Neuroblastoma—A Neural Crest Derived Embryonal Malignancy

Neuroblastoma is a neural crest derived malignancy of the peripheral nervous system and is the most common and deadliest tumor of infancy. It is characterized by clinical heterogeneity with a disease spectrum ranging from spontaneous regression without any medical intervention to treatment resistant tumors with metastatic spread and poor patient survival. The events that lead to the development of neuroblastoma from the neural crest have not been fully elucidated. Here we discuss factors and processes within the neural crest that when dysregulated have the potential to be initiators or drivers of neuroblastoma development. A more precise biological understanding of neuroblastoma causes and cell of origin is highly warranted. This will give valuable information for the development of medicines that specifically target molecules within neuroblastoma cells and also give hint about the mechanisms behind treatment resistance that is frequently seen in neuroblastoma

Rho-associated kinase is a therapeutic target in neuroblastoma

Source at: http://doi.org/10.1073/pnas.1706011114 Neuroblastoma is a peripheral neural system tumor that originates from the neural crest and is the most common and deadly tumor of infancy. Here we show that neuroblastoma harbors frequent mutations of genes controlling the Rac/Rho signaling cascade important for proper migration and differentiation of neural crest cells during neuritogenesis. RhoA is activated in tumors from neuroblastoma patients, and elevated expression of Rho-associated kinase (ROCK)2 is associated with poor patient survival. Pharmacological or genetic inhibition of ROCK1 and 2, key molecules in Rho signaling, resulted in neuroblastoma cell differentiation and inhibition of neuroblastoma cell growth, migration, and invasion. Molecularly, ROCK inhibition induced glycogen synthase kinase 3β-dependent phosphorylation and degradation of MYCN protein. Small-molecule inhibition of ROCK suppressed MYCN-driven neuroblastoma growth in TH-MYCN homozygous transgenic mice and MYCN gene-amplified neuroblastoma xenograft growth in nude mice. Interference with Rho/Rac signaling might offer therapeutic perspectives for high-risk neuroblastoma

GIT1 protects against breast cancer growth through negative regulation of Notch

Notch signalling is reported to be hyperactivated in oestrogen receptor-negative (ER-) breast cancer. Here the authors show that G protein-coupled receptor kinase-interacting protein 1 (GIT1) negatively regulates Notch signalling and tumour growth in ER- breast cancer by blocking Notch ICD nuclear translocation.Hyperactive Notch signalling is frequently observed in breast cancer and correlates with poor prognosis. However, relatively few mutations in the core Notch signalling pathway have been identified in breast cancer, suggesting that as yet unknown mechanisms increase Notch activity. Here we show that increased expression levels of GIT1 correlate with high relapse-free survival in oestrogen receptor-negative (ER(-)) breast cancer patients and that GIT1 mediates negative regulation of Notch. GIT1 knockdown in ER(-) breast tumour cells increased signalling downstream of Notch and activity of aldehyde dehydrogenase, a predictor of poor clinical outcome. GIT1 interacts with the Notch intracellular domain (ICD) and influences signalling by inhibiting the cytoplasm-to-nucleus transport of the Notch ICD. In xenograft experiments, overexpression of GIT1 in ER(-) cells prevented or reduced Notch-driven tumour formation. These results identify GIT1 as a modulator of Notch signalling and a guardian against breast cancer growth.</p

The multiple functions of miR-574-5p in the neuroblastoma tumor microenvironment

Neuroblastoma is the most common extracranial solid tumor in childhood and arises from neural crest cells of the developing sympathetic nervous system. Prostaglandin E2 (PGE2) has been identified as a key pro-inflammatory mediator of the tumor microenvironment (TME) that promotes neuroblastoma progression. We report that the interaction between the microRNA miR-574-5p and CUG-binding protein 1 (CUGBP1) induces the expression of microsomal prostaglandin E2 synthase 1 (mPGES-1) in neuroblastoma cells, which contributes to PGE2 biosynthesis. PGE2 in turn specifically induces the sorting of miR-574-5p into small extracellular vesicles (sEV) in neuroblastoma cell lines. sEV are one of the major players in intercellular communication in the TME. We found that sEV-derived miR-574-5p has a paracrine function in neuroblastoma. It acts as a direct Toll-like receptor 7/8 (TLR7/8) ligand and induces α-smooth muscle actin (α-SMA) expression in fibroblasts, contributing to fibroblast differentiation. This is particularly noteworthy as it has an opposite function to that in the TME of lung carcinoma, another PGE2 dependent tumor type. Here, sEV-derived miR-574-5p has an autokrine function that inhibits PGE2 biosynthesis in lung cancer cells. We report that the tetraspanin composition on the surface of sEV is associated with the function of sEV-derived miR-574-5p. This suggests that the vesicles do not only transport miRs, but also appear to influence their mode of action

Tailored Approaches in Drug Development and Diagnostics: From Molecular Design to Biological Model Systems

Approaches to increase the efficiency in developing drugs and diagnostics tools, including new drug delivery and diagnostic technologies, are needed for improved diagnosis and treatment of major diseases and health problems such as cancer, inflammatory diseases, chronic wounds, and antibiotic resistance. Development within several areas of research ranging from computational sciences, material sciences, bioengineering to biomedical sciences and bioimaging is needed to realize innovative drug development and diagnostic (DDD) approaches. Here, an overview of recent progresses within key areas that can provide customizable solutions to improve processes and the approaches taken within DDD is provided. Due to the broadness of the area, unfortunately all relevant aspects such as pharmacokinetics of bioactive molecules and delivery systems cannot be covered. Tailored approaches within (i) bioinformatics and computer-aided drug design, (ii) nanotechnology, (iii) novel materials and technologies for drug delivery and diagnostic systems, and (iv) disease models to predict safety and efficacy of medicines under development are focused on. Current developments and challenges ahead are discussed. The broad scope reflects the multidisciplinary nature of the field of DDD and aims to highlight the convergence of biological, pharmaceutical, and medical disciplines needed to meet the societal challenges of the 21st century

Preclinical Studies of the Melphalan Prodrug J1 for Cancer Therapy

J1 (L-melphalanyl-L-p-fluorophenylalanyl ethyl ester) is a dipeptide derivative of the alkylating agent melphalan with increased cytotoxicity. In this thesis the preclinical pharmacology of J1 has been characterized. Our results show that J1 rapidly enters the cells, where melphalan is released by hydrolysis. The maximum concentration (Cmax) of melphalan was detected 15 min after exposure to J1 in human cancer cell lines. In comparison, melphalan exposure resulted in a 10-fold lower Cmax that was shifted to later time points. J1 induced more DNA damage and apoptosis than melphalan. The cytotoxic activity and release of melphalan from J1 were inhibited by preincubating cells with the aminopeptidase inhibitor bestatin. In accordance with these results, we showed that J1 is a substrate for aminopeptidase N (APN), which may result in increased tumor selectivity. J1 effectively inhibited cell growth in a set of neuroblastoma cell lines. Athymic mice carrying neuroblastoma xenografts were treated either with equimolar doses of melphalan or J1. J1 inhibited the tumor growth more effectively than melphalan and the untreated control, and was associated with higher caspase-3 activation, fewer proliferating tumor cells and decreased mean vascular density. J1 and melphalan showed similar activity profiles when tested in 176 primary tumor cell cultures from patients, but J1 exhibited 50- to 100-fold higher potency. The difference was greater in some diagnoses (e.g. breast cancer, NHL and AML), and was exceptionally large in some breast cancer samples with aggressive phenotypes. A combination screening of J1 and standard chemotherapeutics yielded mostly additive interactions, except for etoposide which induced synergy in all tested cell lines. In conclusion, the melphalan prodrug J1 is effectively transported into the cells, where aminopeptidases (for example APN) catalyze the formation of melphalan. J1 shows promising preclinical potential in the diagnoses neuroblastoma and breast cancer

Vardagslivet i skuggan av den moderniserade staden: En fallstudie av ett förflyttningsprojekt i Colombo

Uppsatsen är en fallstudie som berör ett förflyttningsprojekt av invånare i informella bosättningar, allmänt känt som slumområden, i Sri Lankas kommersiella huvudstad Colombo. FN:s hållbarhetsmål för Agenda 2030 belyser utvecklingen av den informella bostadssektorn som ett problem i flera utvecklingsländer, däribland Sri Lanka. Utvecklingen som ofta är ett resultat av urbaniseringsprocesser tenderar att skapa ett ökat tryck på mark och kan därmed begränsa de fattigas förmåga att äga mark och bostäder.Modernisering av städer tenderar att förändra stadens rumsliga struktur och gå i linje med marknadsdriven markanvändning och kommersialisering som är tänkt att främja den ekonomiska tillväxten. Marknaden och kommersiell utveckling som ställer stor efterfrågan på central och attraktiv mark i Colombo ockuperas till stor del av informella bosättningar.Marknaden, en statlig agenda för utveckling och modernisering kan vara pådrivande faktorer till att grupper i befolkningen blir förflyttade och tvingade till att påbörja nya liv i en ny livsmiljö. Som ett svar på liknande omständigheter initierades ett omfattande förflyttningsprojekt i Colombo år 2011. Projektet vid namn Urban Regeneration Project grundadesmed visionen att förflytta 68.000 familjer från informella boendeformer till nybyggda höghuskomplex, och därmed uppgradera invånares levnadsstandard, samt nyttomaximera markanvändningen i staden.Förvisso kan ett projekt av denna sort i flera avseenden ses som någonting positivt, där många människor får en förbättrad boendesituation. Däremot, när omstruktureringar av staden sker tenderar inte bara den fysiska miljön att moderniseras, utan även invånarnas vardagsliv. Människor och grupper i alla dess konstellationer av nätverk och relationer kan ses som väsentliga för en levande och fungerande stad. Invånare investerar år av sina liv för att bygga upp relationer till sitt grannskap och medmänniskor vilka inte enkelt är utbytbara. Dessa relationer och nätverk bringar en känsla av tillhörighet men också tillit till sin omgivning som främjar stabilitet och trygghet.The study concerns a relocation project of residents in informal settlements, commonly known as slums, in Sri Lanka's commercial capital Colombo.The UN's Sustainability Goal for Agenda 2030 highlights the developmentof the informal housing sector as an issue in several developing countries, including Sri Lanka. The development that is often a result of urbanization processes tends to create increased pressure on land and can thus limit the poor's ability to own land and housing.Modernization of cities tends to change the spatial structure of the city and align with market-driven land use and commercialization that are intended to promote economic growth. The market and commercial development stand great demand on central and attractive land in Colombo are largely occupied by informal settlements.The market, a state agenda for development and modernization can be driving factors why groups of the population are being displaced andforced to start new lives in a new living environment. In response to similar circumstances, an extensive relocation project was initiated in Colombo in 2011. The project called the Urban Regeneration Project was founded with the vision to move 68,000 families from informal housing to newly built high- rise complexes, thereby upgrading the living standards of residents, and maximizing land use benefits in the city.Indeed, a project of this kind can in many respects be seen as something positive, where several inhabitants get an improved housing situation. On the other hand, when restructuring of the city takes place, not only the physical environment tends to be modernized, but also the everyday lives of the inhabitants. People and groups in all its constellations of networks and relationships are essential for a living and functioning city. Residents invest years of their lives to build relationships with their neighborhood and fellow human beings that are not easily interchangeable. These relationships and networks bring a sense of belonging but also trust in their surroundings that promotes stability and security

Vardagslivet i skuggan av den moderniserade staden: En fallstudie av ett förflyttningsprojekt i Colombo

Uppsatsen är en fallstudie som berör ett förflyttningsprojekt av invånare i informella bosättningar, allmänt känt som slumområden, i Sri Lankas kommersiella huvudstad Colombo. FN:s hållbarhetsmål för Agenda 2030 belyser utvecklingen av den informella bostadssektorn som ett problem i flera utvecklingsländer, däribland Sri Lanka. Utvecklingen som ofta är ett resultat av urbaniseringsprocesser tenderar att skapa ett ökat tryck på mark och kan därmed begränsa de fattigas förmåga att äga mark och bostäder. Modernisering av städer tenderar att förändra stadens rumsliga struktur och gå i linje med marknadsdriven markanvändning och kommersialisering som är tänkt att främja den ekonomiska tillväxten. Marknaden och kommersiell utveckling som ställer stor efterfrågan på central och attraktiv mark i Colombo ockuperas till stor del av informella bosättningar. Marknaden, en statlig agenda för utveckling och modernisering kan vara pådrivande faktorer till att grupper i befolkningen blir förflyttade och tvingade till att påbörja nya liv i en ny livsmiljö. Som ett svar på liknande omständigheter initierades ett omfattande förflyttningsprojekt i Colombo år 2011. Projektet vid namn Urban Regeneration Project grundades med visionen att förflytta 68.000 familjer från informella boendeformer till nybyggda höghuskomplex, och därmed uppgradera invånares levnadsstandard, samt nyttomaximera markanvändningen i staden. Förvisso kan ett projekt av denna sort i flera avseenden ses som någonting positivt, där många människor får en förbättrad boendesituation. Däremot, när omstruktureringar av staden sker tenderar inte bara den fysiska miljön att moderniseras, utan även invånarnas vardagsliv. Människor och grupper i alla dess konstellationer av nätverk och relationer kan ses som väsentliga för en levande och fungerande stad. Invånare investerar år av sina liv för att bygga upp relationer till sitt grannskap och medmänniskor vilka inte enkelt är utbytbara. Dessa relationer och nätverk bringar en känsla av tillhörighet men också tillit till sin omgivning som främjar stabilitet och trygghet.The study concerns a relocation project of residents in informal settlements, commonly known as slums, in Sri Lanka's commercial capital Colombo. The UN's Sustainability Goal for Agenda 2030 highlights the development of the informal housing sector as an issue in several developing countries, including Sri Lanka. The development that is often a result of urbanization processes tends to create increased pressure on land and can thus limit the poor's ability to own land and housing. Modernization of cities tends to change the spatial structure of the city and align with market-driven land use and commercialization that are intended to promote economic growth. The market and commercial development stand great demand on central and attractive land in Colombo are largely occupied by informal settlements. The market, a state agenda for development and modernization can be driving factors why groups of the population are being displaced and forced to start new lives in a new living environment. In response to similar circumstances, an extensive relocation project was initiated in Colombo in 2011. The project called the Urban Regeneration Project was founded with the vision to move 68,000 families from informal housing to newly built high- rise complexes, thereby upgrading the living standards of residents, and maximizing land use benefits in the city. Indeed, a project of this kind can in many respects be seen as something positive, where several inhabitants get an improved housing situation. On the other hand, when restructuring of the city takes place, not only the physical environment tends to be modernized, but also the everyday lives of the inhabitants. People and groups in all its constellations of networks and relationships are essential for a living and functioning city. Residents invest years of their lives to build relationships with their neighborhood and fellow human beings that are not easily interchangeable. These relationships and networks bring a sense of belonging but also trust in their surroundings that promotes stability and security

Significant off-target effects of postulated IGF-1R inhibitor picropodophyllin (PPP) in vitro

The insulin-like growth factor-1 (IGF-1) and its receptors play an important role in the transformation and progression of several malignancies. Several inhibitors of this pathway have been developed and evaluated in clinical trials, a majority of which with discouraging results and several drug candidates have been abandoned. The cyclolignan picropodophyllin (PPP) has been described as a potent and selective inhibitor of IGF-1R, and is currently investigated in clinical trials from which early reports suggest low toxicity and signs of clinical activity. In this report the cytotoxic activity of PPP and sets of standard agents were examined, compared and put in relation to the phosphorylation and expression levels of IGF-1R. The activity of PPP was unrelated to presence or spontaneous phosphorylation of IGF-1R, but correlated in all systems to activity of tubulin inhibitors. This led us to hypothesize that PPP’s effects in these cells were related to tubulin interaction rather than IGF-1R inhibition. Indeed PPP could destabilize microtubule assembly at concentrations needed to induce cytotoxicity cells, and at concentrations achievable in patients. Interestingly, PPP did also inhibit downstream signaling from tyrosine kinase receptors, including the serine/threonine kinase Akt. We could demonstrate that this surprising activity, also reported in previous reports on PPP but then attributed to IGF-1R inhibition, was associated with downregulation of the EGF receptor (EGFR). In summary, this study challenges previous reports on the cyclolignan PPP as an IGF-1R tyrosine kinase inhibitor and instead suggests that PPP targets, directly or indirectly, the microtubule network