Iron inhibits glioblastoma cell migration and polarization.

Glioblastoma is one of the deadliest malignancies facing modern oncology today. The ability of glioblastoma cells to diffusely spread into neighboring healthy brain makes complete surgical resection nearly impossible and contributes to the recurrent disease faced by most patients. Although research into the impact of iron on glioblastoma has addressed proliferation, there has been little investigation into how cellular iron impacts the ability of glioblastoma cells to migrate-a key question, especially in the context of the diffuse spread observed in these tumors.

Sexually dimorphic effect of H-ferritin genetic manipulation on survival and tumor microenvironment in a mouse model of glioblastoma.

Purpose: Iron plays a crucial role in various biological mechanisms and has been found to promote tumor growth. Recent research has shown that the H-ferritin (FTH1) protein, traditionally recognized as an essential iron storage protein, can transport iron to GBM cancer stem cells, reducing their invasion activity. Moreover, the binding of extracellular FTH1 to human GBM tissues, and brain iron delivery in general, has been found to have a sex bias.

Common Mutation in the Gene Modifies Recovery After Intracerebral Hemorrhage.

Background: Intracerebral hemorrhage (ICH) is characterized by bleeding into the brain parenchyma. During an ICH, iron released from the breakdown of hemoglobin creates a cytotoxic environment in the brain through increased oxidative stress. Interestingly, the loss of iron homeostasis is associated with the pathological process of other neurological diseases.

Photodynamic Therapy for Glioblastoma: Illuminating the Path toward Clinical Applicability.

Glioblastoma (GBM) is the most common adult brain cancer. Despite extensive treatment protocols comprised of maximal surgical resection and adjuvant chemo-radiation, all glioblastomas recur and are eventually fatal. Emerging as a novel investigation for GBM treatment, photodynamic therapy (PDT) is a light-based modality that offers spatially and temporally specific delivery of anti-cancer therapy with limited systemic toxicity, making it an attractive option to target GBM cells remaining beyond the margins of surgical resection.

Association Between Iron and Cholesterol in Neuroblastomas.

Background/aim: Neuroblastoma is the most common childhood extracranial solid malignancy. Although cancer cells need iron and lipids for active cell division, possible links between iron and lipid metabolism in neuroblastomas have not been studied.

Materials And Methods: We evaluated the levels and association between iron and cholesterol on in vitro neuroblastoma cancer models.

Biological Activity of a Thiobarbituric Acid Compound in Neuroblastomas.

Background/aim: We have previously reported the identification of the cytotoxic chemotype compound-I (CC-I) from a chemical library screening against glioblastoma.

Materials And Methods: The biological activity of CC-I on drug-resistant neuroblastomas [e.g.

Characterization of a Novel Barbituric Acid and Two Thiobarbituric Acid Compounds for Lung Cancer Treatment.

Background/aim: Previously, we reported the identification of a cytotoxic chemotype compound CC-I (), a derivative of thiobarbituric acid. We also reported the anticancer activity of a series of novel thio- and seleno-barbituric acid analogs.

Materials And Methods: We herein evaluated the effect of and its modified compounds on in vitro and in vivo lung cancer models.

Liposomal delivery of ferritin heavy chain 1 (FTH1) siRNA in patient xenograft derived glioblastoma initiating cells suggests different sensitivities to radiation and distinct survival mechanisms.

Elevated expression of the iron regulatory protein, ferritin heavy chain 1 (FTH1), is increasingly being associated with high tumor grade and poor survival outcomes in glioblastoma. Glioma initiating cells (GICs), a small population of stem-like cells implicated in therapeutic resistance and glioblastoma recurrence, have recently been shown to exhibit increased FTH1 expression. We previously demonstrated that FTH1 knockdown enhanced therapeutic sensitivity in an astrocytoma cell line.

Exosomes impact survival to radiation exposure in cell line models of nervous system cancer.

Radiation is utilized in the therapy of more than 50% of cancer patients. Unfortunately, many malignancies become resistant to radiation over time. We investigated the hypothesis that one method of a cancer cell's ability to survive radiation occurs through cellular communication via exosomes.

Targeting IL-13Rα2 for effective treatment of malignant peripheral nerve sheath tumors in mouse models.

Objective: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft tissue sarcomas that harbor a high potential for metastasis and have a devastating prognosis. Combination chemoradiation aids in tumor control and decreases tumor recurrence but causes deleterious side effects and does not extend long-term survival. An effective treatment with limited toxicity and enhanced efficacy is critical for patients suffering from MPNSTs.

MLN8237 treatment in an orthoxenograft murine model for malignant peripheral nerve sheath tumors.

Objective: Malignant peripheral nerve sheath tumors (MPNSTs) are soft-tissue sarcomas arising from peripheral nerves. MPNSTs have increased expression of the oncogene aurora kinase A, leading to enhanced cellular proliferation. This makes them extremely aggressive with high potential for metastasis and a devastating prognosis; 5-year survival estimates range from a dismal 15% to 60%.

Tumor targeted delivery of doxorubicin in malignant peripheral nerve sheath tumors.

Peripheral nerve sheath tumors are benign tumors that have the potential to transform into malignant peripheral nerve sheath tumors (MPNSTs). Interleukin-13 receptor alpha 2 (IL13Rα2) is a cancer associated receptor expressed in glioblastoma and other invasive cancers. We analyzed IL13Rα2 expression in several MPNST cell lines including the STS26T cell line, as well as in several peripheral nerve sheath tumors to utilize the IL13Rα2 receptor as a target for therapy.

HFE genotype affects exosome phenotype in cancer.

Neuroblastoma is the third most common childhood cancer, and timely diagnosis and sensitive therapeutic monitoring remain major challenges. Tumor progression and recurrence is common with little understanding of mechanisms. A major recent focus in cancer biology is the impact of exosomes on metastatic behavior and the tumor microenvironment.

MRI contrast agent for targeting glioma: interleukin-13 labeled liposome encapsulating gadolinium-DTPA.

Background: Detection of glioma with MRI contrast agent is limited to cases in which the blood-brain barrier (BBB) is compromised as contrast agents cannot cross the BBB. Thus, an early-stage infiltrating tumor is not detectable. Interleukin-13 receptor alpha 2 (IL-13Rα2), which has been shown to be overexpressed in glioma, can be used as a target moiety.

HFE polymorphisms affect survival of brain tumor patients.

The HFE (high iron) protein plays a key role in the regulation of body iron. HFE polymorphisms (H63D and C282Y) are the common genetic variants in Caucasians. Based on frequency data, both HFE polymorphisms have been associated with increased risk in a number of cancers.

Characterization of a novel anti-cancer compound for astrocytomas.

The standard chemotherapy for brain tumors is temozolomide (TMZ), however, as many as 50% of brain tumors are reportedly TMZ resistant leaving patients without a chemotherapeutic option. We performed serial screening of TMZ resistant astrocytoma cell lines, and identified compounds that are cytotoxic to these cells. The most cytotoxic compound was an analog of thiobarbituric acid that we refer to as CC-I.

Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents.

Approximately half of all gliomas are resistant to chemotherapy, and new therapeutic strategies are urgently needed to treat this cancer. We hypothesized that disrupting iron homeostasis in glioma cells could block tumor growth, based on an acute requirement for high levels of iron to meet energy requirements associated with their rapid growth. Ferritin is best known as an intracellular iron storage protein, but it also localizes to tumor cell nuclei where it seems to protect DNA from oxidative damage and to promote transcription.

HFE polymorphisms influence the response to chemotherapeutic agents via induction of p16INK4A.

HFE is a protein that impacts cellular iron uptake. HFE gene variants are identified as risk factors or modifiers for multiple diseases. Using HFE stably transfected human neuroblastoma cells, we found that cells carrying the C282Y HFE variant do not differentiate when exposed to retinoic acid.

Efficacy of interleukin-13 receptor-targeted liposomal doxorubicin in the intracranial brain tumor model.

Human glioblastoma tumors selectively express receptors for interleukin 13 (IL-13). In a previous study, we showed that liposomes, when conjugated with IL-13, will deliver chemotherapeutics to a subcutaneous glioma tumor model in mice much more effectively than conventional unconjugated liposomes. Based on this observation, we developed an intracranial brain tumor model in nude mice using human U87 glioma cells.

Tim-2 is the receptor for H-ferritin on oligodendrocytes.

Oligodendrocytes stain more strongly for iron than any other cell in the CNS, and they require iron for the production of myelin. For most cell types transferrin is the major iron delivery protein, yet neither transferrin receptor protein nor mRNA are detectable in mature oligodendrocytes. Thus an alternative iron delivery mechanism must exist.

Interleukin-13 receptor-targeted nanovesicles are a potential therapy for glioblastoma multiforme.

The difficulties associated with treatment of malignant brain tumors are well documented. For example, local infiltration of high-grade astrocytomas prevents the complete resection of all malignant cells. It is, therefore, critical to develop delivery systems for chemotherapeutic agents that ablate individual cancer cells without causing diffuse damage to surrounding brain tissue.

IL-13Ralpha2 is a glioma-restricted receptor for interleukin-13.

We have found that binding sites for interleukin-13 (IL-13) are overexpressed in a vast majority of high-grade astrocytomas (HGAs). These binding sites for IL-13 are distinct from the physiological receptor in that it does not bind IL-4. We also demonstrated that IL-13 receptor alpha 2 protein chain (IL-13Ralpha2), an IL-4-independent receptor for IL-13, is abundant among HGAs, but not in normal organs.