Molecular Mechanisms in Brain Metastasis

2019 ◽  
pp. 31-41
Author(s):  
Ekrem Emrah Er ◽  
Adrienne Boire
Keyword(s):  
Brain Metastasis ◽  
Molecular Mechanisms

scholarly journals Genetic mutations associated with lung cancer metastasis to the brain.

2019 ◽  
Vol 5 (suppl) ◽  
pp. 41-41
Author(s):  
ChunXia Su ◽  
Juan Zhou ◽  
Xiangling Chu ◽  
Jing Zhao
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Genetic Alterations ◽  
Mapk Signaling ◽  
Primary Tumors ◽  
Cell Lung Carcinoma ◽  
The Brain

41 Background: Lung cancer is the most common cause of mortality in both men and women, accounting for one-quarter of all cancer deaths. Most lung cancer-associated deaths result from metastasis, especially brain metastasis. Metastasis associated mutations are important biomarkers for metastasis prediction and outcome improvement. The current study aimed to reveal the molecular mechanisms and the genetic alterations involved in metastasis from lung tumors to the brain. Methods: We carried out whole exome sequencing (WES) of the primary tumors and the corresponding brain metastases from 15 patients with metastatic non-small-cell lung carcinoma. Results: We identified novel lung cancer metastases associated genes (CHEK2P2, BAGE2, AHNAK2) and epigenetic factors (miR-4436A, miR-6077). Lung-brain metastasis samples have more similar Ti/Tv(transition/transversion) profile with brain cancer. Focal adhesion, PI3K-Akt signaling pathway, MAPK signaling pathway are some of the most important tumor onset and metastasis pathways. Alternative splicing, Methylation and EGF-like domain are important metabolic abnormal for the lung-metastasis cancers. Conclusions: We conducted a pairwise lung-brain metastasis based WES and identified some novel metastasis related mutations which provided potential biomarkers for prognosis and targeted therapeutics.

scholarly journals Blood-Brain Barrier Integrity and Breast Cancer Metastasis to the Brain

2011 ◽  
Vol 2011 ◽  
pp. 1-12 ◽  
Author(s):  
Farheen Arshad ◽  
Lili Wang ◽  
Christopher Sy ◽  
Shalom Avraham ◽  
Hava Karsenty Avraham
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Brain Barrier ◽  
Treatment Modalities ◽  
Blood Brain ◽  
The Brain

Brain metastasis, an important cause of cancer morbidity and mortality, occurs in at least 30% of patients with breast cancer. A key event of brain metastasis is the migration of cancer cells through the blood-brain barrier (BBB). Although preventing brain metastasis is immensely important for survival, very little is known about the early stage of transmigration and the molecular mechanisms of breast tumor cells penetrating the BBB. The brain endothelium plays an important role in brain metastasis, although the mechanisms are not clear. Brain Microvascular Endothelial Cells (BMECs) are the major cellular constituent of the BBB. BMECs are joined together by intercellular tight junctions (TJs) that are responsible for acquisition of highly selective permeability. Failure of the BBB is a critical event in the development and progression of several diseases that affect the CNS, including brain tumor metastasis development. Here, we have delineated the mechanisms of BBB impairment and breast cancer metastasis to the brain. Understanding the molecular mediators that cause changes in the BBB should lead to better strategies for effective treatment modalities targeted to inhibition of brain tumors.

scholarly journals RNA Sequencing Analysis Reveals Interactions between Breast Cancer or Melanoma Cells and the Tissue Microenvironment during Brain Metastasis

2017 ◽  
Vol 2017 ◽  
pp. 1-10 ◽  
Author(s):  
Ryo Sato ◽  
Teppei Nakano ◽  
Mari Hosonaga ◽  
Oltea Sampetrean ◽  
Ritsuko Harigai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Rna Sequencing ◽  
Brain Tissue ◽  
Molecular Mechanisms ◽  
Sequencing Analysis ◽  
Primary Tumors ◽  
The Brain

Metastasis is the main cause of treatment failure and death in cancer patients. Metastasis of tumor cells to the brain occurs frequently in individuals with breast cancer, non–small cell lung cancer, or melanoma. Despite recent advances in our understanding of the causes and in the treatment of primary tumors, the biological and molecular mechanisms underlying the metastasis of cancer cells to the brain have remained unclear. Metastasizing cancer cells interact with their microenvironment in the brain to establish metastases. We have now developed mouse models of brain metastasis based on intracardiac injection of human breast cancer or melanoma cell lines, and we have performed RNA sequencing analysis to identify genes in mouse brain tissue and the human cancer cells whose expression is associated specifically with metastasis. We found that the expressions of the mouse genes Tph2, Sspo, Ptprq, and Pole as well as those of the human genes CXCR4, PLLP, TNFSF4, VCAM1, SLC8A2, and SLC7A11 were upregulated in brain tissue harboring metastases. Further characterization of such genes that contribute to the establishment of brain metastases may provide a basis for the development of new therapeutic strategies and consequent improvement in the prognosis of cancer patients.

scholarly journals A melanoma és az agyi áttétképződés molekuláris háttere

2017 ◽  
Vol 158 (28) ◽  
pp. 1083-1091 ◽  
Author(s):  
Frida Katona ◽  
Balázs Murnyák ◽  
György Marko-Varga ◽  
Tibor Hortobágyi
Keyword(s):  
Brain Metastasis ◽  
Molecular Mechanisms ◽  
Gene Mutations ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Phosphatidylinositol 3 Kinase ◽  
Mitogen Activated Protein ◽  
Aggressive Tumors ◽  
Kinase Signaling Pathway ◽  
Kinase Pathway

Abstract: Malignant melanoma is one of the most aggressive tumors which often gives metastasis to distant organs thereby limiting the chances of survival. Brain metastasis occurs in nearly half of the advanced tumors. In order to improve outcome early diagnosis is important. The discovery and better understanding of genetic and epigenetic changes is essential for developing new effective therapies, which can designate promising therapeutic targets. Melanoma most often is caused by gene mutations of the mitogen-activated protein kinase pathway, the phosphatidylinositol 3-kinase signaling pathway, and the cell cycle regulatory molecules, respectively. The molecular process of brain metastasis has not been fully elucidated. In our review we summarize the genetic alterations and molecular mechanisms playing a role in the development of melanoma and its brain metastasis. Orv Hetil. 2017; 158(28): 1083–1091.

scholarly journals RADI-03. A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance

2021 ◽  
Vol 3 (Supplement_3) ◽  
pp. iii18-iii18
Author(s):  
Lauritz Miarka ◽  
Catia Moteiro ◽  
Celine Dalmasso ◽  
Coral Fustero-Torre ◽  
Natalia Yebra ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Brain Barrier ◽  
Breast Adenocarcinoma ◽  
Therapeutic Benefits ◽  
Blood Brain ◽  
The Brain

Abstract Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFkB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. In conclusion, we identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

P02.01 A strategy to personalize the use of radiation in patients with brain metastasis based on S100A9-mediated resistance

2021 ◽  
Vol 23 (Supplement_2) ◽  
pp. ii17-ii17
Author(s):  
L Miarka ◽  
C Monteiro ◽  
C Dalmasso ◽  
N Yebra ◽  
C Fustero-Torre ◽  
...  
Keyword(s):  
Brain Metastasis ◽  
Blood Brain Barrier ◽  
Molecular Mechanisms ◽  
Unmet Need ◽  
Brain Barrier ◽  
Breast Adenocarcinoma ◽  
Therapeutic Benefits ◽  
Blood Brain ◽  
The Brain

Abstract BACKGROUND Finding effective treatment options for patients with brain metastasis remains an unmet need. Given the limitations imposed by the blood-brain-barrier for systemic approaches, radiotherapy offers a superior ability to access the brain. While clinical practice recently adapted the use of stereotactic radiosurgery (SRS), Whole-Brain-Radiotherapy (WBRT) continuous to be an important treatment option, since many patients present with multifocal lesions or bad performance scores, rendering them ineligible for SRS. Unfortunately, overall survival of patients remains unaffected by radiotherapy. Despite this clinical data, the molecular mechanisms that allow metastatic cells to resist radiotherapy in the brain is unknown. MATERIAL AND METHODS We have applied WBRT to experimental brain metastasis from lung and breast adenocarcinoma and validated their resistance in vivo. RESULTS An unbiased search to identify potential mediators of resistance identified the S100A9-RAGE-NFκB-JunB pathway. Targeting this pathway genetically reverts the resistance to radiotherapy and increases therapeutic benefits in vivo. In two independent cohorts of brain metastasis from lung and breast adenocarcinoma patients, levels of S100A9 correlate with the response to radiotherapy, offering a novel approach to stratify patients according to their expected benefit. In order to make this biomarker also available for brain metastasis patients receiving palliative WBRT without preceding surgery, we complemented our tumor-specimen based approach with the less invasive detection of S100A9 from liquid biopsies. Here, serum S100A9 also correlated with a worse response to WBRT in brain metastasis patients. Furthermore, we have validated the use of a blood-brain-barrier permeable RAGE inhibitor to restore radio-sensitivity in experimental brain metastasis models in vivo and in patient-derived organotypic cultures of radio-resistant brain metastasis ex vivo. CONCLUSION We identified S100A9 as a major mediator of radio-resistance in brain metastasis and offer the molecular framework to personalize radiotherapy by exploiting it as a biomarker and as a therapeutic target, thus maximizing the benefits for the patient.

Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic options

2017 ◽  
Vol 40 (5) ◽  
pp. 419-441 ◽  
Author(s):  
Meysam Yousefi ◽  
Tayyeb Bahrami ◽  
Arash Salmaninejad ◽  
Rahim Nosrati ◽  
Parisa Ghaffari ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastasis ◽  
Molecular Mechanisms ◽  
Therapeutic Options

scholarly journals Identification of potential genes related to breast cancer brain metastasis in breast cancer patients

2021 ◽  
Author(s):  
Lijian Zhang ◽  
Luxuan Wang ◽  
Hua Yang ◽  
Chunhui Li ◽  
Chuan Fang
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Principal Component ◽  
Enrichment Analysis ◽  
Functional Enrichment ◽  
Breast Cancer Patients ◽  
Breast Cancer Brain Metastasis ◽  
Geo Database

Brain metastases (BM) usually develop in breast cancer patients. Thus, the molecular mechanisms of breast cancer brain metastasis (BCBM) are of great importance in designing therapeutic strategies to treat or prevent BCBM. This study attempted to identify novel diagnostic and prognostic biomarkers of BCBM. Two datasets (GSE125989 and GSE100534) were obtained from the Gene Expression Omnibus (GEO) database to find differentially expressed genes (DEGs) in cases of breast cancer with and without brain metastasis. A total of 146 overlapping DEGs, including 103 up-regulated genes and 43 down-regulated genes, were identified. Functional enrichment analysis showed that these DEGs were mainly enriched for functions including extracellular matrix organization and collagen catabolic fibril organization. Using protein-protein interaction (PPI) and principal component analysis (PCA) analysis, we identified 10 key genes, including LAMA4, COL1A1, COL5A2, COL3A1, COL4A1, COL5A1, COL5A3, COL6A3, COL6A2, and COL6A1. Additionally, COL5A1, COL4A1, COL1A1, COL6A1, COL6A2 and COL6A3 were significantly associated with the overall survival of BC patients. Furthermore, COL6A3, COL5A1, and COL4A1 were potentially correlated with BCBM in human epidermal growth factor 2 (HER2) expression. Additionally, the miR-29 family might participate in the process of metastasis by modulating the cancer microenvironment. Based on datasets in the GEO database, several DEGs have been identified as playing potentially important roles in BCBM in BC patients.

scholarly journals Drug resistance occurred in a newly characterized preclinical model of lung cancer brain metastasis.

2020 ◽  
Author(s):  
Neal Shah ◽  
Zhongwei Liu ◽  
Rachel M. Tallman ◽  
Afroz Mohammad ◽  
Samuel A Sprowls ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Drug Resistance ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Lung Cancer Cells ◽  
Cardiac Ventricle

Abstract Background Cancer metastasis and drug resistance have traditionally been studied separately, though these two lethal pathological phenomena almost always occur concurrently. Brain metastasis occurs in a large proportion of lung cancer patients (~30%). Once diagnosed, patients have a poor prognosis surviving typically less than 1 year due to lack of treatment efficacy. Methods Human metastatic lung cancer cells (PC-9-Br) were injected into the left cardiac ventricle of female athymic nude mice. Brain lesions were allowed to grow for 21 days, animals were then randomized into treatment groups and treated until presentation of neurological symptoms or when moribund. Prior to tissue collection mice were injected with Oregon Green and 14C-Aminoisobutyric acid followed by an indocyanine green vascular washout. Tracer accumulation was determined by quantitative fluorescent microscopy and quantitative autoradiography. Survival was tracked and tumor burden was monitored via bioluminescent imaging. Extent of mutation differences and acquired resistance was measured in-vitro through half-maximal inhibitory assays and qRT-PCR analysis. Results A PC-9 brain seeking line (PC-9-Br) was established. Mice inoculated with PC-9-Br resulted in a significantly decreased survival time compared with mice inoculated with parental PC-9. Non-targeted chemotherapy with cisplatin and etoposide (51.5 days) significantly prolonged survival of PC-9-Br brain metastases in mice compared to vehicle control (42 days) or cisplatin and pemetrexed (45 days). Further in-vivo imaging showed greater tumor vasculature in mice treated with cisplatin and etoposide compared to non-tumor regions, which was not observed in mice treated with vehicle or cisplatin and pemetrexed. More importantly, PC-9-Br showed significant resistance to gefitinib by in-vitro MTT assays (IC50>2.5 µM at 48hrs and 0.1 µM at 72hrs) compared with parental PC-9 (IC50: 0.75 µM at 48hrs and 0.027 µM at 72hrs). Further studies on the molecular mechanisms of gefitinib resistance revealed that EGFR and phospho-EGFR were significantly decreased in PC-9-Br compared with PC-9. Expression of E-cadherin and vimentin did not show EMT in PC-9-Br compared with parental PC-9, and PC-9-Br had neither T790 mutation nor amplifications of MET and HER2 compared with parental PC-9. Conclusion Our study demonstrated that brain metastases of lung cancer cells may independently prompt drug resistance without drug treatment.

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