Cancer Flashcards
Normal cellular proliferation
- Growth factor binds to its specific receptor
- Transient and limited activation of growth factor receptor
- Cascade of biochemical events leading to eventual signal transduction to the nucleus
- Induction and activation of nuclear regulatory factors that initiate DNA transcription
- Expression of genes involved in cell growth and proliferation
Hallmarks of Cancer
- Growth signal autonomy
- Evasion of growth inhibitory signals
- Evasion of apoptotic cell death
- Unlimited replicative potential
- Angiogenesis
- Invasion and metastasis
- Avoiding immune destruction
- Reprogramming energy metabolism
- Genomic instability
- Tumour promoting inflammation
MOA of Growth signal autonomy = Cancer-inducing mutations
- Overexpression of Platelet Derived Growth Factor (PDGF)
- Amplification and change in structure of growth factor receptor
- Cell signalling molecules/transducers
- Activation of transcription factors
- Activation of cell cycle regulators
MOA of Amplification of growth factor receptor
Amplification of HER2 (Herceptin): test for breast cancer using
1. Fluorescence in situ hybridisation
2. Immunohistochemistry
Changes in structure:
1. Constitutive activation of receptor (ligand-independent receptor)
2. EGFR tyrosine kinase mutations
**EGFR tyrosine kinase inhibitors are used as therapy
Cell signalling molecules/transducers
RAS family genes (NRAS, KRAS, HRAS)
RAF family genes (BRAF) > RAF activates MAPK, which activates transcription of Myc and D cyclines
MOA of Activation of transcription factors
Myc:
- Master transcription factor of cell growth
- Activates expression of many genes involved in cell growth
- Upregulated in many cancers (e.g. Burkitt’s lymphoma, neuroblastoma)
MOA of Activation of cell cycle regulators
Mutations of cyclins and cyclin-dependent kinases
Cell cycle: G1 > S > G2 > Mitosis
MOA of Evasion of growth inhibitory signals: Familial Adenomatous Polyposis
Germline loss-of-function mutation involving APC
Predisposition to colonic cancers (and other GIT cancers)
- Normal APC function is to form a destructive complex that degrades Beta-catenin in the absence of WNT signalling
In absence of APC, elevated levels of B-catenin translocate to nucleus
Activates genes involved in cell proliferation
Accumulation of mutations cause carcinogenesis
MOA of Evasion of Apoptotic Cell Death: extrinsic & intrinsic apoptotic pathways
- Loss of p53, leading to reduced production of pro-apoptotic factors such as BAX
- Reduced egress of cytochrome c from mitochondria as a result of upregulation of anti-apoptotic factors such as BCL2
e.g. BCL2 upregulated by t(14;18) translocation activating IGH promoter and promoting the formation of follicular lymphoma - Loss of apoptotic peptidase activating factor 1 (APAF1)
- Upregulation of inhibitors of apoptosis (IAP)
- Reduced CD95 level
- Inactivation of death-induced signalling complex e.g. FADD, Fas-associated death domain
MOA of Unlimited replicative potential
Cancer cells reactivate telomerase to maintain the length of their telomeres
MOA of Angiogenesis: Transcription factors
Downregulation of anti-angiogenic factors: p53 protein + Thrombospondin 1 (TSP1) which is activated by p53
Upregulation of pro-angiogenic factors:
- Vascular endothelial growth factor (VEGF)*
- Platelet-derived growth factor (PDGF)
- Fibroblast growth factor (FGF)
*Anti-VEGF monoclonal antibodies can be used to treat
MOA of Angiogenesis: During tumour angiogenesis
- Many oncogenes (e.g. Ras, MAPK) upregulate VEGF expression to stimulate angiogenesis
- Relative lack of oxygen due to hypoxia stabilises heat-inducible factor (HIF1a, an oxygen-sensitive TF) > transcription of VEGF
- Loss of p53 > removes cell cycle checkpoints > decrease in antiangiogenic molecules (e.g. TSP-1) > indirect promotion of angiogenesis
MOA of Invasion and metastasis
- Cancer cells loosen from each other and become mobile
- Epithelial-mesenchymal transition
- Involves loss of e-cadherin function - Breach the basement membrane by secreting proteolytic enzymes - metalloproteinases
- Traverse the interstitial connective tissues
- Gain access to the circulation by invading the vascular basement membrane
- Transit through the vasculature in single cells or tumour emboli
- Extravasate from blood vessels
- Form micrometastases that eventually grow into macroscopic tumours
- Angiogenesis and growth
MOA of Reprogramming energy metabolism
Aerobic glycolysis/Warburg effect
Glycolytic intermediates help cancer cells achieve rapid cell growth
PET scan shows increased uptake of glucose
Normal immunologic surveillance
Cytotoxic T cells bind to MHC class I molecules displaying tumour antigens
Tumour antigens:
- Products of mutated oncogenes and tumour suppressor genes
- Overexpressed or aberrantly expressed proteins
- Tumour antigens produced by oncogenic viruses
- Oncofoetal genes
- Altered glycolipids and glycoproteins
MOA of Avoiding immune destruction
- Loss of tumour-specific antigens
- Reduced/loss of expression of MHC molecules
- Production of immunosuppressive factors (e.g. TGF-Beta) by cancer cells
- Expression of immunosuppressive receptors on cell surface (e.g. programmed death ligand 1 - PDL1 binds to PD1 on T cells to suppress T cell response)*
*Immune checkpoint therapy: Anti-PDL1/PD1 agent to provide relief of T cell inhibition
Genome instability: DNA Mismatch Repair Deficiency
Defects in MMR proteins
Increases mutation rate > acquisition of multiple mutations in oncogenes and TSGs > hypermutable phenotype > carcinogenesis
Microsatellite instability
What is microsatellite instability?
Change in length of short tandem repeat sequences
Arises from:
Loss of function mutations - HNPCC
- Familial colon carcinomas
- Germline mutations in one of 4 MMR genes > second hit > loss of MMR function > MMR deficiency
- Increased mutation rate > further genetic hits > malignancy
Epigenetic mechanisms (e.g. DNA methylation of MLH1 gene promoter)
Cancers with genomic instability are susceptible to what therapy?
Anti-PD-1-based immunotherapy, because of the high tumour mutational load
Genomic instability: Breakdown of genome surveillance mechanism (p53)
Some things that activate p53:
- DNA damage
- Aberrant growth signals
- Oncogene activation
- Cell stress (e.g. hypoxia, nucleotide depletion)
Some p53 downstream effects:
- Senescence/cell cycle arrest
- DNA repair
- Activation of apoptosis
- Inhibition of angiogenesis
What is Li-Fraumeni syndrome?
Germline loss of function mutation of TP53 gene
Multiple primary tumours with wide spectrum
MOA of Tumour-promoting inflammation
- Enhances tumour-genesis and progression
- Brings bioactive molecules to site of tumour formation including growth factors, pro-angiogenic factors, ECM modifying enzymes, and reactive oxygen species (mutagenic)
HNPCC
Colorectal, endometrium, ovary, stomach
Caused by mutation in mismatch repair genes
Familial adenomatous polyposis (FAP)
Colorectal
Caused by mutation in APC
Characteristics of hereditary cancer syndromes
Rare
Familial clustering
Autosomal dominant
Acute myeloid leukemia
Risk factors
- Pre-natal exposure to x-rays
- Post-natal exposure to large amounts of radiation
- Genetics conditions e.g. Down syndrome, Bloom syndrome, Ataxia telangiectasia
Associated with cytogenetic abnormalities
Treatment is bone marrow transplant
Breast cancer
Risk factors:
- Mutation of BRCA1/2 gene
- Familial history of breast cancer
- Increasing age
- Gender
- Certain neoplastic & benign conditions of breast
- Certain obstetric and menstrual history
- Use of exogenous hormones
Colon cancer
Mostly multifactorial - genetic = single gene defects HNPCC, FAP
Grading is?
Degree of differentiation
1. Cellular architecture
- Pleomorphism of cells
2. Cytological atypia
- Nuclear pleomorphism
- High nuclear to cytoplasm ratio
- Hyperchromatic
- Prominent nucleolus
- Irregularly shaped nucleus
3. Frequent mitosis
- Presence of mitotic figures
Staging is?
Extent of spread - TNM
- Tumour size
- Nodes: extent of regional lymph node metastasis
- Metastasis to distal organs
Grading/staging can?
Inform malignancy/aggressiveness/prognosis
Guide treatment and patient counselling
Higher grade/stage = less possibility for surgical resection
Poorer prognosis = replacing curative methods with palliative care
Histopathological features of squamous cell carcinoma
- Keratin pearls - forms in regions where squamous cells form concentric layers
- Pavementing of cells
- Intercellular bridges
- Epithelial dysplasia - basal cell hyperplasia, irregular epithelial stratification, premature keratinisation etc.
Histopathological features in lung squamous cell carcinoma
Conversion of pseudostratified columnar epithelial cells to squamous cells > Epithelial cell dysplasia > Invasion of basement membrane > Squamous cell carcinoma
Loss of cilia & mucous secreting cells
What are paraneoplastic syndromes?
Symptom in cancer patients that cannot be attributed to local or distant spread of metastatic tumour or to hormonal effects of the tissues from which the tumour originally arose
Examples of paraneoplastic syndrome
Small cell carcinoma > ACTH secretion > Cushing’s syndrome
Small cell carcinoma > ADH secretion > Syndrome of inappropriate ADH release (SIADH)
Squamous cell carcinoma > PTH-like protein secretion > Hypercalcemia
Routes of cancer spread
Haematogenous (e.g. liver cancer, portal vein)
Lymphatic spread (e.g. breast cancer > axillary lymph nodes)
Transcoelomic spread (body cavities): ovarian cancer - peritoneal cavity > stomach
Local infiltration
- Surrounding structures e.g. rectum > bladder/cervix
- Perineural e.g. head and neck cancers via nerves
