Maria Caffo

Innovative Therapeutic Strategies in the Treatment of Brain Metastases

Brain metastases (BM) are the most common intracranial tumors and their incidence is increasing. Untreated brain metastases are associated with a poor prognosis and a poor performance status. Metastasis development involves the migration of a cancer cell from the bulk tumor into the surrounding tissue, extravasation from the blood into tissue elsewhere in the body, and formation of a secondary tumor. In the recent past, important results have been obtained in the management of patients affected by BM, using surgery, radiation therapy, or both. Conventional chemotherapies have generally produced disappointing results, possibly due to their limited ability to penetrate the blood–brain barrier. The advent of new technologies has led to the discovery of novel molecules and pathways that have better depicted the metastatic process. Targeted therapies such as bevacizumab, erlotinib, gefitinib, sunitinib and sorafenib, are all licensed and have demonstrated improved survival in patients with metastatic disease. In this review, we will report current data on targeted therapies. A brief review about brain metastatic process will be also presented.

ROS and Brain Gliomas: An Overview of Potential and Innovative Therapeutic Strategies

Reactive oxygen species (ROS) represent reactive products belonging to the partial reduction of oxygen. It has been reported that ROS are involved in different signaling pathways to control cellular stability. Under normal conditions, the correct function of redox systems leads to the prevention of cell oxidative damage. When ROS exceed the antioxidant defense system, cellular stress occurs. The cellular redox impairment is strictly related to tumorigenesis. Tumor cells, through the generation of hydrogen peroxide, tend to the alteration of cell cycle phases and, finally to cancer progression. In adults, the most common form of primary malignant brain tumors is represented by gliomas. The gliomagenesis is characterized by numerous molecular processes all characterized by an altered production of growth factor receptors. The difficulty to treat brain cancer depends on several biological mechanisms such as failure of drug delivery through the blood-brain barrier, tumor response to chemotherapy, and intrinsic resistance of tumor cells. Understanding the mechanisms of ROS action could allow the formulation of new therapeutic protocols to treat brain gliomas.

Embolized meningiomas: risk of overgrading and neo-angiogenesis

Pre-operative embolization (POE) of meningiomas may induce histological changes which simulate malignancy, possibly resulting in overgrading. Aims of the present study were to identify clues to distinguish malignancy-related features from POE-related changes and to test for overgrading the grading scheme currently in use, in embolized meningiomas. In addition, we aimed to analyze whether the POE procedure may stimulate neo-angiogenesis in meningiomas. The histological features of a series of embolized meningiomas were evaluated and considered for grading assessment. In the same cases neo-angiogenesis was quantified by the evaluation of microvessel density (MVD) and correlated with the interval between POE and surgery. Necrosis and macronucleoli represented common findings in embolized meningiomas. Nonetheless, in most of the cases, necrosis showed an abrupt line of demarcation from the viable tumour tissue, and macronucleoli were restricted to peri-necrotic areas. Suggesting that these were POE-associated changes, exclusion of necrotic areas with an abrupt line of transition and focal macronucleoli from grading assessment resulted in increased specificity and positive predictive value in the identification of recurring meningiomas. In our cohort, MVD significantly increased with the time between POE and surgery, suggesting that POE procedure may induce neo-angiogenesis in meningiomas. In conclusion, a risk of overgrading there exists in embolized meningiomas, as a consequence of the frequent evidence of necrosis and prominent nucleoli in these tumours. In order to avoid overgrading, we suggest that necrosis showing an abrupt line of demarcation and focal peri-necrotic macronucleoli are not included in grading assessment. Also, caution should be used in the interpretation of MVD as a prognostic factor in embolized meningioma, as it may also result from POE procedure.

Clinicopathological characteristics, hormone receptor status and matrix metallo-proteinase-9 (MMP-9) immunohistochemical expression in spinal meningiomas.

Meningiomas involving the spinal meninges show a reduced tendency to recur compared to those of the intracranial compartment. Nonetheless, due to the few reports with a significant number of patients, their biological characteristics largely remain to be investigated. With the aim of clarifying the biology of these tumors, we examined in the present paper the clinicopathological features, the estrogen receptor (ER) and progesterone receptor (PR) status, as well as the Ki-67 labeling index (LI) and matrix metallo-proteinase-9 (MMP-9) expression of 58 spinal meningiomas. Ki-67 LI ranged between 1% and 5% (median: 1%); no expression of ER was found in all the cases, whereas PR immunoexpression was found in 86% of the tumors. High MMP-9 expression was encountered in 46% of meningiomas, and it was significantly correlated with the percentage of PR expression. The recurrence rate was 1.7%. The only recurred case showed high MMP-9 expression, absence of PR and low Ki-67 LI. Our findings confirm that spinal meningiomas are indolent tumors with low growth fraction and recurrence rate. In these neoplasms, high MMP-9 expression seems to be associated with the development of recurrences only in the absence of PR expression. Thus, the evaluation of both MMP-9 and PR expression might be of use in the identification of spinal meningiomas at higher risk of relapse.

Graphene in neurosurgery: the beginning of a new era.

Nanotechnology has revolutionized the approach to different fields of industry and medicine. Among the new nanomaterial used, one of the most promising appears to be graphene. Its versatility, due to a particular chemical configuration, confers to it enormous potential of application. Graphene has recently been tested also in biomedical research with excellent results. Neurosurgery can benefit of this material for therapeutic purposes such as targeting controlled drug/gene delivery in brain tumor treatment, as well as photothermal and photodynamic cancer therapy, improving biosensing and bioimaging, and lastly as biocompatible material for intracranial and/or spinal devices. However, it still remains an experimental material whose in vitro and in vivo toxicity is tested with controversial results for the human health. Noteworthy is the fact that it is not possible so far to know its long-term toxicity.

Heavy metals and epigenetic alterations in brain tumors.

Heavy metals and their derivatives can cause various diseases. Numerous studies have evaluated the possible link between exposure to heavy metals and various cancers. Recent data show a correlation between heavy metals and aberration of genetic and epigenetic patterns. From a literature search we noticed few experimental and epidemiological studies that evaluate a possible correlation between heavy metals and brain tumors. Gliomas arise due to genetic and epigenetic alterations of glial cells. Changes in gene expression result in the alteration of the cellular division process. Epigenetic alterations in brain tumors include the hypermethylation of CpG group, hypomethylation of specific genes, aberrant activation of genes, and changes in the position of various histones. Heavy metals are capable of generating reactive oxygen assumes that key functions in various pathological mechanisms. Alteration of homeostasis of metals could cause the overproduction of reactive oxygen species and induce DNA damage, lipid peroxidation, and alteration of proteins. In this study we summarize the possible correlation between heavy metals, epigenetic alterations and brain tumors. We report, moreover, the review of relevant literature.

Epigenetic effects of cadmium in cancer: focus on melanoma.

Cadmium is a highly toxic heavy metal, which has a destroying impact on organs. Exposure to cadmium causes severe health problems to human beings due to its ubiquitous environmental presence and features of the pathologies associated with pro-longed exposure. Cadmium is a well-established carcinogen, although the underlying mechanisms have not been fully under-stood yet. Recently, there has been considerable interest in the impact of this environmental pollutant on the epigenome. Be-cause of the role of epigenetic alterations in regulating gene expression, there is a potential for the integration of cadmium-induced epigenetic alterations as critical elements in the cancer risk assessment process. Here, after a brief review of the ma-jor diseases related to cadmium exposure, we focus our interest on the carcinogenic potential of this heavy metal. Among the several proposed pathogenetic mechanisms, particular attention is given to epigenetic alterations, including changes in DNA methylation, histone modifications and non-coding RNA expression. We review evidence for a link between cadmium-induced epigenetic changes and cell transformation, with special emphasis on melanoma. DNA methylation, with reduced expression of key genes that regulate cell proliferation and apoptosis, has emerged as a possible cadmium-induced epigenetic mechanism in melanoma. A wider comprehension of mechanisms related to this common environmental contaminant would allow a better cancer risk evaluation.

Antisense Oligonucleotides Therapy in the Treatment of Cerebral Gliomas: A Review

Patients affected by cerebral gliomas, despite classical strategies adopted, show a very poor prognosis. Current treatment consists of regimens that include surgical debulking, radiation therapy, and systemic chemotherapy. However, the median survival after surgery and radiation therapy alone is 9 months, and systemic chemotherapy is minimally effective. Advances in molecular biology have better depicted the mechanisms involved in the genesis of cerebral gliomas and identified specific gene sequences to be targeted in the malignant cell genome. Gene expression can be blocked using various strategies. The concept of antisense-mediated gene inhibition has now emerged as a potentially powerful alternative or adjunct to conventional cancer chemotherapy. This strategy is able to block selectively glioma cells which interfer to gliomagenesis molecular pathways. The antisense molecules, delivered inside the brain, penetrate into glioma cells blocking specific genic functions. Antisense oligonucleotides are complementary to the target mRNA and this bind cause the block and/or the reduction of the encoded protein synthesis. Genes coding for growth factors and their receptors, proto-oncogenes, cellular proteases, kinases, and proteins important in cell cycle control and apoptosis represent ideal target for antisense oligonucleotides treatment. In this study, we report the most relevant findings of antisense oligonucleotides application in gliomas treatment.

Interleukin-8 overexpression in astrocytomas is induced by prostaglandin E2 and is associated with the transcription factors CCAAT/enhancer-binding protein-β and CCAAT/enhancer-binding homologous protein.

BACKGROUND:The upregulation of microsomal prostaglandin E synthase-1 (mPGES-1) and the overexpression of interleukin-8 (IL-8) have been separately linked to glioma malignancy. OBJECTIVE:To evaluate (1) the correlation between the mRNA levels of IL-8, mPGES-1, and the main transcription factors (TFs) activating the IL-8 promoter in human brain tumors of different grades; (2) the role of prostaglandin E2 (PGE2) on IL-8 activation and the expression of these TFs in tumor-derived cells; and (3) the biological impact of PGE2 treatment and mPGES-1 silencing on IL-8 synthesis and tumorigenesis. METHODS:Quantitative real-time polymerase chain reaction, transfection experiments, and cell proliferation and apoptosis assays were performed. RESULTS:Regardless of histological grade, a significant positive association between IL-8 expression and mPGES-1, CCAAT/enhancer-binding protein-β (C/EBP-β) and C/EBP Homologous Protein (CHOP) mRNA levels was found only in astrogliomas (P < .001). The correlation was not significant in the other brain tumors. PGE2-treated astroglioma cells showed a marked upregulation of IL-8, C/EBP-β, and CHOP, as well as increased proliferation and decreased apoptosis compared with untreated cells. mPGES-1-silenced astroglioma cells displayed decreased IL-8 synthesis, accompanied by reduced cell growth and an increased rate of apoptosis. The other brain tumor cells were unaffected either by PGE2 treatment or by mPGES-1 knockout. CONCLUSION:(1) PGE2 is responsible for IL-8 overexpression, independently of the malignancy grade, in astrogliomas only. (2) C/EBP-β and CHOP may be involved in mediating PGE2-induced IL-8 activation in these tumors. (3) mPGES-1 inhibition may have potential as a form of adjuvant therapy for astrogliomas.

Antisense Oligonucleotides in the Treatment of Cerebral Gliomas. Review of Concerning Patents

Gliomas are the most common and malignant primary brain tumors in the adult population. Despite the intensive research on cancer pathology, real mechanisms concerning glioma progression are not completely understood. The prognosis in patients affected by malignant gliomas is still very unfavorable. Recent genomic analyses have revealed patterns of molecular changes within tumor subclasses that harbor distinct underlying biology, clinical prognosis, and pathogenic routes. So, novel treatments will have to be able to interfere at different molecular levels in gliomagenesis minimizing the toxicity. In particular, antisense oligonucleotides are able to inhibit expression of specific genes by interfering with transcription or, more usually, with translation. In this review, we will focus on mechanisms of antisense oligonucleotides reporting clinical and experimental studies. We will also report a large number of patents which adopt the antisense oligonucleotides as potential therapeutic approach in gliomas treatment.