Breaking News
November 20, 2018 - Health sector coalition urges Government to safeguard patients in future UK-EU relationship
November 20, 2018 - Study evaluates second-hand marijuana smoke exposure among children
November 20, 2018 - Scientists identify three genes responsible for recurrent molar pregnancies
November 20, 2018 - Researchers identify multisystem disorder caused by bi-allelic variants in CCDC47 gene
November 20, 2018 - Dining Out With Allergies Is Tough, But These Steps Can Help
November 20, 2018 - Breastfeeding protects infants from antibiotic-resistant bacteria
November 20, 2018 - AI matched, outperformed radiologists in screening X-rays for certain diseases | News Center
November 20, 2018 - Adolescents increasingly choose marijuana over cigarettes, alcohol
November 20, 2018 - World’s first medical imaging scanner produces diagnostic scan of the whole human body
November 20, 2018 - Cytocybernetics receives NIMH award to move into neuronal drug development
November 20, 2018 - Recreational drug may help people regain trust in others
November 20, 2018 - Researchers identify gene vital for post-stroke recovery
November 20, 2018 - Scientists identify novel target for neuron regeneration, functional recovery in spinal cord injury
November 20, 2018 - Skeletal imitation reveals how bones grow atom-by-atom
November 20, 2018 - Autism behaviors show unique brain network fingerprints in infants
November 20, 2018 - Location matters for inflammation clearance
November 20, 2018 - Towards finding a druggable cancer target
November 20, 2018 - Ultragenyx Announces Intent to Submit New Drug Application to U.S. FDA for UX007 for the Treatment of Long-chain Fatty Acid Oxidation Disorders in Mid-2019
November 20, 2018 - Cooling ‘brains on fire’ to treat Parkinson’s
November 20, 2018 - Less pollution could increase the average lifespan of Copenhageners by an entire year in 2040
November 20, 2018 - Abramson Cancer Center becomes the 28th member institution of National Comprehensive Cancer Network
November 20, 2018 - The plug and play time-resolved spectrometer from PicoQuant
November 20, 2018 - Breakthrough technology offers new hope to people with glaucoma, retinitis and macular degeneration
November 20, 2018 - New report highlights key focus areas to help cancer screening realize its full potential
November 20, 2018 - International experts to discuss strategies to maintain spatial orientation in old age
November 20, 2018 - Low-protein, high-carb diet may promote healthy brain ageing
November 20, 2018 - Scientists discover new inhibitor that decreases lung inflammation
November 20, 2018 - Participation project calls for relaxing research ban on germline interventions
November 20, 2018 - Karyopharm’s Selinexor Receives Fast Track Designation from FDA for the Treatment of Patients with Relapsed or Refractory Diffuse Large B-cell Lymphoma
November 20, 2018 - Arthritis by the Numbers: Book of Trusted Facts & Figures
November 20, 2018 - Drug homing method helps rethink Parkinson’s
November 20, 2018 - AHF commends the passage of global AIDS funding in the House, calls for swift approval
November 20, 2018 - The search for new psychiatric disorder treatments
November 20, 2018 - New research offers hope for simpler way to diagnose and treat cancer
November 20, 2018 - Study sheds light on the infection mechanism of influenza virus
November 20, 2018 - Storage failures of eggs and embryos gain a new perspective
November 20, 2018 - Buyers of short-term health plans: Wise or shortsighted?
November 20, 2018 - Study indicates that frogs in virus-exposed groups breed at young age
November 20, 2018 - FDA Alerts Health Care Professionals and Patients Not To Use Sterile Drug Products from Pharm D Solutions
November 20, 2018 - Asthma may contribute to childhood obesity epidemic
November 20, 2018 - Live probiotics can change existing gut flora and alter immune response
November 20, 2018 - Researchers to explore the enigmatic role of unstructured protein in regulating circadian function
November 20, 2018 - Many patients with adenomas do not receive colonoscopy within recommended time frame
November 20, 2018 - Drug used to treat PTSD does not reduce suicidal thinking, may worsen nightmares and insomnia
November 20, 2018 - In-person social contact may offer protection against depression and PTSD symptoms
November 20, 2018 - Routine HCV testing in correctional facilities can best identify and treat disease, say researchers
November 20, 2018 - Molecular DNA analysis could facilitate more accurate prognosis, treatment of aggressive brain tumors
November 20, 2018 - Breast Cancer Recurrence Rate Not Up With Autologous Fat Transfer
November 20, 2018 - Beta 2 Microglobulin (B2M) Tumor Marker Test: MedlinePlus Lab Test Information
November 20, 2018 - Could bariatric surgery make men more virile?
November 20, 2018 - Urine test to check if patients take their medications will save the NHS money, say researchers
November 20, 2018 - Study reveals impact of residual inflammatory risk on clinical outcomes after PCI
November 20, 2018 - RNAi therapy shown to alleviate preeclampsia
November 20, 2018 - Replacement of dysfunctional microglia has therapeutic potential for neurodegenerative diseases
November 20, 2018 - Forming 3D Neuronal Models of the Brain
November 20, 2018 - Shoulder ultrasounds could be used to predict diabetes
November 20, 2018 - SGLT2 Inhibitors for Diabetes Linked to Increased Risk for Amputation
November 20, 2018 - Stem cell transplant cements Arizona men’s father-son bond
November 20, 2018 - Scientists try to develop portable systems that can quickly produce biologics on demand
November 20, 2018 - Automating Data Capture and Image Analysis in Continuous Experiments
November 20, 2018 - New drug shows promise for treating people with peanut allergy
November 20, 2018 - Researchers develop novel mouse model to study immunomodulatory therapies
November 20, 2018 - “Britain must not go backward on antibiotic controls to appease US trade deals” – Jim Moseley, CEO of Red Tractor
November 20, 2018 - Widespread errors in ‘proofreading’ cause inherited blindness
November 20, 2018 - Reaping the benefits of living longer
November 20, 2018 - New Program Hopes to Make Early Detection and Treatment of ALS a Reality
November 19, 2018 - Artificial bone-like substance mimics the way real bone grows at atomic level
November 19, 2018 - FDA Grants Orphan Drug Designation To RGX-181 Gene Therapy For The Treatment Of CLN2 Form Of Batten Disease
November 19, 2018 - Systemic mastocytosis – Genetics Home Reference
November 19, 2018 - Eye trauma secondary to falls in older adults increasing
November 19, 2018 - Empowering women in India to improve their health: A Q&A
November 19, 2018 - Researchers have trained a computer to analyze breast cancer images and classify tumors
November 19, 2018 - New glucose binding molecule could be key to better metabolic control for diabetics
November 19, 2018 - Biologists uncover novel genetic control of lipid maintenance and its potential connection to lifespan
November 19, 2018 - Warmer winters may set scene for higher rates of violent crimes
November 19, 2018 - Personalized program of physical exercise effective in reversing functional decline in the elderly
November 19, 2018 - Acacia Pharma Resubmits Barhemsys New Drug Application
November 19, 2018 - PDL1 (Immunotherapy) Tests: MedlinePlus Lab Test Information
November 19, 2018 - Transforming pregnancy research with a smartphone app
November 19, 2018 - Stanford Medicine magazine explores how digital technology is changing health care
Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant

Dying cancer cells make remaining glioblastoma cells more aggressive and therapy-resistant

image_pdfDownload PDFimage_print
Electron microscopic image of a single human lymphocyte. Credit: Dr. Triche National Cancer Institute

A surprising form of cell-to-cell communication in glioblastoma promotes global changes in recipient cells, including aggressiveness, motility, and resistance to radiation or chemotherapy.

Paradoxically, the sending cells in this signaling are glioblastoma cells that are undergoing programmed cell death, or apoptosis, according to research by a team at institutes in the United States, Russia and South Korea.

The dying cancer cells send their signals by means of extracellular vesicles induced and released during apoptosis. These vesicles—small, membrane-bound blobs known as exosomes—carry components that alter RNA splicing in the recipient glioblastoma cells, and this altered splicing promotes therapy resistance and aggressive migration.

This mechanism thus becomes a possible target for new therapies to treat glioblastoma, a primary brain cancer, and the mechanism may apply to other cancer types as well.

“Clinically, our data may provide the rationale to the molecular targeting of RNA splicing events or specific splicing factors for novel cancer therapies,” said Ichiro Nakano, M.D., Ph.D., leader of the international study being published in Cancer Cell. “This may lead to decreased acquisition of therapy resistance, as well as reduction in the migration of cancer cells.”

Nakano is an academic neurosurgeon at the University of Alabama at Birmingham who conducts both brain tumor translational research and clinical brain tumor surgery. He is professor of neurosurgery in the UAB School of Medicine and a senior scientist for the UAB Comprehensive Cancer Center.

Glioblastoma exhibits invasive behavior, abrupt growth and poor patient survival. As the number of the cancer cells rapidly increases, abundant apoptotic tumor cells are intermingled with neighboring proliferating tumor cells. The apoptotic cells can account for up to 70 percent of the tumor cell population.

The discovery of this unusual cell-to-cell communication began with a simple experiment—injecting a combination of lethally irradiated human glioblastoma cells, which makes them apoptotic, and “healthy” glioblastoma cells into a mouse xenograft model. This combination led to much more aggressive tumor growth, as seen in brain scans, compared to “healthy” glioblastoma cells or irradiated glioblastoma cells alone. The combination was also more therapy-resistant.

The UAB researchers and colleagues found that, after induction of apoptosis, glioblastoma cells shed significantly higher numbers of exosomes with larger average sizes.

Those apoptotic exosomes, when combined with “healthy” glioblastoma cells, significantly increased tumor growth in the xenograft model and cell motility in bench experiments. Also, while the “healthy” glioblastoma cells alone had a clear border between the tumor and adjacent normal tissue in the xenograft, the glioblastoma cells co-injected with apoptotic exosomes invaded into adjacent brain tissue. Exosomes shed by non-apoptotic cells did not have these effects.

To discover the mechanism underlying these changes, the researchers looked at what was inside the apoptotic exosomes. The vesicles were enriched with spliceosomal proteins and several U snRNAs—parts of the cellular machinery that remove introns from pre-messenger RNA.

These are normally confined to the nuclei of cells; but the Nakano team found that, as the glioblastoma cells underwent apoptosis, the spliceosomal proteins were transported out of the nucleus to the cell cytoplasm, where they could be packaged into vesicles for release.

Glioblastoma cell subtypes include the proneural subtypes and the mesenchymal subtype. Recent data have shown that, after therapy, glioblastoma cells shift from the less aggressive proneural subtype to the more aggressive and therapy-resistant mesenchymal subtype. The researchers found that apoptotic exosomes induced substantial alternate RNA splicing in recipient cells that resembled the splicing patterns found in the mesenchymal glioblastoma subtype.

Part of this was caused by the splicing factor RBM11, which is encapsulated in the vesicles. The researchers found that exogenous RBM11 caused upregulation of endogenous RBM11 in the recipient cells and activated glycolysis. Overexpression of RBM11 increased the migration of glioblastoma cells.

They also found that RBM11 altered RNA splicing to produce an isoform of the protein cyclinD1 that promotes DNA repair and an isoform of the protein MDM4 that has significantly higher anti-apoptotic activity. These changes can make the cells more therapy-resistant.

Examination of the Cancer Genome Atlas database showed that elevated expression of those two isoforms is associated with poor prognoses for glioblastoma patients.

Finally, the Nakano-led team looked at paired glioblastoma specimens of primary and recurrent tumors from matched patients. In most of the 43 pairs of matched samples, the RBM11 protein levels were substantially higher in the recurrent glioblastoma compared to the original, untreated tumors. In two other patient cohorts, they found that the higher RBM11 levels correlated with poor post-surgical survival for glioma patients.


Explore further:
A maestro that conducts the invasiveness of glioblastoma tumors

More information:
“Apoptotic cell-derived extracellular vesicles promote malignancy of glioblastoma via intercellular transfer of splicing factors,” Cancer Cell (2018). DOI: 10.1016/j.ccell.2018.05.012

Journal reference:
Cancer Cell

Provided by:
University of Alabama at Birmingham

Tagged with:

About author

Related Articles