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Special Issue "Brain Metastasis 2014"

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".

Deadline for manuscript submissions: closed (30 March 2014)

Special Issue Editor

Guest Editor
Prof. Dr. Dario Marchetti

Director, Center of the Biomarker Research Program at Houston Methodist Research Institute, and Professor of Pathology and Genomic Medicine at Methodist Hospital, MS: R7-102, 6670 Bertner Avenue, Houston, TX 77030, USA
Website | E-Mail
Interests: the biology and therapeutic utility of circulating tumor cells (CTCs); mechanisms of brain metastasis; breast cancer dormancy; roles of heparanase in development and disease

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Keywords

  • brain metastasis
  • molecular determinants
  • biological systems
  • pre-clinical models
  • therapeutic interventions
  • drug therapy
  • new drug discovery
  • biomarkers
  • brain metastasis prevention and/or treatment
  • genomics
  • proteomics
  • metabolomics

Related Special Issue

Published Papers (14 papers)

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Research

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Open AccessArticle Brain Metastases from Lung Cancer Show Increased Expression of DVL1, DVL3 and Beta-Catenin and Down-Regulation of E-Cadherin
Int. J. Mol. Sci. 2014, 15(6), 10635-10651; doi:10.3390/ijms150610635
Received: 23 January 2014 / Revised: 14 May 2014 / Accepted: 27 May 2014 / Published: 13 June 2014
Cited by 9 | PDF Full-text (1020 KB) | HTML Full-text | XML Full-text
Abstract
The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas
[...] Read more.
The susceptibility of brain to secondary formation from lung cancer primaries is a well-known phenomenon. In contrast, the molecular basis for invasion and metastasis to the brain is largely unknown. In the present study, 31 brain metastases that originated from primary lung carcinomas were analyzed regarding over expression of Dishevelled-1 (DVL1), Dishevelled-3 (DVL3), E-cadherin (CDH1) and beta-catenin (CTNNB1). Protein expressions and localizations were analyzed by immunohistochemistry. Genetic alterations of E-cadherin were tested by polymerase chain reaction (PCR)/loss of heterozygosity (LOH). Heteroduplex was used to investigate mutations in beta-catenin. DVL1 and DVL3 showed over expression in brain metastasis in 87.1% and 90.3% of samples respectively. Nuclear staining was observed in 54.8% of cases for DVL1 and 53.3% for DVL3. The main effector of the Wnt signaling, beta-catenin, was up-regulated in 56%, and transferred to the nucleus in 36% of metastases. When DVL1 and DVL3 were up-regulated the number of cases with nuclear beta-catenin significantly increased (p = 0.0001). Down-regulation of E-cadherin was observed in 80% of samples. Genetic analysis showed 36% of samples with LOH of the CDH1. In comparison to other lung cancer pathologies, the diagnoses adenocarcinoma and small cell lung cancer (SCLC) were significantly associated to CDH1 LOH (p = 0.001). Microsatellite instability was detected in one metastasis from adenocarcinoma. Exon 3 of beta-catenin was not targeted. Altered expression of Dishevelled-1, Dishevelled-3, E-cadherin and beta-catenin were present in brain metastases which indicates that Wnt signaling is important and may contribute to better understanding of genetic profile conditioning lung cancer metastasis to the brain. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Figures

Open AccessArticle Gamma Knife Treatment of Brainstem Metastases
Int. J. Mol. Sci. 2014, 15(6), 9748-9761; doi:10.3390/ijms15069748
Received: 30 March 2014 / Revised: 1 May 2014 / Accepted: 5 May 2014 / Published: 30 May 2014
Cited by 11 | PDF Full-text (240 KB) | HTML Full-text | XML Full-text
Abstract
The management of brainstem metastases is challenging. Surgical treatment is usually not an option, and chemotherapy is of limited utility. Stereotactic radiosurgery has emerged as a promising palliative treatment modality in these cases. The goal of this study is to assess our single
[...] Read more.
The management of brainstem metastases is challenging. Surgical treatment is usually not an option, and chemotherapy is of limited utility. Stereotactic radiosurgery has emerged as a promising palliative treatment modality in these cases. The goal of this study is to assess our single institution experience treating brainstem metastases with Gamma Knife radiosurgery (GKRS). This retrospective chart review studied 41 patients with brainstem metastases treated with GKRS. The most common primary tumors were lung, breast, renal cell carcinoma, and melanoma. Median age at initial treatment was 59 years. Nineteen (46%) of the patients received whole brain radiation therapy (WBRT) prior to or concurrent with GKRS treatment. Thirty (73%) of the patients had a single brainstem metastasis. The average GKRS dose was 17 Gy. Post-GKRS overall survival at six months was 42%, at 12 months was 22%, and at 24 months was 13%. Local tumor control was achieved in 91% of patients, and there was one patient who had a fatal brain hemorrhage after treatment. Karnofsky performance score (KPS) >80 and the absence of prior WBRT were predictors for improved survival on multivariate analysis (HR 0.60 (p = 0.02), and HR 0.28 (p = 0.02), respectively). GKRS was an effective treatment for brainstem metastases, with excellent local tumor control. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessArticle In Vitro Treatment of Melanoma Brain Metastasis by Simultaneously Targeting the MAPK and PI3K Signaling Pathways
Int. J. Mol. Sci. 2014, 15(5), 8773-8794; doi:10.3390/ijms15058773
Received: 24 March 2014 / Revised: 4 May 2014 / Accepted: 6 May 2014 / Published: 16 May 2014
Cited by 6 | PDF Full-text (2405 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide
[...] Read more.
Malignant melanoma is the most lethal form of skin cancer, with a high propensity to metastasize to the brain. More than 60% of melanomas have the BRAFV600E mutation, which activates the mitogen-activated protein kinase (MAPK) pathway [1]. In addition, increased PI3K (phosphoinositide 3-kinase) pathway activity has been demonstrated, through the loss of activity of the tumor suppressor gene, PTEN [2]. Here, we treated two melanoma brain metastasis cell lines, H1_DL2, harboring a BRAFV600E mutation and PTEN loss, and H3, harboring WT (wild-type) BRAF and PTEN loss, with the MAPK (BRAF) inhibitor vemurafenib and the PI3K pathway associated mTOR inhibitor temsirolimus. Combined use of the drugs inhibited tumor cell growth and proliferation in vitro in H1_DL2 cells, compared to single drug treatment. Treatment was less effective in the H3 cells. Furthermore, a strong inhibitory effect on the viability of H1_DL2 cells, when grown as 3D multicellular spheroids, was seen. The treatment inhibited the expression of pERK1/2 and reduced the expression of pAKT and p-mTOR in H1_DL2 cells, confirming that the MAPK and PI3K pathways were inhibited after drug treatment. Microarray experiments followed by principal component analysis (PCA) mapping showed distinct gene clustering after treatment, and cell cycle checkpoint regulators were affected. Global gene analysis indicated that functions related to cell survival and invasion were influenced by combined treatment. In conclusion, we demonstrate for the first time that combined therapy with vemurafenib and temsirolimus is effective on melanoma brain metastasis cells in vitro. The presented results highlight the potential of combined treatment to overcome treatment resistance that may develop after vemurafenib treatment of melanomas. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessCommunication CB2 Receptor Activation Inhibits Melanoma Cell Transmigration through the Blood-Brain Barrier
Int. J. Mol. Sci. 2014, 15(5), 8063-8074; doi:10.3390/ijms15058063
Received: 31 March 2014 / Revised: 4 April 2014 / Accepted: 22 April 2014 / Published: 8 May 2014
Cited by 4 | PDF Full-text (416 KB) | HTML Full-text | XML Full-text
Abstract
During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB). The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes.
[...] Read more.
During parenchymal brain metastasis formation tumor cells need to migrate through cerebral endothelial cells, which form the morphological basis of the blood-brain barrier (BBB). The mechanisms of extravasation of tumor cells are highly uncharacterized, but in some aspects recapitulate the diapedesis of leukocytes. Extravasation of leukocytes through the BBB is decreased by the activation of type 2 cannabinoid receptors (CB2); therefore, in the present study we sought to investigate the role of CB2 receptors in the interaction of melanoma cells with the brain endothelium. First, we identified the presence of CB1, CB2(A), GPR18 (transcriptional variant 1) and GPR55 receptors in brain endothelial cells, while melanoma cells expressed CB1, CB2(A), GPR18 (transcriptional variants 1 and 2), GPR55 and GPR119. We observed that activation of CB2 receptors with JWH-133 reduced the adhesion of melanoma cells to the layer of brain endothelial cells. JWH-133 decreased the transendothelial migration rate of melanoma cells as well. Our results suggest that changes induced in endothelial cells are critical in the mediation of the effect of CB2 agonists. Our data identify CB2 as a potential target in reducing the number of brain metastastes originating from melanoma. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Figures

Open AccessArticle 3D Radiation Therapy Boost Improves the Outcome of Whole Brain Radiation Therapy Treated RPA II Patients with One or Two Brain Metastases
Int. J. Mol. Sci. 2014, 15(5), 7554-7562; doi:10.3390/ijms15057554
Received: 6 February 2014 / Revised: 7 April 2014 / Accepted: 24 April 2014 / Published: 2 May 2014
Cited by 3 | PDF Full-text (288 KB) | HTML Full-text | XML Full-text
Abstract
Purpose: to evaluate the role of whole brain radiotherapy (WBRT) and radiation boost (RB) for 208 patients recursive partitioning analysis (RPA) II with 1 or 2 brain metastases (BM) at a single institution. Methods and Materials: the dose of WBRT was 30 Gy
[...] Read more.
Purpose: to evaluate the role of whole brain radiotherapy (WBRT) and radiation boost (RB) for 208 patients recursive partitioning analysis (RPA) II with 1 or 2 brain metastases (BM) at a single institution. Methods and Materials: the dose of WBRT was 30 Gy (10 fractions of 3 Gy). One hundred thirty-two patients (63.5%) benefited from RB of 9 Gy in 3 fractions of 3 Gy at the metastatic site. Patients had 1 or 2 BM in 122 (58.7%) and 86 cases (41.3%), respectively. Results: patients with one or two metastases had similar survival (4.6 and 5.1 months, respectively) (p = 0.4). Median overall survival (OS) for patients treated with WBRT and RB, and with WBRT alone was 5.9 and 3.7 months, respectively (p = 0.03). The 6-, 12- and 24-month OS rates after WBRT and RB were 48.5%, 25% and 10.6%, respectively, while WBRT alone resulted in OS rates of 34%, 22.4% and 3.2%, respectively (p = 0.03). After WBRT and RB, the 6-, 12- and 24-month local control rates were 92%, 82% and 67%, respectively, while they were 81.2%, 75% and 37.5%, respectively, after WBRT alone (p = 0.03). The 6-, 12- and 24-month brain control rates after WBRT and RB were 88.7%, 75.8% and 62%, respectively, and after WBRT alone they were 78.5%, 59% and 37.7%, respectively (p = 0.03). Conclusion: additional boost delivered with 3D conformal radiotherapy improves local and brain control rates significantly as well as overall survival for RPA II patients with 1 or 2 unresectable BM. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessArticle Treatment of Single or Multiple Brain Metastases by Hypofractionated Stereotactic Radiotherapy Using Helical Tomotherapy
Int. J. Mol. Sci. 2014, 15(4), 6910-6924; doi:10.3390/ijms15046910
Received: 24 March 2014 / Revised: 10 April 2014 / Accepted: 11 April 2014 / Published: 22 April 2014
Cited by 5 | PDF Full-text (805 KB) | HTML Full-text | XML Full-text
Abstract
This study investigated the clinical outcomes of a 4-fraction stereotactic radiotherapy (SRT) study using helical tomotherapy for brain metastases. Between August 2009 and June 2013, 54 patients with a total of 128 brain metastases underwent SRT using tomotherapy. A total dose of 28
[...] Read more.
This study investigated the clinical outcomes of a 4-fraction stereotactic radiotherapy (SRT) study using helical tomotherapy for brain metastases. Between August 2009 and June 2013, 54 patients with a total of 128 brain metastases underwent SRT using tomotherapy. A total dose of 28 or 28.8 Gy at 80% isodose was administered in 4 fractions for all tumors. The mean gross tumor volume (GTV) was 1.9 cc. Local control (LC) rates at 6, 12, and 18 months were 96%, 91%, and 88%, respectively. The 12-month LC rates for tumors with GTV ≤0.25, >0.25 and ≤1, and >1 cc were 98%, 82%, and 93%, respectively; the rates were 92% for tumors >3 cc and 100% for >10 cc. The 6-month rates for freedom from distant brain failure were 57%, 71%, and 55% for patients with 1, 2, and >3 brain metastases, respectively. No differences were significant. No major complications were observed. The 4-fraction SRT protocol provided excellent tumor control with minimal toxicity. Distant brain failure was not so frequent, even in patients with multiple tumors. The results of the current study warrant a prospective randomized study comparing single-fraction stereotactic radiosurgery (SRS) with SRT in this patient population. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Figures

Open AccessArticle Immuno-Expression of Endoglin and Smooth Muscle Actin in the Vessels of Brain Metastases. Is There a Rational for Anti-Angiogenic Therapy?
Int. J. Mol. Sci. 2014, 15(4), 5663-5679; doi:10.3390/ijms15045663
Received: 20 January 2014 / Revised: 10 March 2014 / Accepted: 25 March 2014 / Published: 2 April 2014
Cited by 4 | PDF Full-text (989 KB) | HTML Full-text | XML Full-text
Abstract
Despite ongoing clinical trials, the efficacy of anti-angiogenic drugs for the treatment of brain metastases (BM) is still questionable. The lower response rate to anti-angiogenic therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be
[...] Read more.
Despite ongoing clinical trials, the efficacy of anti-angiogenic drugs for the treatment of brain metastases (BM) is still questionable. The lower response rate to anti-angiogenic therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be insensitive to these drugs, although the biological reasons underlining this phenomenon are still to be clarified. With the aim of assessing whether the targets of anti-angiogenic therapies are actually present in BM, in the present study, we analyzed the microvessel density (MVD), a measure of neo-angiogenesis, and the vascular phenotype (mature vs. immature) in the tumor tissue of a series of BM derived from different primary tumors. By using immunohistochemistry against endoglin, a specific marker for newly formed vessels, we found that neo-angiogenesis widely varies in BM depending on the site of the primary tumor, as well as on its histotype. According to our results, BM from lung cancer displayed the highest MVD counts, while those from renal carcinoma had the lowest. Then, among BM from lung cancer, those from large cell and adenocarcinoma histotypes had significantly higher MVD counts than those originating from squamous cell carcinoma (p = 0.0043; p = 0.0063). Of note, MVD counts were inversely correlated with the maturation index of the endoglin-stained vessels, reflected by the coverage of smooth muscle actin (SMA) positive pericytes (r = −0.693; p < 0.0001). Accordingly, all the endoglin-positive vessels in BM from pulmonary squamous cell carcinoma and renal carcinoma, displayed a mature phenotype, while vessels with an immature phenotype were found in highly vascularized BM from pulmonary large cell and adenocarcinoma. The low MVD and mature phenotype observed in BM from some primary tumors may account for their low sensitivity to anti-angiogenic therapies. Although our findings need to be validated in correlative studies with a clinical response, this should be taken into account in therapeutic protocols in order to avoid the adverse effects of useless therapies. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)

Review

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Open AccessReview Brain Metastases in Gastrointestinal Cancers: Is there a Role for Surgery?
Int. J. Mol. Sci. 2014, 15(9), 16816-16830; doi:10.3390/ijms150916816
Received: 25 June 2014 / Revised: 11 September 2014 / Accepted: 15 September 2014 / Published: 22 September 2014
Cited by 1 | PDF Full-text (1177 KB) | HTML Full-text | XML Full-text
Abstract
About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and
[...] Read more.
About 10% of all cancer patients will develop brain metastases during advanced disease progression. Interestingly, the vast majority of brain metastases occur in only three types of cancer: Melanoma, lung and breast cancer. In this review, we focus on summarizing the prognosis and impact of surgical resection of brain metastases originating from gastrointestinal cancers such as esophageal, gastric, pancreatic and colorectal cancer. The incidence of brain metastases is <1% in pancreatic and gastric cancer and <4% in esophageal and colorectal cancer. Overall, prognosis of these patients is very poor with a median survival in the range of only months. Interestingly, a substantial number of patients who had received surgical resection of brain metastases showed prolonged survival. However, it should be taken into account that all these studies were not randomized and it is likely that patients selected for surgical treatment presented with other important prognostic factors such as solitary brain metastases and exclusion of extra-cranial disease. Nevertheless, other reports have demonstrated long-term survival of patients upon resection of brain metastases originating from gastrointestinal cancers. Thus, it appears to be justified to consider aggressive surgical approaches for these patients. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessReview The Diagnosis and Treatment of Pseudoprogression, Radiation Necrosis and Brain Tumor Recurrence
Int. J. Mol. Sci. 2014, 15(7), 11832-11846; doi:10.3390/ijms150711832
Received: 31 March 2014 / Revised: 5 June 2014 / Accepted: 25 June 2014 / Published: 3 July 2014
Cited by 12 | PDF Full-text (943 KB) | HTML Full-text | XML Full-text
Abstract
Radiation therapy is an important modality used in the treatment of patients with brain metastatic disease and malignant gliomas. Post-treatment surveillance often involves serial magnetic resonance imaging. A challenge faced by clinicians is in the diagnosis and management of a suspicious gadolinium-enhancing lesion
[...] Read more.
Radiation therapy is an important modality used in the treatment of patients with brain metastatic disease and malignant gliomas. Post-treatment surveillance often involves serial magnetic resonance imaging. A challenge faced by clinicians is in the diagnosis and management of a suspicious gadolinium-enhancing lesion found on imaging. The suspicious lesion may represent post-treatment radiation effects (PTRE) such as pseudoprogression, radiation necrosis or tumor recurrence. Significant progress has been made in diagnostic imaging modalities to assist in differentiating these entities. Surgical and medical interventions have also been developed to treat PTRE. In this review, we discuss the pathophysiology, clinical presentation, diagnostic imaging modalities and provide an algorithm for the management of pseudoprogression, radiation necrosis and tumor recurrence. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessReview MicroRNAs in Brain Metastases: Potential Role as Diagnostics and Therapeutics
Int. J. Mol. Sci. 2014, 15(6), 10508-10526; doi:10.3390/ijms150610508
Received: 16 April 2014 / Revised: 22 May 2014 / Accepted: 6 June 2014 / Published: 11 June 2014
Cited by 4 | PDF Full-text (1439 KB) | HTML Full-text | XML Full-text
Abstract
Brain metastases remain a daunting adversary that negatively impact patient survival. Metastatic brain tumors affect up to 45% of all cancer patients with systemic cancer and account for ~20% of all cancer-related deaths. A complex network of non-coding RNA molecules, microRNAs (miRNAs), regulate
[...] Read more.
Brain metastases remain a daunting adversary that negatively impact patient survival. Metastatic brain tumors affect up to 45% of all cancer patients with systemic cancer and account for ~20% of all cancer-related deaths. A complex network of non-coding RNA molecules, microRNAs (miRNAs), regulate tumor metastasis. The brain micro-environment modulates metastatic tumor growth; however, defining the precise genetic events that promote metastasis in the brain niche represents an important, unresolved problem. Understanding these events will reveal disease-based targets and offer effective strategies to treat brain metastases. Effective therapeutic strategies based upon the biology of brain metastases represent an urgent, unmet need with immediate potential for clinical impact. Studies have demonstrated the ability of miRNAs to distinguish normal from cancerous cells, primary from secondary brain tumors, and correctly categorize metastatic brain tumor tissue of origin based solely on miRNA profiles. Interestingly, manipulation of miRNAs has proven effective in cancer treatment. With the promise of reduced toxicity, increased efficacy and individually directed personalized anti-cancer therapy, using miRNA in the treatment of metastatic brain tumors may prove very useful and improve patient outcome. In this review, we focus on the potential of miRNAs as diagnostic and therapeutic targets for the treatment of metastatic brain lesions. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
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Open AccessReview SPECT and PET Serve as Molecular Imaging Techniques and in Vivo Biomarkers for Brain Metastases
Int. J. Mol. Sci. 2014, 15(6), 9878-9893; doi:10.3390/ijms15069878
Received: 30 March 2014 / Revised: 13 May 2014 / Accepted: 14 May 2014 / Published: 3 June 2014
Cited by 6 | PDF Full-text (432 KB) | HTML Full-text | XML Full-text
Abstract
Nuclear medicine techniques (single photon emission computerized tomography, SPECT, and positron emission tomography, PET) represent molecular imaging tools, able to provide in vivo biomarkers of different diseases. To investigate brain tumours and metastases many different radiopharmaceuticals imaged by SPECT and PET can be
[...] Read more.
Nuclear medicine techniques (single photon emission computerized tomography, SPECT, and positron emission tomography, PET) represent molecular imaging tools, able to provide in vivo biomarkers of different diseases. To investigate brain tumours and metastases many different radiopharmaceuticals imaged by SPECT and PET can be used. In this review the main and most promising radiopharmaceuticals available to detect brain metastases are reported. Furthermore the diagnostic contribution of the combination of SPECT and PET data with radiological findings (magnetic resonance imaging, MRI) is discussed. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessReview Molecular Biology of Brain Metastasis
Int. J. Mol. Sci. 2014, 15(6), 9519-9530; doi:10.3390/ijms15069519
Received: 28 March 2014 / Revised: 17 April 2014 / Accepted: 9 May 2014 / Published: 28 May 2014
Cited by 5 | PDF Full-text (333 KB) | HTML Full-text | XML Full-text
Abstract
Metastasis to the central nervous system (CNS) remains a major cause of morbidity and mortality in patients with systemic cancer. As the length of survival in patients with systemic cancer improves, thanks to multimodality therapies, focusing on metastases to the CNS becomes of
[...] Read more.
Metastasis to the central nervous system (CNS) remains a major cause of morbidity and mortality in patients with systemic cancer. As the length of survival in patients with systemic cancer improves, thanks to multimodality therapies, focusing on metastases to the CNS becomes of paramount importance. Unique interactions between the brain’s micro-environment, blood-brain barrier, and tumor cells are hypothesized to promote distinct molecular features in CNS metastases that may require tailored therapeutic approaches. This review will focus on the pathophysiology, epigenetics, and immunobiology of brain metastases in order to understand the metastatic cascade. Cancer cells escape the primary tumor, intravasate into blood vessels, survive the hematogenous dissemination to the CNS, arrest in brain capillaries, extravasate, proliferate, and develop angiogenic abilities to establish metastases. Molecular biology, genetics, and epigenetics are rapidly expanding, enabling us to advance our knowledge of the underlying mechanisms involved. Research approaches using cell lines that preferentially metastasize in vivo to the brain and in vitro tissue-based studies unfold new molecular leads into the disease. It is important to identify and understand the molecular pathways of the metastatic cascade in order to target the investigation and development of more effective therapies and research directions. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Open AccessReview Brain Metastasis-Initiating Cells: Survival of the Fittest
Int. J. Mol. Sci. 2014, 15(5), 9117-9133; doi:10.3390/ijms15059117
Received: 15 April 2014 / Revised: 12 May 2014 / Accepted: 13 May 2014 / Published: 22 May 2014
PDF Full-text (548 KB) | HTML Full-text | XML Full-text
Abstract
Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only
[...] Read more.
Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)
Figures

Open AccessReview Rationale for the Use of Upfront Whole Brain Irradiation in Patients with Brain Metastases from Breast Cancer
Int. J. Mol. Sci. 2014, 15(5), 8138-8152; doi:10.3390/ijms15058138
Received: 31 March 2014 / Revised: 22 April 2014 / Accepted: 25 April 2014 / Published: 8 May 2014
Cited by 3 | PDF Full-text (214 KB) | HTML Full-text | XML Full-text
Abstract
Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a
[...] Read more.
Breast cancer is the second most common cause of brain metastases and deserves particular attention in relation to current prolonged survival of patients with metastatic disease. Advances in both systemic therapies and brain local treatments (surgery and stereotactic radiosurgery) have led to a reappraisal of brain metastases management. With respect to this, the literature review presented here was conducted in an attempt to collect medical evidence-based data on the use of whole-brain radiotherapy for the treatment of brain metastases from breast cancer. In addition, this study discusses here the potential differences in outcomes between patients with brain metastases from breast cancer and those with brain metastases from other primary malignancies and the potential implications within a treatment strategy. Full article
(This article belongs to the Special Issue Brain Metastasis 2014)

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