is guided by prognostic scores (Recursive Partitioning Analysis and diagnostic-specific Graded Prognostic Assessment-DS-GPA). The survival benefit of surgical resection seems limited to the subgroup of patients with controlled systemic disease and good performance status. Leptomeningeal disease (LMD) can be a complication, especially in posterior fossa metastases undergoing a “piecemeal” resection. Radiosurgery of the resection cavity may offer comparable survival and local control as postoperative whole-brain radiotherapy (WBRT). WBRT alone is now the treatment of choice only for patients with single or multiple BMs not amenable to surgery or radiosurgery, or with poor prognostic factors. To reduce the neurocognitive sequelae of WBRT intensity modulated radiotherapy with hippocampal sparing, and pharmacological approaches (memantine and donepezil) have been investigated. In the last decade, a multitude of molecular abnormalities have been discovered. Approximately 33% of patients with non-small cell lung cancer (NSCLC) tumors and epidermal growth factor receptor mutations develop BMs, which are targetable with different generations of tyrosine kinase inhibitors (TKIs: gefitinib, erlotinib, afatinib, icotinib, and osimertinib). Other “druggable” alterations seen in up to 5% of NSCLC patients are the rearrangements of the “anaplastic lymphoma kinase” gene TKI (crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib). In human epidermal growth factor receptor 2-positive, breast cancer targeted therapies have been widely used (trastuzumab, trastuzumab-emtansine, lapatinib-capecitabine, and neratinib). Novel targeted and immunotherapeutic agents have also revolutionized the systemic management of melanoma (ipilimumab, nivolumab, pembrolizumab, and BRAF inhibitors dabrafenib and vemurafenib).

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The role of the neural niche in brain metastasis

Cited by 25 publications

References 24 publications

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Brain microvascular endothelial cell exosome–mediated S100A16 up‐regulation confers small‐cell lung cancer cell survival in brain

Tumor microenvironment differences between primary tumor and brain metastases

Mechanisms and Therapy for Cancer Metastasis to the Brain

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