Schiapparelli, Paula

Abstract Around fifteen to thirty percent of stage IV breast cancer metastasizes to the brain, severely decreasing the quality of life of these patients by causing neurological decline and eventually death. In metastatic cancers there is a small subset of cells in the primary tumor bulk called Metastatic Tumor Initiating Cells (MTICs) which are able to escape and produce a niche establishment at distal sites where they can quickly become resistant to surgery and radiation. Melatonin has shown an inhibitory role in the viability and invasiveness of breast cancer and in modulating the expression of proteins related to Breast Cancer Stem Cells (BCSCs). These findings suggest its potential anti-metastatic role in different breast cancer cell lines. In this study we aimed to evaluate the effects of melatonin treatment in vitro for breast cancer brain metastasis. The cell line MDA-BT was originally obtained from MDA-MB-231, passed through the rat’s heart and then isolated once engrafted as a tumor in the brain. After a dose response assay, cells were treated with melatonin at doses of 1500 and 3000 µM for 48hrs. Clonogenic assay, MTT, as well as a stem cell signature through RT-qPCR, including CD44, CD24 and ALDH1 markers, were performed to evaluate the malignancy of the MTICs. The results showed that melatonin at high doses impacts morphology, declines viability, reduces colony formation ability, and decreases stemness in MDA-BT cells. Therefore, our findings highlight melatonin as a relevant therapeutic candidate to target breast cancer brain metastases.

Malignant brain tumor, including the most common type glioblastoma, are histologically heterogeneous and invasive tumors known as the most devastating neoplasms with high morbidity and mortality. Despite multimodal treatment including surgery, radiotherapy, chemotherapy, and immunotherapy, the disease inevitably recurs and is fatal. This lack of curative options has motivated researchers to explore new treatment strategies and to develop new drug delivery systems (DDSs); however, the unique anatomical, physiological, and pathological features of brain tumors greatly limit the effectiveness of conventional chemotherapy. In this context, we review the recent progress in the development of nanoparticle‐basedDDSsaiming to address the key challenges in transporting sufficient amount of therapeutic agents into the brain tumor areas while minimizing the potential side effects. We first provide an overview of the standard treatments currently used in the clinic for the management of brain cancers, discussing the effectiveness and limitations of each therapy. We then provide an in‐depth review of nanotherapeutic systems that are intended to bypass the blood–brain barrier, overcome multidrug resistance, infiltrate larger tumorous tissue areas, and/or release therapeutic agents in a controlled manner.WIREs Nanomed Nanobiotechnol2018, 10:e1479. doi: 10.1002/wnan.1479This article is categorized under:Implantable Materials and Surgical Technologies > Nanomaterials and ImplantsTherapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease

Abstract Human neural progenitor cell (NPC) migration within the subventricular zone (SVZ) of the lateral ganglionic eminence is an active process throughout early brain development. The migration of human NPCs from the SVZ to the olfactory bulb during fetal stages resembles what occurs in adult rodents. As the human brain develops during infancy, this migratory stream is drastically reduced in cell number and becomes barely evident in adults. The mechanisms regulating human NPC migration are unknown. The Slit–Robo signaling pathway has been defined as a chemorepulsive cue involved in axon guidance and neuroblast migration in rodents. Slit and Robo proteins expressed in the rodent brain help guide neuroblast migration from the SVZ through the rostral migratory stream to the olfactory bulb. Here, we present the first study on the role that Slit and Robo proteins play in human-derived fetal neural progenitor cell migration (hfNPC). We describe that Robo1 and Robo2 isoforms are expressed in the human fetal SVZ. Furthermore, we demonstrate that Slit2 is able to induce a chemorepellent effect on the migration of hfNPCs derived from the human fetal SVZ. In addition, when Robo1 expression is inhibited, hfNPCs are unable to migrate to the olfactory bulb of mice when injected in the anterior SVZ. Our findings indicate that the migration of human NPCs from the SVZ is partially regulated by the Slit–Robo axis. This pathway could be regulated to direct the migration of NPCs in human endogenous neural cell therapy.