Simply Science

Role of NKCC1 in tumor glioma tumor migration

Patients with glioblastoma have poor prognosis and short survival despite current therapies. The mechanisms that confer glioblastoma cells this invasive behavior and their regulation have not been fully elucidated. The main goal of this project is to understand the mechanisms that some ion transporters, like the NKCC1 protein, use to increase cell migration, and how different factors, like chemoattractive substances affect this process. Our final proposal is to use this knowledge to develop new therapeutic targets to improve survival of this devastating disease.

Radiation-Induced Disruption of Neural Stem Cell Migration

Neural stem cells reside in the subventricular zone of the brain. It is a key location for adult neurogenesis. When a patient receives whole brain, or even targeted radiation, the subventricular zone in many cases receives a substantial dose of radiotherapy as well. While a great deal is known about how radiation affects stem cells, very little is known about the effects of radiation on migration of new born cells. Since these new born stem cells may be recruited to the tumor, and may even attack the tumor cells, more must be studied about the effects that radiation has upon these cells’ migratory capabilities.
Our research includes plans to determine the ability of radiation to arrest the migration of progenitor cells along an established pathway, to measure the effect of local radiation on stem cells in the subventricular zone and on their microenvironment, and to determine whether new born stem cells are attracted to a site of radiation damage and/or tumor altering their established migration paths, and identify underlying micro environmental factors and molecular pathways. A second aspect of therapeutic neural stem cells that we will investigate is how radiation alters the ability of endogenous neural stem cells to participate in repair.

We have found that irradiation of the subventricular zone in the brain eliminates the dividing neural stem cells. We have also observed that radiation has a strong inhibitory effect on the migration of newborn cells. We are currently in the process of understanding if the newborn stem cells follow alternate migratory paths or if they die in the irradiated environment.
Our results will directly inform clinical trials in the near future. Future trials may include, for example, a prospective trial to assess the efficacy of stem cell sparing radiation for which our data will provide important information on dose/volume endpoints. Another trial might combine radiation with molecular or pharmacological agents to promote neural progenitor cell survival, migration and differentiation.

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Stem Cells in Human Pituitary Tumors

This research project focuses on the pituitary gland, which is about the size of an almond and sits at the base of the skull. It functions as the "master regulator" of the hormone system. The anterior pituitary gland is a common site of tumor formation. Pituitary tumors are the third most common brain tumor, so this is a very important area of research. While there has been extensive research in the field of pituitary tumor formation, we have not yet clearly been able to define how these tumors arise in individuals without inherited genetic mutations. Recent evidence suggests that the adult pituitary gland may contain a population of progenitor or stem cells. We are investigating the possibility that pituitary tumors may also harbor a population of stem cells, which play a key role in tumor growth. We study pituitary tumor cell lines obtained from patients with pituitary tumors and compare these cells to normal pituitary cells obtained from autopsy cases of patients who died of other causes.

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Effects of Slit on the Migration of Human Brain Tumor Stem Cells

Our interest is on studying the effects of slit proteins on the migratory behavior of human neural progenitor cells and brain tumor stem cells. Glioma patients’ poor outcomes are largely due to the invasive nature of the tumors and necessitate more understanding of brain tumor cell migration. We study the effect of Slit proteins and their Robo receptors on glioma cell migration. Slit proteins and Robo receptors form a chemorepulsive system involved in neuronal axon guidance and migration. We characterize the expression of Slit and Robo proteins in glioma samples, as well as evaluate the effect of Slit proteins on glioma cell migration and invasion in vitro and in animal models. It is our hope that increased understanding of signaling that directs pediatric glioma migration will result in future therapies that target and prevent brain tumor dispersal.

The Role of Platelet-Derived Growth Factor in the Migration of Human Adipose-Derived Mesenchymal Stem Cells

Each year 40,000 people are diagnosed with primary brain tumors, the majority of which are glioblastoma (GB). Glioblastoma is the most common brain tumor in adults and is the most malignant subtype. Despite best treatments with maximum surgical resection, radiation and chemotherapy, long-term survival of GB patients is rare (median survival is 14.6 months). Complete surgical resection is a challenge due to the diffusely infiltrative growth pattern of GB, and systemic therapy is limited by the selectivity of the blood brain barrier (BBB). According to the World Health Organization, astrocytomas are classified as either localized or diffuse based on how they interact with their immediate microenvironment. Localized GB exhibit limited invasiveness and a restricted pattern of growth. On the other hand, diffuse GB is invasive at the peritumoral edge and is able to metastasize to distant sites. The success of current therapies has been met with limitations due to the disseminated nature of these tumors. The use of mesenchymal stem cells (MSC) has become an attractive option. Mesenchymal stem cells (MSCs) are adult stem cells traditionally found in the bone marrow. However, MSCs can be obtained from fat (adipose) tissue, umbilical cord blood, peripheral blood, fallopian tube, and fetal liver and lung. These cells are also multipotent and can differentiate into various mesenchymal lineage cells including adipocytes (fat), osteocytes (bone), and chondrocytes (cartilage), muscle and skin.


MSCs derived from fat tissue, known as adipose-derived mesenchymal stem cells (hAMSCs), are attractive for clinical use because they possess a natural affinity for tumors, can be easily isolated from fat tissue, grow well to expand to the numbers required for application, and can be genetically modified through various methods. Thus, MSCs have enormous therapeutic potential for brain tumor therapy. Platelet-derived growth factor (PDGF) and its receptor PDGF-R are over expressed in gliomas. PDGF is a strong inducer of cell migration and therefore targeting this molecule could potentially enhance the migration of therapeutic hAMSCs towards gliomas.

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BMP4 Engineered Mesenchymal Stem Cell Therapy for Glioblastoma

Dr. Chesler’s research focuses on studying the interactions between adipose derived mesenchymal stem cells and brain tumors, namely Glioblastoma. The aim of this research is to develop new techniques to use these mesenchymal stem cells to deliver novel treatments to Glioblastomas in a relatively non-invasive manner. To date, Dr. Chesler's work has focused on the genetic manipulation of adipose-derived mesenchymal stem cells to develop a system in which these cells will produce and secrete compounds which have anti-glioma properties preferentially when coming into close contact with these tumors to minimize the exposure and affects upon surround healthy tissues.
This work provides an avenue for the development of future treatments which may be used in addition to surgery, radiation, and current chemotherapy regimens to help fight this horrible disease.

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Understanding the Pathophysiology of Chordomas

Chordomas are tumors that arise from the osseous spine and skull base and comprise 2-4% of all bone cancers. They are often refractory to treatment with a median survival of approximately 6 years. Recent reports on the incidence and survival patterns of chordoma patients underscore the dismal prognosis of this disease with long-term survival rates at 5, 10 and 20 years precipitously dropping to 67%, 40% and 13%, respectively. Like gliomas and other aggressive malignancies of the neuroaxis, the invasive nature of this cancer often involves critical neurovascular structures of the spine and skull base making complete surgical resection impossible in 50% of the cases of sacral chordomas and even more difficult in the mobile spine and skull base. Our long-term goal is to understand the biology of chordomas and the molecular aberrations these rare tumors harbor.

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Metabolic Adaptation of Human Glioblastoma Cells to Glycolysis Inhibition

Glioblastoma (GBM), the most common primary central nervous system malignancy in adults, is universally fatal despite aggressive surgery and combined chemoradiotherapy. The identification of novel therapeutic targets is an ongoing and necessary challenge. One potential avenue of investigation centers on the observation that GBMs upregulate glycolysis (anaerobic utilization of glucose) independent of the presence of molecular oxygen. Presumably, this is a metabolic adaptation to the hypoxic stress placed on these tumors due to a growth rate that exceeds their vascular supply. Our research goal is to evaluate role of glycolysis in the behavior of GBMs and how glioma cells respond to glycolysis inhibition. We use 2-deoxyglucose (2-DG), a potent inhibitor of glucose metabolism to manipulate this system. We will determine whether 2-DG has an effect on proliferation, migration, and speed of motility of GBM cells.

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