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 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.

scholarly journals Downregulation of TREM2 Expression Exacerbates Neuroinflammatory Responses Through TLR4-Mediated MAPK Signaling Pathway in a Transgenic Mouse Model of Alzheimer’s Disease

2021 ◽  
Author(s):  
John Bosco Ruganzu ◽  
Xiaoqian Peng ◽  
Yingying He ◽  
Xiangyuan Wu ◽  
Quzhao Zheng ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mechanistic Study ◽  
Model Of Alzheimer’S Disease ◽  
Bv2 Cells ◽  
The Brain

Abstract Activation of glial cells and neuroinflammation play an important role in the onset and development of Alzheimer’s disease (AD). Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglia-specific receptor in the brain that is involved in regulating neuroinflammation. However, the precise effects of TREM2 on neuroinflammatory responses and its underlying molecular mechanisms in AD have not been studied in detail. Here, we employed a lentiviral-mediated strategy to downregulation of TREM2 expression on microglia in the brain of APPswe/PS1dE9 (APP/PS1) transgenic mice and BV2 cells. Our results showed that TREM2 downregulation significantly aggravated AD-related neuropathology including Aβ accumulation, peri-plaque microgliosis and astrocytosis, as well as neuronal and synapse-associated proteins loss, which was accompanied by a decline in cognitive ability. The further mechanistic study revealed that downregulation of TREM2 expression initiated neuroinflammatory responses through toll-like receptor 4 (TLR4)-mediated mitogen-activated protein kinase (MAPK) signaling pathway and subsequent stimulating the production of pro-inflammatory cytokines in vivo and in vitro. Moreover, blockade of p38, JNK, and ERK1/2 inhibited the release of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) induced by Aβ1−42 in TREM2-knocked down BV2 cells. Taken together, these findings indicated that TREM2 might be a potential therapeutic target for AD and other neuroinflammation related diseases.

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.

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

2019 ◽  
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.

Metastatic NSCLC: Can molecular biology guide surgical decision making?

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e18045-e18045
Author(s):  
Paola Ulivi ◽  
Sandro Mattioli ◽  
Maurizio Puccetti ◽  
Laura Capelli ◽  
Wainer Zoli ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Decision Making ◽  
Brain Metastasis ◽  
Lung Lesion ◽  
Bronchioloalveolar Carcinoma ◽  
Ras Gene ◽  
Primary Tumors ◽  
Ras Mutation ◽  
Gene Status ◽  
The Brain

e18045 Background: Guidelines do not recommend surgical resection of metastatic non-small cell lung cancer (NSCLC), with the exception of single brain or adrenal gland lesions, and further resection in the event of a new lung metastasis is generally not indicated. A different therapeutic approach is used in patients with multiple primary lesions. Can molecular alterations help to distinguish between independent primary tumors and metastatic lesions? Methods: A 74-year old woman underwent bilateral inferior lobectomy in May 2008 for two different synchronous NSCLC (adenocarcinoma and adenocarcinoma in situ, formally known as “bronchioloalveolar carcinoma” – J Thorac Oncol 2011;6:244–285). Three months after surgery the patient developed a single symptomatic brain metastasis. A CT scan also highlighted a suspect lingular lesion of the lung. Stereotaxic brain radiotherapy was carried out followed by systemic platinum-based chemotherapy. The brain metastasis showed very good radiological partial remission (PR) while the lung lesion remained stable after 4 cycles of chemotherapy. After two years’ follow-up the brain metastasis remained in PR whereas the lung lesion had progressed, and fine needle aspirate revealed adenocarcinoma. Results: Molecular analysis showed that EGFR gene status was wild type in all three tumors, whereas K-ras gene status differed. With regard to the two synchronous tumors, a barely visible G12C K-ras gene mutation was found in the bronchioloalveolar carcinoma, while a G12D K-ras mutation was detected in the adenocarcinoma. Moreover, K-ras gene status in the lingular node revealed a G12A mutation. On the basis of these results we hypothesized the presence of a third lung cancer and it was decided to proceed with surgery. The patient underwent laparoscopic lingulectomy which confirmed the diagnosis of adenocarcinoma with the same G12A K-ras mutation. Conclusions: This case highlights the importance of the molecular characterization of tumors in patients with multiple lesions. Different alterations within a single gene in different lesions are indicative of an independent clonal origin and suggestive of separate primary tumors rather than secondary lesions, thus facilitating treatment decision making.

Radiosurgery for patients with recurrent small cell lung carcinoma metastatic to the brain: outcomes and prognostic factors

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 247-254 ◽  
Author(s):  
Jason Sheehan ◽  
Douglas Kondziolka ◽  
John Flickinger ◽  
L. Dade Lunsford
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Lung Carcinoma ◽  
Small Cell Lung Carcinoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Content Type ◽  
The Brain ◽  
Fine Print

Object. Lung carcinoma is the leading cause of death from cancer. More than 50% of those with small cell lung cancer develop a brain metastasis. Corticosteroid agents, radiotherapy, and resection have been the mainstays of treatment. Nonetheless, median survival for patients with small cell lung carcinoma metastasis is approximately 4 to 5 months after cranial irradiation. In this study the authors examine the efficacy of gamma knife surgery for treating recurrent small cell lung carcinoma metastases to the brain following tumor growth in patients who have previously undergone radiation therapy, and they evaluate factors affecting survival. Methods. A retrospective review of 27 patients (47 recurrent small cell lung cancer brain metastases) undergoing radiosurgery was performed. Clinical and radiographic data obtained during a 14-year treatment period were collected. Multivariate analysis was utilized to determine significant prognostic factors influencing survival. The overall median survival was 18 months after the diagnosis of brain metastases. In multivariate analysis, factors significantly affecting survival included: 1) tumor volume (p = 0.0042); 2) preoperative Karnofsky Performance Scale score (p = 0.0035); and 3) time between initial lung cancer diagnosis and development of brain metastasis (p = 0.0127). Postradiosurgical imaging of the brain metastases revealed that 62% decreased, 19% remained stable, and 19% eventually increased in size. One patient later underwent a craniotomy and tumor resection for a tumor refractory to radiosurgery and radiation therapy. In three patients new brain metastases were demonstrating on follow-up imaging. Conclusions. Stereotactic radiosurgery for recurrent small cell lung carcinoma metastases provided effective local tumor control in the majority of patients. Early detection of brain metastases, aggressive treatment of systemic disease, and a therapeutic strategy including radiosurgery can extend survival.

scholarly journals The Liquid Biopsy for Lung Cancer: State of the Art, Limitations and Future Developments

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3923
Author(s):  
Daniel Di Capua ◽  
Dara Bracken-Clarke ◽  
Karine Ronan ◽  
Anne-Marie Baird ◽  
Stephen Finn
Keyword(s):  
Lung Cancer ◽  
Lung Carcinoma ◽  
Targeted Therapies ◽  
Liquid Biopsy ◽  
Genetic Alterations ◽  
Rapid Progression ◽  
Liquid Biopsies ◽  
Cell Lung Carcinoma ◽  
Genetic Sequencing ◽  
Tissue Biopsy

Lung cancer is a leading cause of cancer-related deaths, contributing to 18.4% of cancer deaths globally. Treatment of non-small cell lung carcinoma has seen rapid progression with targeted therapies tailored to specific genetic drivers. However, identifying genetic alterations can be difficult due to lack of tissue, inaccessible tumors and the risk of complications for the patient with serial tissue sampling. The liquid biopsy provides a minimally invasive method which can obtain circulating biomarkers shed from the tumor and could be a safer alternative to tissue biopsy. While tissue biopsy remains the gold standard, liquid biopsies could be very beneficial where serial sampling is required, such as monitoring disease progression or development of resistance mutations to current targeted therapies. Liquid biopsies also have a potential role in identifying patients at risk of relapse post treatment and as a component of future lung cancer screening protocols. Rapid developments have led to multiple platforms for isolating circulating tumor cells (CTCs) and detecting circulating tumor DNA (ctDNA); however, standardization is lacking, especially in lung carcinoma. Additionally, clonal hematopoiesis of uncertain clinical significance must be taken into consideration in genetic sequencing, as it introduces the potential for false positives. Various biomarkers have been investigated in liquid biopsies; however, in this review, we will concentrate on the current use of ctDNA and CTCs, focusing on the clinical relevance, current and possible future applications and limitations of each.

scholarly journals The gastrin releasing peptide, GRP, is differentially expressed in brain metastatic breast cancer.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Brain Metastasis ◽  
Microarray Data ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Clinical Problem ◽  
Primary Tumors ◽  
Gastrin Releasing Peptide ◽  
The Brain

Metastasis to the brain is a clinical problem in patients with breast cancer (1-3). We mined published microarray data (4, 5) to compare primary and metastatic tumor transcriptomes to discover genes associated with brain metastasis in patients with metastatic breast cancer. We found that the gastrin releasing peptide, encoded by GRP, was among the genes whose expression was most different in the brain metastases of patients with metastatic breast cancer as compared to primary tumors of the breast. Molecular functions of gastrin releasing peptide may be relevant to the processes by which tumor cells of the breast metastasize to the breast. Down-regulation of GRP may be an important event for metastasis of primary tumor-derived cancer cells to the brain in humans with metastatic breast cancer.

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