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Cancers
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Brain Metastases: From Mechanisms to Treatment
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Brain Metastases: From Mechanisms to Treatment

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Metastasis".

Deadline for manuscript submissions: 30 April 2025 | Viewed by 6626

Special Issue Editors

Prof. Dr. Dawen Zhao

E-Mail Website
Guest Editor
Departments of Biomedical Engineering and Cancer Biology, Wake Forest School of Medicine, Winston Salem, NC, USA
Interests: molecular imaging diagnosis; magnetic resonance imaging; glioma; drug delivery systems; nanotechnology; cancer imaging
Prof. Dr. Michael Chan

E-Mail Website
Guest Editor
Department of Radiation Oncology, Wake Forest School of Medicine, Winston Salem, NC, USA
Interests: stereotactic radiosurgery, brain metastasis velocity, brain metastasis biomarkers

Special Issue Information

Dear Colleagues,

Brain metastasis is the most common intracranial malignancy in adults. The current standard of care for brain metastasis includes surgical resection, stereotactic radiosurgery (SRS) and/or whole brain radiotherapy (WBRT). However, the prognosis for patients with brain metastasis is extremely poor, with a median survival of 8 to 16 months.

We are putting together a Special Issue of Cancers focusing on brain metastasis, which we hope will include recent advances in understanding mechanisms that underlie the development of brain metastasis and its tumor microenvironment (TME), such as the blood–tumor barrier (BTB), and in seeking new disease-specific biomarkers and novel treatment and combinatory treatment. We welcome contributions of both preclinical and clinical studies, as review articles or original research papers, on this clinically significant topic.

Prof. Dr. Dawen Zhao
Prof. Dr. Michael Chan
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • brain metastasis
  • the tumor microenvironment
  • blood–tumor barrier
  • novel biomarkers and therapeutics
  • radiation therapy

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Published Papers (5 papers)

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Research

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12 pages, 1301 KiB  
Article
Genomic Signature for Initial Brain Metastasis Velocity (iBMV) in Non-Small-Cell Lung Cancer Patients: The Elusive Biomarker to Predict the Development of Brain Metastases?
by Sarah E. Glynn, Claire M. Lanier, Ariel R. Choi, Ralph D’Agostino, Jr., Michael Farris, Mohammed Abdulhaleem, Yuezhu Wang, Margaret Smith, Jimmy Ruiz, Thomas Lycan, William Jeffrey Petty, Christina K. Cramer, Stephen B. Tatter, Adrian W. Laxton, Jaclyn J. White, Jing Su, Christopher T. Whitlow, David R. Soto-Pantoja, Fei Xing, Yuming Jiang, Michael Chan and Corbin A. Helisadd Show full author list remove Hide full author list
Cancers 2025, 17(6), 991; https://doi.org/10.3390/cancers17060991 - 15 Mar 2025
Viewed by 625
Abstract
Background/Objectives: No prior studies have attempted to identify a biomarker for initial brain metastasis velocity (iBMV), with limited studies attempting to correlate genomic data with the development of brain metastases. Methods: Patients with non-small-cell lung cancer (NSCLC) who underwent next-generation sequencing [...] Read more.
Background/Objectives: No prior studies have attempted to identify a biomarker for initial brain metastasis velocity (iBMV), with limited studies attempting to correlate genomic data with the development of brain metastases. Methods: Patients with non-small-cell lung cancer (NSCLC) who underwent next-generation sequencing (NGS) were identified in our departmental database. iBMV was calculated by dividing the number of BMs by the interval of time between primary cancer and BM diagnosis. Two-sample t-testing was used to identify mutations statistically associated with iBMV (p < 0.1). A value of +1 was assigned to each mutation with a positive association (“deleterious genes”), and a value of −1 to each with an inverse association (“protective genes”). The sum of these values was calculated to define iBMV risk scores of −1, 0 and 1. Pearson correlation test was used to determine the association between iBMV risk score and calculated iBMV, and a competing risk analysis assessed for death as a competing risk to the development of BMs. Results: A total of 312 patients were included in the analysis, 218 of whom (70%) developed brain metastases. “Deleterious genes” included ARID1A, BRAF, CDK4, GNAQ, MLH1, MSH6, PALB2, RAD51D, RB1 and TSC1; “protective genes” included ARAF, IDH1, MYC, and PTPN11. iBMV risk scores of 1, 0 and −1, predicted an 88%, 61% and 65% likelihood of developing a BM (p < 0.01). A competing risk analysis found a significant association between iBMV risk scores of 1 vs. 0 and 1 vs. −1, and the likelihood of developing a BM using death as a competing risk. Overall survival (OS) at 1 and 2 years for patients with iBMV risk scores of 1, 0 and −1 was 72% vs. 84% vs. 85% and 46% vs. 69% vs. 70% (p < 0.02). Conclusions: Development of a genomic signature for iBMV via non-invasive liquid biopsy appears feasible in NSCLC patients. Patients with a positive iBMV risk score were more likely to develop brain metastases. Validation of this signature could lead to a biomarker with the potential to guide treatment recommendations and surveillance schedules. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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11 pages, 645 KiB  
Article
Characterizing the Natural History of Pediatric Brain Tumors Presenting with Metastasis
by Victor M. Lu and Toba N. Niazi
Cancers 2025, 17(5), 775; https://doi.org/10.3390/cancers17050775 - 24 Feb 2025
Viewed by 404
Abstract
Background: The natural history of pediatric patients with metastasis of primary brain tumors within and outside the central nervous system is poorly understood, as too are possible clinical correlates with outcome. Correspondingly, the aim of this study was to interrogate a national database [...] Read more.
Background: The natural history of pediatric patients with metastasis of primary brain tumors within and outside the central nervous system is poorly understood, as too are possible clinical correlates with outcome. Correspondingly, the aim of this study was to interrogate a national database to characterize this diagnosis and its clinical course in pediatric patients. Methods: The U.S. National Cancer Database (NCDB) was interrogated between the years 2005–2016 for all patients aged 18 years and younger with a primary brain tumor diagnosis, as well as evidence of disease metastasis at initial diagnosis. Data were summarized and overall survival (OS) was modeled using Kaplan–Meier and Cox regression analyses. Results: Out of a total of 8615 pediatric brain tumor patients, 356 (4%) had evidence of metastasis at initial diagnosis. Compared to patients without metastasis, patients with metastasis were statistically younger, more often male, and less likely to have private health insurance (all p < 0.050). With respect to clinical characteristics, the primary tumors of patients with metastasis were statistically more likely to be located in the cerebellum; be of higher histologic grading, with a higher proportion of medulloblastoma diagnoses and lower proportion of malignant glioma and pilocytic astrocytoma diagnoses; and were more likely to be treated by subtotal surgical resection, chemotherapy and radiation therapy (all p < 0.050) when compared to patients without metastasis. Five-year OS for those with metastasis was significantly lower than those without (48% vs. 75%, p < 0.001), with the median overall survival for patients with metastasis being 53 months (95% CI 29–86). Multivariate analysis indicated that a shorter OS was independently associated with the primary diagnoses of malignant glioma (HR 27.7, p = 0.020) and Atypical Teratoid/Rhabdoid Tumor (ATRT, HR 41.1, p = 0.041) and with WHO grades 3 (HR 20.1, p = 0.012) and 4 (HR 11.5, p < 0.001). Longer OS was significantly and independently associated with surgery (HR 0.49, p < 0.001), chemotherapy (HR 0.53, p = 0.041), and radiation therapy (HR 0.57, p = 0.026). Conclusions: Although uncommon, pediatric brain tumors with evidence of metastasis at initial diagnosis will present with a distinct socioeconomic and clinical profile compared to patients without metastasis. Multiple predictors are independently associated with overall prognosis, and understanding these features should be validated in prospective efforts to identify vulnerable patients earlier in order to maximize the impact of treatment. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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23 pages, 7293 KiB  
Article
Construction of a miRNA Panel for Differentiating Lung Adenocarcinoma Brain Metastases and Glioblastoma
by Bernadett Torner, Dóra Géczi, Álmos Klekner, István Balogh, András Penyige and Zsuzsanna Birkó
Cancers 2025, 17(4), 581; https://doi.org/10.3390/cancers17040581 - 8 Feb 2025
Viewed by 731
Abstract
Background/Objectives: Brain metastases (BM) are the most common type of intracranial malignant tumor and are associated with high mortality. More than 50% of BM cases originate from lung cancer, and lung adenocarcinoma (LUAD) is most commonly associated with the development of BM (25%). [...] Read more.
Background/Objectives: Brain metastases (BM) are the most common type of intracranial malignant tumor and are associated with high mortality. More than 50% of BM cases originate from lung cancer, and lung adenocarcinoma (LUAD) is most commonly associated with the development of BM (25%). The differential diagnosis of solitary BM and glioblastoma (GBM)—one of the most aggressive and fatal malignant brain tumors—remains a considerable challenge. Given the major role of microRNAs (miRNAs) in regulating gene expression, their clinical potential as biomarkers for tumor diagnosis and prognosis offers significant promise. Methods: Next-generation RNA Sequencing (RNA-seq) was used to assess the miRNA expression profiles of 6 LUAD-BM, 6 GBM, and 6 control (non-tumoral brain tissue samples) human brain tissue samples. miRNAs exhibiting the most significant differential expression in LUAD-BM patients in comparison to both control subjects and GBM patients were selected for validation through RT-qPCR. Results: The analysis of RNA-seq data revealed the presence of 229 differentially expressed miRNAs in the comparison between LUAD-BM and control samples and 46 in the comparison between LU-AD-BM and GBM samples. Eight miRNAs were selected for further analysis, four of which were upregulated and four downregulated, based on the significant differences in their expression levels observed between the LUAD-BM samples and the other two groups, as confirmed with the Mann–Whitney U test. Functional enrichment analysis was also conducted based on a miRNA-centered target analysis performed using the miRNet tool. To assess the diagnostic potential of these differentially expressed miRNAs, we performed a receiver operating characteristic (ROC) curve analysis. Conclusions: A panel of eight miRNAs was identified in human brain tissue samples, exhibiting high accuracy in distinguishing LUAD-BM from both GBM and control samples. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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15 pages, 4099 KiB  
Article
Exposed Phosphatidylserine as a Biomarker for Clear Identification of Breast Cancer Brain Metastases in Mouse Models
by Lulu Wang, Alan H. Zhao, Chad A. Arledge, Fei Xing, Michael D. Chan, Rolf A. Brekken, Amyn A. Habib and Dawen Zhao
Cancers 2024, 16(17), 3088; https://doi.org/10.3390/cancers16173088 - 5 Sep 2024
Cited by 1 | Viewed by 1482
Abstract
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor [...] Read more.
Brain metastasis is the most common intracranial malignancy in adults. The prognosis is extremely poor, partly because most patients have more than one brain lesion, and the currently available therapies are nonspecific or inaccessible to those occult metastases due to an impermeable blood–tumor barrier (BTB). Phosphatidylserine (PS) is externalized on the surface of viable endothelial cells (ECs) in tumor blood vessels. In this study, we have applied a PS-targeting antibody to assess brain metastases in mouse models. Fluorescence microscopic imaging revealed that extensive PS exposure was found exclusively on vascular ECs of brain metastases. The highly sensitive and specific binding of the PS antibody enables individual metastases, even micrometastases containing an intact BTB, to be clearly delineated. Furthermore, the conjugation of the PS antibody with a fluorescence dye, IRDye 800CW, or a radioisotope, 125I, allowed the clear visualization of individual brain metastases by optical imaging and autoradiography, respectively. In conclusion, we demonstrated a novel strategy for targeting brain metastases based on our finding that abundant PS exposure occurs on blood vessels of brain metastases but not on normal brain, which may be useful for the development of imaging and targeted therapeutics for brain metastases. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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Review

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29 pages, 2666 KiB  
Review
Deciphering the Blood–Brain Barrier Paradox in Brain Metastasis Development and Therapy
by Jens Jeshu Peters, Chubei Teng, Kang Peng and Xuejun Li
Cancers 2025, 17(2), 298; https://doi.org/10.3390/cancers17020298 - 17 Jan 2025
Viewed by 2568
Abstract
Gatekeeper or accomplice? That is the paradoxical role of the blood–brain barrier (BBB) in developing brain metastasis (BM). BM occurs when cancerous cells from primary cancer elsewhere in the body gain the ability to metastasize and invade the brain parenchyma despite the formidable [...] Read more.
Gatekeeper or accomplice? That is the paradoxical role of the blood–brain barrier (BBB) in developing brain metastasis (BM). BM occurs when cancerous cells from primary cancer elsewhere in the body gain the ability to metastasize and invade the brain parenchyma despite the formidable defense of the BBB. These metastatic cells manipulate the BBB’s components, changing them from gatekeepers of the brain to accomplices that aid in their progression into the brain tissue. This dual role of the BBB—as both a protective system and a potential facilitator of metastatic cells—highlights its complexity. Even with metastasis therapy such as chemotherapy, BM usually recurs due to the BBB limiting the crossing of drugs via the efflux transporters; therefore, treatment efficacy is limited. The pathophysiology is also complex, and our understanding of the paradoxical interplay between the BBB components and metastatic cells still needs to be improved. However, advancements in clinical research are helping to bridge the knowledge gap, which is essential for developing effective metastasis therapy. By targeting the BBB neurovascular unit components such as the polarization of microglia, astrocytes, and pericytes, or by utilizing technological tools like focused ultrasound to transiently disrupt the BBB and therapeutic nanoparticles to improve drug delivery efficiency to BM tissue, we can better address this pathology. This narrative review delves into the latest literature to analyze the paradoxical role of the BBB components in the manifestation of BM and explores potential therapeutic avenues targeting the BBB–tumor cell interaction. Full article
(This article belongs to the Special Issue Brain Metastases: From Mechanisms to Treatment)
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