Lecture 19 - Cancer signalling and disease Flashcards
What are the hallmarks of cancer?
- Sustaining proliferation signalling
- Evading growth suppressors
- Avoiding immune destruction
- Enabling replicative immortality
- Activating invasion and metastasis
- Inducing angiogenesis
- Resisting cell death
- Dysregulating cellular energetics
How are signalling pathways affected in cancer?
Signalling pathways controlling cell survival, proliferation, differentiation and migratory potential are altered in cancer
What genes are relevant to cancer?
FOUR classes of genes encoding normal signalling proteins that are principal targes of genetic damage, relevant to oncogenesis:
(1) Growth-promoting proto-oncogenes
(2) Growth-inhibiting tumour suppressor genes
(3) Genes involved in DNA repair
(4) Genes that regulate programmed cell death (apoptosis)
Describe the normal steps in proliferation
Which aspects of this could lead to carcinogenesis, to a greater and lesser extent?
GF
GF receptor
Intracellular kinase
Transcription; translation
Cell enters cell cycle
Proliferation
Carcinogenesis:
Commonly:
* Mutant receptor - always “on”
* Mutant intracellular kinase
* Mutant transcription factor
Not so common:
* Mutant cyclins and CDKs
* Over-expression of GFs
What are the types of cancer-causing gene mutations?
- Single base pair mutation causing the transformation of a wild-type proto-oncogene to turn into a mutated oncogene: leads to a constitutively active protein or an inactivation of a tumour suppressor gene
- Oncogene amplifications: e.g., N-MYC containing region replicated/amplified causing abnormal chromosomes causing extra protein + double minutes
- Gene translocations and fusions: generation of oncogenic chimeric mutations. DNA breakage and splicing – juxtaposition of the coding sequence of one gene with the transcription regulatory sequence of another gene
o EXAMPLE: parathyroid adenoma due to cyclin-D1 gene spliced to PTH gene promoter. Important for cell cycle progression.
o Coding region is unaffected – it is the promoter region that is spliced
What are types of immunohistochemical proliferation markers for cancer?
Ki-67: Ki-67 is a nuclear antigen that is expressed in proliferating cells during all phases of the cell cycle except for G0. It is widely used as a proliferation marker in various cancers, including breast, prostate, and colorectal cancers.
PCNA: Proliferating cell nuclear antigen (PCNA) is a nuclear protein that is required for DNA replication and repair. It is expressed in proliferating cells during the S-phase of the cell cycle and is commonly used as a proliferation marker in various cancers.
MCM: Minichromosome maintenance protein (MCM) is a family of proteins that are involved in DNA replication and are expressed in proliferating cells during the G1, S, and G2 phases of the cell cycle. MCM proteins are commonly used as proliferation markers in various cancers, including breast, prostate, and lung cancers.
Cyclin D1: Cyclin D1 is a regulatory protein that is involved in cell cycle progression from G1 to S-phase. It is expressed in proliferating cells and is commonly used as a proliferation marker in various cancers, including breast and prostate cancers.
PHH3: Phosphohistone H3 (PHH3) is a histone protein that is phosphorylated during mitosis and is involved in chromosome condensation and segregation. It is a highly specific marker of mitotic cells and is commonly used as a proliferation marker in various cancers.
What are the components of proliferation signalling in cancer cells?
- Mutant receptor: making it constitutively active, independent to the GF ligand
- Mutant intracellular kinase: making in constitutively active, insensitive to phosphatase
- Mutant Transcription Factor: rare
o E.g., N-MYC
What are the major cell signalling pathways regulating proliferation in cancer?
PI3K/Akt/mTOR pathway: The PI3K/Akt/mTOR pathway is a critical signaling pathway that regulates cell growth and proliferation. Dysregulation of this pathway is commonly found in cancer and can promote cell survival and resistance to therapy.
MAPK/ERK pathway: The MAPK/ERK pathway is another key signaling pathway that is involved in cell proliferation, survival, and differentiation. Aberrant activation of this pathway is commonly found in cancer and can promote uncontrolled cell growth and proliferation.
Wnt/β-catenin pathway: The Wnt/β-catenin pathway is involved in the regulation of cell proliferation, differentiation, and survival. Dysregulation of this pathway is frequently observed in cancer and can promote tumor growth and progression.
Notch pathway: The Notch signaling pathway is involved in cell proliferation, differentiation, and apoptosis. Aberrant activation of this pathway is commonly found in cancer and can promote cell proliferation and tumor growth.
Hedgehog pathway: The Hedgehog pathway is involved in cell proliferation, differentiation, and embryonic development. Dysregulation of this pathway is commonly observed in cancer and can promote tumor growth and progression.
TGF-β pathway: The TGF-β pathway is involved in cell proliferation, differentiation, and apoptosis. Dysregulation of this pathway is frequently observed in cancer and can promote tumor growth and metastasis.
What is the oncogene-TSG synergy in the PI3K pathway?
- PTEN deletion hyperproliferation
- Mutation of p1110 catalytic subunit small tumours, slow growing and does not progress much
- PTEN deletion and mutation of p1110 catalytic subunit fast growing tumour
How do cancer cells evade apoptosis?
- Increased cell division + normal apoptosis = tumour
- Normal cell division + decreased apoptosis = tumour
Normal p53 protein causes cell suicide whereas non-functional p53 protein causes uncontrolled cell division
Tumour cell shows:
1. Reduced Fas (CD95)
2. Inactivation of death-induced signalling complex
3. Higher BCL2 (anti-apoptotic)
4. Reduced levels of pro-apoptotic BAX resulting from the loss of p53
5. Loss of APAF-1
6. Upregulation of caspase inhibitors
What is the relationship between angiogenesis and cancer cells?
- During mild hypoxia – a certain transcription factor controlling angiogenesis is promoted
- Oxygen level is the signalling to instruct blood vessels to undergo angiogenesis
- Drugs that inhibit angiogenesis can help cancer therapy to slow the tumour growth – won’t completely stop it
Telomeres and immortality: cancer cells avoid senescence - Tumour cells reactivate telomerase, maintain telomere length for each generation, thus avoiding mitotic catastrophe
- Avoids senescence + achieves immortality even though they have an instable genome (accumulating mutations)
What is the process of metastasis ?
- Clonal expansion, growth, diversification and angiogenesis
- Detachment of tumour cells from each other forming a metastatic clone
- Degradation of ECM by adhesion and invasion of basement membrane
- Attachment to novel ECM components + intravasation
- Interaction with host lymphoid cells
- Tumour cell embolus
- Adhesion to basement membrane again
- Extravasation
- Metastatic deposit, angiogenesis + growth
How does tumour cell heterogeneity occur?
Tumour cell heterogeneity refers to the presence of different subpopulations of cancer cells within a single tumor. There are several mechanisms by which tumor cell heterogeneity can occur:
Genetic mutations
Epigenetic changes
Tumour microenvironment (includes stromal cells, immune cells, and extracellular matrix components)
Cancer stem cells
Clonal evolution
* Driver genes vs secondary and tertiary genetic changes
What is dysplasia?
Change in cell or tissue phenotype
Abnormality of development
Epithelial anomaly of growth and differentiation
List the types of mutations that occur in cancer
Errors in DNA replication that are not repaired
* e.g. BRCA1 & BRCA2
* Accumulation of errors in “hotspots” (TSFs, oncogenes)
Point mutations
* Activation of oncogenes
* Inactivation of TSGs
Amplification of oncogenes
* CNV
Chromosomal rearrangements
