Semester 5 Chapter 2
Cell Signaling: "Glioblastoma"
Notes
Learning Outcomes
● Glioblastoma etiology & risk factors
● Glioblastoma molecular subtypes
● Cell types located within brain tumor microenvironment
● Glioblastoma treatment options
Glioblastoma: Introduction & Epidemiology
Definition: Glioblastoma multiforme (GBM) = grade IV astrocytic tumor & represents most
aggressive form of malignant glioma
Incidence:
● Accounts for ~60% of malignant gliomas
● ~16,000 new brain tumor diagnoses per year in UK
● Malignant gliomas are the most common & deadliest primary CNS tumors
Cell of Origin:
● Typically arises from astrocytes (star-shaped glial cells providing structural and
metabolic support)
● Can also involve oligodendrocytic lineage
Biological Features:
● Highly invasive and supported by rich vascularization
● Heterogeneity:
○ Intertumoral: Different patients show distinct genetic/molecular profiles → variable
therapy response
○ Intratumoral: Multiple clones within same tumor mass → therapy resistance
Types:
- Primary GBM (90%): Arises de novo from normal glial cells via multistep tumorigenesis;
poor prognosis
- Secondary GBM (10%): Evolves from lower-grade astrocytomas (diffuse/anaplastic);
slightly better prognosis
Note: Morphologically indistinguishable, but differ in genetic pathways
Histological Hallmarks:
● High cellularity
● Mitotic activity
● Vascular proliferation
● Necrosis
1
,Semester 5 Chapter 2
Cell Signaling: "Glioblastoma"
Epidemiological Trends:
● More common in men than women
● Higher incidence in white populations compared to black populations
Genetic Syndromes Increasing Risk:
● Cowden, Turcot, Li-Fraumeni, Neurofibromatosis type 1 & 2, Tuberous sclerosis,
Familial schwannomatosis
Protective Associations:
● Inversely correlated with atopic diseases (asthma, eczema, hay fever)
Environmental & Lifestyle Factors:
● Preventive lifestyle measures are ineffective
● Screening is not useful — early diagnosis does not improve outcomes
● No increased risk from mobile phones, EMFs, head injury, diet (N-nitroso compounds,
aspartame, red meat), pesticides, or season of birth
○ Ionising radiation (IR): Established risk factor. IR activates the DNA damage
response (DDR) pathway
○ Glioblastoma initiating cells (GICs) show enhanced DNA repair kinetics
compared to non-GICs → contributes to therapy resistance
Glial Cell Types
Glial cells = non-neuronal cells in central nervous system (CNS). They maintain homeostasis,
provide structural support, and regulate neuronal signaling. In glioblastoma, these cells are
often the cells of origin or part of the tumor microenvironment.
Central Nervous System:
● Astrocytes
○ Morphology: Star-shaped, most abundant glial cells
○ Functions:
■ Maintain blood–brain barrier
■ Regulate neurotransmitter uptake/release
■ Provide metabolic support to neurons
■ Secrete growth factors and cytokines that influence neuronal survival
○ Relevance to GBM:
■ Astrocytes are primary cell of origin for glioblastoma
■ Their ability to proliferate and respond to injury makes them susceptible to
oncogenic transformation
● Microglial cells - defend
○ Morphology: Small, mobile immune cells of the CNS
○ Functions:
■ Act as resident macrophages
■ Mediate immune surveillance and phagocytosis
■ Release inflammatory cytokines
2
, Semester 5 Chapter 2
Cell Signaling: "Glioblastoma"
○ Relevance to GBM:
■ Microglia are recruited into the tumor microenvironment
■ They can be “hijacked” by GBM cells to promote angiogenesis, invasion,
and immune evasion
● Ependymal cells - line cavities
○ Morphology: Ciliated epithelial cells lining ventricles
○ Functions:
■ Produce and circulate cerebrospinal fluid (CSF)
■ Form a barrier between CSF and brain tissue
○ Relevance to GBM:
■ Rarely the direct origin of gliomas, but can be disrupted by tumor growth
■ Important in maintaining CNS homeostasis, which GBM often disturbs
● Oligodendrocytes
○ Morphology: Smaller glial cells with few processes
○ Functions:
■ Produce myelin sheaths (80% lipid, 20% protein) that insulate axons
■ One oligodendrocyte can myelinate multiple axons simultaneously.
○ Relevance to GBM:
■ Oligodendrocytic lineage tumors (oligodendrogliomas) share pathways
with GBM.
■ Alterations in PDGFR signaling are common in oligodendrocyte-derived
gliomas
Peripheral Nervous System:
● Satellite cells - surround neuron cell bodies
● Schwann cells - insulate, help form myelin sheath
High-Yield Links to Glioblastoma
● Astrocytes → GBM origin
● Oligodendrocytes → PDGFR pathway involvement
● Microglia → tumor-supportive immune cells
● Ependymal cells → structural disruption in advanced disease
Glioblastoma
Gradation:
Gliomas are graded by the World Health Organization (WHO) based on histological and
molecular features. The grade reflects aggressiveness, prognosis, and therapeutic response.
Low-Grade Gliomas
Grade I – Pilocytic Astrocytoma:
● Typically occurs in children
● Slow-growing, well-circumscribed
● Often curable with surgical resection
● Prognosis: Excellent (common long-term survival)
3
Cell Signaling: "Glioblastoma"
Notes
Learning Outcomes
● Glioblastoma etiology & risk factors
● Glioblastoma molecular subtypes
● Cell types located within brain tumor microenvironment
● Glioblastoma treatment options
Glioblastoma: Introduction & Epidemiology
Definition: Glioblastoma multiforme (GBM) = grade IV astrocytic tumor & represents most
aggressive form of malignant glioma
Incidence:
● Accounts for ~60% of malignant gliomas
● ~16,000 new brain tumor diagnoses per year in UK
● Malignant gliomas are the most common & deadliest primary CNS tumors
Cell of Origin:
● Typically arises from astrocytes (star-shaped glial cells providing structural and
metabolic support)
● Can also involve oligodendrocytic lineage
Biological Features:
● Highly invasive and supported by rich vascularization
● Heterogeneity:
○ Intertumoral: Different patients show distinct genetic/molecular profiles → variable
therapy response
○ Intratumoral: Multiple clones within same tumor mass → therapy resistance
Types:
- Primary GBM (90%): Arises de novo from normal glial cells via multistep tumorigenesis;
poor prognosis
- Secondary GBM (10%): Evolves from lower-grade astrocytomas (diffuse/anaplastic);
slightly better prognosis
Note: Morphologically indistinguishable, but differ in genetic pathways
Histological Hallmarks:
● High cellularity
● Mitotic activity
● Vascular proliferation
● Necrosis
1
,Semester 5 Chapter 2
Cell Signaling: "Glioblastoma"
Epidemiological Trends:
● More common in men than women
● Higher incidence in white populations compared to black populations
Genetic Syndromes Increasing Risk:
● Cowden, Turcot, Li-Fraumeni, Neurofibromatosis type 1 & 2, Tuberous sclerosis,
Familial schwannomatosis
Protective Associations:
● Inversely correlated with atopic diseases (asthma, eczema, hay fever)
Environmental & Lifestyle Factors:
● Preventive lifestyle measures are ineffective
● Screening is not useful — early diagnosis does not improve outcomes
● No increased risk from mobile phones, EMFs, head injury, diet (N-nitroso compounds,
aspartame, red meat), pesticides, or season of birth
○ Ionising radiation (IR): Established risk factor. IR activates the DNA damage
response (DDR) pathway
○ Glioblastoma initiating cells (GICs) show enhanced DNA repair kinetics
compared to non-GICs → contributes to therapy resistance
Glial Cell Types
Glial cells = non-neuronal cells in central nervous system (CNS). They maintain homeostasis,
provide structural support, and regulate neuronal signaling. In glioblastoma, these cells are
often the cells of origin or part of the tumor microenvironment.
Central Nervous System:
● Astrocytes
○ Morphology: Star-shaped, most abundant glial cells
○ Functions:
■ Maintain blood–brain barrier
■ Regulate neurotransmitter uptake/release
■ Provide metabolic support to neurons
■ Secrete growth factors and cytokines that influence neuronal survival
○ Relevance to GBM:
■ Astrocytes are primary cell of origin for glioblastoma
■ Their ability to proliferate and respond to injury makes them susceptible to
oncogenic transformation
● Microglial cells - defend
○ Morphology: Small, mobile immune cells of the CNS
○ Functions:
■ Act as resident macrophages
■ Mediate immune surveillance and phagocytosis
■ Release inflammatory cytokines
2
, Semester 5 Chapter 2
Cell Signaling: "Glioblastoma"
○ Relevance to GBM:
■ Microglia are recruited into the tumor microenvironment
■ They can be “hijacked” by GBM cells to promote angiogenesis, invasion,
and immune evasion
● Ependymal cells - line cavities
○ Morphology: Ciliated epithelial cells lining ventricles
○ Functions:
■ Produce and circulate cerebrospinal fluid (CSF)
■ Form a barrier between CSF and brain tissue
○ Relevance to GBM:
■ Rarely the direct origin of gliomas, but can be disrupted by tumor growth
■ Important in maintaining CNS homeostasis, which GBM often disturbs
● Oligodendrocytes
○ Morphology: Smaller glial cells with few processes
○ Functions:
■ Produce myelin sheaths (80% lipid, 20% protein) that insulate axons
■ One oligodendrocyte can myelinate multiple axons simultaneously.
○ Relevance to GBM:
■ Oligodendrocytic lineage tumors (oligodendrogliomas) share pathways
with GBM.
■ Alterations in PDGFR signaling are common in oligodendrocyte-derived
gliomas
Peripheral Nervous System:
● Satellite cells - surround neuron cell bodies
● Schwann cells - insulate, help form myelin sheath
High-Yield Links to Glioblastoma
● Astrocytes → GBM origin
● Oligodendrocytes → PDGFR pathway involvement
● Microglia → tumor-supportive immune cells
● Ependymal cells → structural disruption in advanced disease
Glioblastoma
Gradation:
Gliomas are graded by the World Health Organization (WHO) based on histological and
molecular features. The grade reflects aggressiveness, prognosis, and therapeutic response.
Low-Grade Gliomas
Grade I – Pilocytic Astrocytoma:
● Typically occurs in children
● Slow-growing, well-circumscribed
● Often curable with surgical resection
● Prognosis: Excellent (common long-term survival)
3
