MOD 1 Cancer Bio Flashcards
Carcinogenesis causes
Physical (Ionising Radiation, Asbestos) – Radiation affects cells by directly damaging DNA
Chemical (Cigarette Smoke, Industrial Dyes, ETOH, burnt food) – often found bound to DNA, and likely to damage DNA directly
Viral:
- HPV16/18 - cervical cancer
- HHV8 (Human Herpes Virus 8) - Kaposi’s sarcoma
- EBV – variety of different malignancies associated
- HCV – Hepatocellular carcinoma
Chronic Inflammation E.g. H pylori and GI cancer
What is a Mutagen?
Any chemical that has the ability to cause mutations in DNA
Classification of cancer causing viruses?
Cancer causing viruses can be either acutely transforming or slowly transforming:
o Acutely transforming means the virus carries an oncogene which is immediately activated once inside the cell – e.g. HPV virus
o Slowly transforming means the virus genome is inserted near a proto-oncogene, and the virus promotor region causes over-expression of that proto-oncogene – e.g. HCV
Apoptosis: Intrinsic
Caspase 9
Cell stress –> Cyt C into cytoplasm
Apoptosome complex: Apaf1, Procaspase 9, ATP, Cyt C
Forms heptamer - each Apaf1 can bind 1 procaspase 9
Therefore 7 procaspase 9 molecules cleaved and activated
XIAP
Regulates Intrinsic pathway:
Inhibits dimerisation of procaspase 9
BCL-2 family
Regulates Intrinsic pathway by altering mit membrane permeability
Pro-apoptotic: BH3 only, Bax, Bak
Ant-apoptotic: Bcl-2-like
Apoptosis: Extrinsic
Caspase 8
Two adaptor proteins:
- FADD (positive regulator) –> Binds to Fas receptor, Procaspase 8 binds –> DISC
- FLIP (negative regulator) - Cellular Flice-like inhibitory protein
N.b. Receptor mediated pathway soon activates intrinsic pathway anyway via activated Bid that enhances Cyt C release
Other mechanisms of cell death
Necrosis – Death due to injury by Toxins or Pathogens; Associated with Immune response and occurs in regulated, genetic manner, regulated e.g. by RIPK1 and RIPK3
Autophagy – Catabolic, Self-degradation Process
Mitotic Catastrophe (Triggered by Aberrant Mitosis)
Anoikis – “Homelessness” - Response to adherent cells due to loss of Cell Cell/Matrix Interactions
Entosis – Engulfed cells which are degraded by the Lysosome
Pyroptosis – Caspase-1 Dependent Cell Death
Role of EMT transcription factors?
- Loss of Apico-basal polarity
- Enable the conversion from an epithelial to a spindle-like/fibroblastic morphology
- Directly inhibit expression of adherins junctions and tight junctions
- Increase expression of matrix degrading enzymes (MMPs)
- Increased motility
- Heightened resistance to apoptosis
What drives tumour metastasis?
Genomic Instability:
o Point mutations and chromosomal aberration leads to karyotype abnormalities and abnormal gene products
o Dysregulation of multiple downstream biological events is involved in tumour initiation and progression
However, not sufficient to explain rapid and reversible ability to differentiate…
Non-Genomic Instability:
o Phenotypic changes not genetic in origin
o Response to regulatory/biochemical perturbations (e.g. growth factors, hypoxia, chemotherapy, tumour microenvironment) – switches between cellular states
o Activation of transcription factors or signalling pathways
o RNA processing and translational control
o Post-transcriptional and post-translational modification
Non-genetic plasticity also occurs in somatic cells; Clonally identical but trans-differentiation which occurs in developmental pathways determines differentiation.
- Allows reactivation of developmental signal in non-development contexts i.e. cancer
Mesenchymal vs Amoeboid migration
Mesenchymal:
- Occurs in Dense ECM
- Actin Polymerisation and formation of Stress Fibres, Focal Adhesion Complexes, Secretion of MMP
- Formation of the Invadopodia
Examples: Fibrosarcoma, glioblastoma, epithelial cancers
Amoiboid:
- Occurs in Sparse ECM
- Cortical Actomyosin Contraction
- Use of Hydrostatic Pressure
Examples: Lymphoma, small-cell lung cancer, small-cell prostate cancer
What is anoikis resistance
Anoikis – programmed cell death induced upon cell detachment from ECM
o Resistance to anoikis occurs through Integrin switching and activation of anti-apoptotic signalling pathways (AKT/PI3K)
This therefore allows for survival of circulating tumour cells
Soil and Seed vs Mechanical Entrapment
S&S
- Cells can only metastasise only in location biochemically and physiologically favourable for implantation and growth
ME
- Metastasis formation is due to mechanical and circulatory factors; First organ encountered by CTC would be site of greatest tumour cell arrest and formation of Metastatic colonies
Pharm control of metastases
- Prevention formation of Focal Adhesion Complex – FAK Inhibitors
- Preventing Epithelial Mesenchymal Transformation – c-Met Inhibitors
- Blocking ECM interactions – MMP Inhibitors
- Anti-Angiogenic Therapy – Bevacizumab (=Avastin, Anti VEGF Monoclonal ab);
o NB: Complete eradication of tumour vasculature prevents chemotherapy and radiotherapy from working
Limitations of current anti-metastases therapies
Current therapy fails to account for potential molecular and proliferative differences between different sub-populations of tumour cells
Could explain why majority of treatment fails in metastatic disease
“Selection” for resistant cells; Relapse is increasingly resistant
Concept of cancer stem cells:
o Indefinite proliferation
o Tumourigenic population
o Able to self-renew and differentiate into cells with non-stem cell characteristics
Erlotinib - effect and relevance?
Erlotinib/gefitinib:
- TK inhibitor against EGFR receptor
- Initial response to the drug was disappointing
o However a small subset of patients (10 to 20%) with non small cell lung cancer (NSCLC) responded well to EGFR kinase inhibitors
o Those patients who responded well had an oncogenic mutation of the EGF receptor
Oestrogens as risk factors for breast cancer - examples?
- HRT and OCP increase risk
- Plasma levels of oestradiol in post-menopausal women are significantly correlated with breast cancer risk
- It is the lifetime of exposure to oestrogens that are particularly important:
o Early age of onset of menarche (<11 y/o)
o Late age to menopause (>55)
o Late first full-time pregnancy
o Nulliparity vs multiparity
o Breast feeding is protective – associated with reduced levels of oestrogen
o Obesity in post-menopausal women
SERM - example and MOA?
E.g. Tamoxifen – bind competitively to ER, with tissue specific effects
SERD - example and MOA
E.g. Fulvestrant – bind competitively to ER to promote ER degradation
ATLAS study findings
For women with ER+ BrCa, continuing Tamoxifen for 10 years rather than stopping at 5 provides reduction in reoccurance and mortality
10 years of therapy can halve BrCa mortality during the second decade after diagnosis
How is oestrogen signalling targeted in hormonal BrCa therapy?
Lowering oestrogen levels:
Premenopausal
- Ovarian oblation
- LHRH agonists
Post-menopausal
- Aromatase inhibitors
Ant-oestrogen therapies - MOA?
The ER receptor is a transcription factor
o It is recruited to particular regions of the genome
Conformational change occurs to the ER when oestrogen binds, permitting the recruitment of regulatory regions – enhancers, promoters of target genes
There is recruitment of co-regulatory molecules called co-activators
All of these processes act to permit transcription of genes that drive cell survival and proliferation
Resistance to hormonal therapies
De novo: Tumour independent of a requirement for oestrogen despite being ER+
Acquired:
- Usually, the ER itself is NOT lost.
- Growth promotion of initially oestrogen-dependent tumours by other mitogenic pathways
- Ligand-independent signalling - EGF activates ER receptor indirectly - it binds a TK at cell surface!
- ER post-translational modifications
- Co-activators/Co-repressors
