Module 1 - Neurodevelopment and Stem Cells Flashcards
What is the composition of the blood-brain barrier?
Blood vessel of endothelial cells (with tight junctions) surrounded by astrocytes and pericytes.
What is the incidence and number of new cases every year of primary CNS cancer?
2%, 5,000
What other clinical syndromes are related to which CNS tumours genetically?
• Neurofibromatosis 2, NF2, (Ependymoma, Meningiomas) • NF1 (Pilocytic Astrocytoma) • Tuberous Sclerosis 1, TS1, (Astrocytoma) • Tuberous Sclerosis 2 , TS2 • Li-Fraumeni, p53, (Glioblastoma). • Von Hippel Lindau, VHL, (Hemangioglioblastomas) • Cowden syndrome, PTEN, • Gorlin syndrome, PTCH1, • Turcot’s syndrome (APC, adenomatous polyposis coli) Inverse association between AD and PD and CNS cancer and low risk of CNS cancer in patients with allergies.
Give an example of an environmental risk factor for CNS tumours?
Ionising radiation
Symptoms and signs of CNS tumour:
Headache Weakness Clumsiness Difficulty Walking Seizures Children: Above + Seizures with fever, persistent vomiting without known cause, precocious puberty, growth retardation, sleep apnoea, vision problems, back pain, changes in personality, irritability, staring, repetitive automatic movements
How do you diagnose a CNS tumour?
CT/MRI/fMRI/MR spectroscopy/PET
Assessment, guiding resections, biopsies, response to treatment and recurrences
Two types of biopsies:
Stereotactic (for inoperable, 0.5cm tissue) and open (inoperable, 1cm)
What is pseudoinvasion of tumour cells?
Along the Virchow-Robin space - subaracnoid space between blood vessels and pia down sulci
Post-operative management:
• Conventional fractionated radiotherapy • Chemotherapy (Temozolomide) • Gamma knife • Proton beam • Steroids (usually pre-op) • Anti-angiogenic factors (Avastin) • Drugs to control symptoms More resection during surgery is associated with better prognosis for gliomas. (Sanai 2008?) Avoid overtreatment as anticancer treatments can cause brain damage too.
What is the staging for CNS tumours? What is the grading system for CNS tumours?
No staging for CNS tumours, apart for medulloblastoma. Grading: I - long term survival/cured II - death after 5 years III - death within 5 years IV - death within 1 year Based on histotype, molecular genetics.
What types of gliomas are there?
Astrocytoma: including juvenile pilocytic astrocytoma, low grade astrocytoma,
anaplastic astrocytoma, or glioblastoma.
• Ependymoma
• Oligodendroglioma
• Mixed Glioma (also called Oligoastrocytoma): These tumours usually contain a
high proportion of more than one type of cell, most often astrocytes and
oligodendrocytes. Occasionally, ependymal cells are also found
• Optic Glioma: These tumours may involve any part of the optic pathway, and they
have the potential to spread along these pathways. Most of these tumours occur in
children under the age of 10.
• Gliomatosis Cerebri: This is an uncommon brain tumor that features widespread
glial tumour cells in the brain. This tumour is different from other gliomas because it
is scattered and widespread, typically involving two or more lobes of the brain. It
could be considered a “widespread low-grade glioma” because it does not have the
malignant features seen in high-grade tumours.
What is the grading for astrocytomas?
Pilocytic Astrocytoma—These grade I astrocytomas typically stay in the area where they started and do not spread. They are considered the “most benign” of all the
astrocytomas. Two other, less well known grade I astrocytomas are cerebellar astrocytoma and desmoplastic infantile astrocytoma. They form sacs of fluid (cysts), or may be enclosed within a
cyst. Although they are usually slow-growing, these tumors can become very large.
• Diffuse Astrocytoma (also called Low-Grade or Astrocytoma Grade II) Types: Fibrillary, Gemistocytic, Protoplasmic Astrocytoma—These grade II astrocytomas tend to invade surrounding tissue and grow at a relatively slow pace. They tend to contain microcysts and mucous-like fluid. They are
grouped by the appearance and behaviour of the cells for which they are named.
• Anaplastic Astrocytoma—An anaplastic astrocytoma is a grade III tumor. These rare tumours require more aggressive treatment than benign pilocytic astrocytoma. They tend to have tentacle-like projections that grow into
surrounding tissue, making them difficult to completely remove during surgery.
• Subependymal Giant Cell Astrocytoma— Are ventricular tumors associated with
tuberous sclerosis.
• Astrocytoma Grade IV (also called Glioblastoma, previously named “Glioblastoma
Multiforme,” “Grade IV Glioblastoma,” and “GBM”)— There are two types of astrocytoma grade IV—primary, or de novo, and secondary. Primary tumors are very aggressive and
the most common form of astrocytoma grade IV. The secondary tumors are those which originate as a lower-grade tumor and evolve into a grade IV tumor. They may contain cystic material, calcium deposits,
blood vessels, and/or a mixed grade of cells.
How are astrocytomas managed?
Surgery, if necessary then radiotherapy and/or chemotherapy. Scans to monitor progress. Recurrence is treated in the same way.
What is the grading for oligodendrigliomas?
5% of all brain tumours, found in cerebral hemispheres and is either low (WHO grade II) or high (WHO grade III, or anaplastic). Chemosensitive, better prognosis with astrocytomas.
What is the grading for ependymomas?
Subependymomas (grade I): Typically slow-growing tumors, near a ventricle.
• Myxopapillary ependymomas (grade I): Typically slow-growing tumors, lower part of the spinal column.
• Ependymomas (grade II): The most common of the ependymal tumors. This type can be further divided into the following subtypes, including cellular ependymomas, papillary
ependymomas, clear cell ependymomas, and tancytic ependymomas. Along, within or next to the ventricular system.
• Anaplastic ependymomas (grade III): Typically faster-growing tumors. Brain in adults, posterior fossa in children.
Soft, grey or red tumours, cysts or mineral calcifications.
What is the grading for medulloblastomas?
WHO grade IV.
Fast growing, cerebellum -> spine, children, can metastasise. RT and chemo.
What is the grading of meningiomas?
Grade I - benign
II - atypical, 20%
III - anaplastic, 1%, lethal within 1 year.
Adults, seizures, compression. 24-30% intracranial tumours.
What is the most common tumour in the brain?
Secondary - metastases. 25-45% all cancer patients, increasing incidence.
No grading, any primary tumour, metastases in meninges and bone too.
How does metastasis occur?
Epithelial-mesenchymal transition -> invasive properties. Degradation of basement membrane + remodeling of extracellular matrix by proteinases. Intravasation of tumour cells, arrest in capillary bed, extravasate. Can be dormant, eventually grow into secondary tumour, more ECM remodeling and angiogenesis. Cells undergo anoikis (detachment-induced apoptosis).
Why is chemotherapy not great?
5-10% reaches tumour.
Cancer gene therapy targets…
cytotoxic, tumour suppressor, anti-vascular, anti-angiogenic genes, etc.
Why are eukaryotic viral vectors not great?
Uptake by liver, reticuloendothelial system. Broad tropism for normal tissues causing toxicity, poor penetration into tumour tissues and antiviral neutralising antibodies.
What characteristics do drugs that cross the blood-brain barrier exhibit?
Lipophilic, low molecular weight (<600 Da). p-glycoprotein act as effluc pump for anticancer drugs.
What can be given to increase drug delivery to the brain?
Intracranial infusion of hypertonic arabinose or mannitol - dilate cerebral blood vessels, shrink endothelial cells -> leaky tight junctions.
Convection enhanced delivery (catheter under positive pressure).
Polymeric vesicles.
Why anti-angiogenic therapies?
- Endothelial cells lining the blood vessels are directly accessible to drugs via the systemic circulation.
- It is estimated that up of 100 tumour cells are sustained by a single endothelial cell.
- Endothelial cells are genetically more stable and are therefore unlikely to acquire resistance to therapy.
- The Tumour endothelium expresses specific markers, cell surface receptors, that are absent or barely detectable in the normal quiescent blood vessels (zip codes, vascular
receptors) . (Hajitou, 2006)
Vascular targets in angiogenic blood vessels:
Endothelial cells: VEGF and it’s receptors, MMP-2 and -9, EGFR
Pericytes: aminopeptidases APA and APN, NG2 proteoglycan, PDGFRs
Limitations of anti-angiogenic agents:
i) Short half-lives
ii) High chance of non specific accumulation
iii) Inefficient accumulation at the diseased site
iv) Severe side effects at high doses
v) Poor tissue and cellular membrane permeability in vivo requiring cell
transduction systems when the molecular target is intracellular
vi) Tumour resistance due to GBM heterogeneity
Which vectors have been used in gene therapy?
Retroviruses - A class of viruses that can create double-stranded DNA copies of their RNA genomes. These copies of its genome can be integrated into the chromosomes of host
cells. Human immunodeficiency virus (HIV) is a retrovirus.
Adenoviruses (Ad) - A class of viruses with double-stranded DNA genomes that cause respiratory, intestinal, and eye infections in humans. The virus that causes the common cold is an adenovirus.
Herpes simplex viruses (HSV) - A class of double-stranded DNA viruses that infect a particular cell type, neurons. Herpes simplex virus type 1 is a common human pathogen
that causes cold sores.
Adeno-associated viruses (AAV) - A class of small, single-stranded DNA viruses that can insert their genetic material at a specific site on chromosome 19.
Liposomes - artificial lipid sphere with aqueous core, requires a large amount of DNA and only works in certain tissues.
Cationic polymers - polymers-DNA complexes.
Bacteriophages - virus infects only bacteria, humans are constantly exposed to them with no adverse effects. Ligand-directed targeting. Can cross blood-brain barrier.
Why are adeno-associated viruses good vectors for gene therapy?
1- AAV is not currently known to cause disease.
2- AAV causes a very mild immune response.
3- AAV can infect both dividing and quiescent cells
4- AAV persists in an extrachromosomal state without integrating into the
genome of the host cell.
