Lecture 18 - Genes and cancer Flashcards
What is cancer?
Cancer is a heterogenous group of ~200 diseases - characterised by;
* Uncontrolled cell growth not subject to usual regulatory controls
* Cell spreading - invasion of tissue around the tumour and metastasize to distant sites
Cancer cells remain undifferentiated or dedifferentiate
Cell signalling responses are dysregulated - e.g. contact inhibition, apoptosis, proliferation/inhibition signalling
The process of cancer formation is carcinogenesis - driven by mutations and epigenetic changes in somatic tissues
How are tumours named?
Tumours are named depending on their tissue of origin
* Carcinoma - of epithelial origin, accounts for 80-90% of human cancers
* Sarcoma - originates in supportive and connective tissues such as bones, tendons, cartilage, muscle and fat.
* Lymphoma - Blood an lymph tumours that develop from lymphocytes
* Leukaemia - Usually begin in the bone marrow and result in high numbers of abnormal blood cells
Brain cancer - Blastoma, brain and spinal cord cancers.
Describe the progressive changes in the formation of malignant tumours.
Increased cell divisions (tissues with large amounts of replication) = increased risk of cancer
Directly proportional, however genetic risk factors can change the incidence in individuals with the risk factor.
Progressive changes in the formation of malignant tumours
Abnormal increase in cell numbers may be:
* Hyperplasia - cells divide more rapidly than normal
* Dysplasia - Cells change form
Neoplasms (tumours)
* Benign tumours have localised cell growth - stay in one place
* Malignant tumours (cancers) - cells ca invade neighbouring tissues and spread. Cancer cells invade normal tissue and enter the blood and lymph so metastases form at distant sites.
How does mutation drive progression towards cancer.
Mutation drives progression towards cancer
* Mutations arise through errors in DNA replication (spontaneous base tautomerization, replication of DNA damage) that escape repair
* Actively dividing cells are predisposed to forming tumours
○ Epithelial cells - carcinomas (90% of all cancers)
○ Blood cells - leukaemia and lymphomas
○ Stromal tissue - sarcomas
A multistep event model for development of cancer
Tumours are monoclonal - all cells descend from a single starting cell. This does not mean all the tumour cells are identical.
A typical adult tumour may have 5-8 driver mutations (and hundreds of passenger mutations
Driver mutation - mutation that directly or indirectly confers a selective growth advantage to the cell in which it occurs. Early driver mutation typically give cells a growth advantage
Passenger mutation - mutation that has no direct or indirect effect on the selective growth advantage of the cell in which it occurred.
What genes can contribute to cancer when over or underactive?
The current count implicates 743 genes with causal contributions to cancer
A number of genes implicated particularly those involved in cell proliferation and cell death.
Positive regulators: (cause cancer if overactive)
* Classical oncogenes
* Telomerase
* Anti-apoptotic genes
Negative regulators: (cause cancer if inhibited)
* Classical tumour suppressor genes
* Indirectly acting tumour suppressor genes
Apoptotic genes
What is the importance of the balance between cell proliferation and cell death.
The balance between cell proliferation and cell death
* Normal growth occurs when proliferation > cell death
* Normal repair occurs when proliferation = cell death
* Complex intercellular signalling pathways control cellular proliferation
* Signalling pathways may send signals to:
○ Proliferate
○ Arrest cell cycle
The cell cycle
Loss of cell cycle control is a common feature in cancer
Describe the normal eukaryotic cell cycle.
The normal cell cycle
The cell cycle is the process by which eukaryotic cells duplicate and divide
During each cell cycle cells must replicate all chromosomes and then distribute chromosomes into two daughter cells.
The events of the eukaryotic cell cycle
* S phase: DNA synthesis, creating two identical sister chromatids
* G2 phase: A gap phase allowing growth and preparation for separation of the sister chromatids. The mitotic spindle begins to form.
* M phase: includes mitosis ( nuclear envelope breaks down, chromosomes are attached to spindle and sister chromatids separated to opposite sides of the cell) and cytokines (the cell divides to create two daughter cells ‘born’ in G1).
* Centrosome
* G1 phase: growth before chromosome duplication.
* G0 - quiescent cells exited from cell cycle
Restriction point (start transition) - is environment favourable for division
G2/M transition - Is all DNA replicated is environment favourable
M/A transition - Are all chromosomes properly attached to spindle
Describe checkpoints that halt the cell cycle.
Checkpoints: intrinsic pathways that halt cell cycle
Checkpoint pathways - internal ‘quality control’ mechanisms that halt the cell cycle when things go wrong.
Different pathways monitor essential cellular processes and activate specific responses when errors are detected.
Responses include activation of DNA repair and delaying progression of the cell cycle
Cell cycle can be arrested at the G1/S transition, during S phase, the G2/M transition and metaphase anaphase transition.
* G1 checkpoint - DNA damage checkpoint can arrest cell cycle progression at the G1 checkpoint (restriction point) or G2/M checkpoint
* S phase checkpoint - DNA replication checkpoint pathway can inhibit further DNA replication during S phase
Spindle assembly/metaphase checkpoint blocks initiation of anaphase and the exit from mitosis.
What cyclins are present at different stages of the cell cycle.
Different cyclins present during different stages of cell cycle interact with different Cdks to drive cell cycle forward.
* Cyclin D Cdk 4,6 / G1 CDK is important in G1
* Cyclin E Cdk 2 / G1/S-Cdk
* Cyclin A Cdk2 / S Cdk
* Cyclin B Cdk1 / M Cdk
Each cyclin-Cdk complex activates
* Events in their cell cycle phase
* Cyclin-Cdk in the next cell cycle phase - E.g. by promoting expression of the next cyclin, drives cell cycle progression.
>400 cyclin-Cdk substrates - roles in e.g. DNA replication, protein synthesis, chromosome condensation, mitosis and cell division.
What is the role of cyclin-Cdks in the cell cycle.
Progression of the cell cycle is dependent on:
1. Activation of cell-cycle phase specific Cdk activity
2. Elimination of proteins from previous cell cycle stages, by degradation by ubiquitin mediated proteolysis machinery.
Cyclin-Cdks regulate protein degradation by:
Phosphorylation of cell cycle regulators making them substrates for the SCF complex (ubiquitin ligase)
Phosphorylation some ubiquitin ligases, activating them (Anaphase promoting complex or cyclosome APC/C)
Describe the structure of a checkpoint pathway.
Checkpoint pathways have sensors, transducers and effectors
Damage-specific sensors bind to the damaged DNA ( sensor e.g. RPS/MRN complex - L8)
Sensors activate transducers, which launch the damage response (ATR/ATM - L8)
Transducers activate effectors, which perform checkpoint functions e.g. DNA repair proteins and produce proteins that arrest cell cycle or repair DNA.
Prolonged arrest leads to apoptosis in many multicellular eukaryotes.
How do defects in attachment of chromosmes to mitotic spindle activate a checkpoint.
The mitotic spindle is also monitored for defects
Lack of attachment or incorrect attachment, of chromosomes to the spindle could lead to incorrect numbers of chromosomes in daughter cells.
The spindle assembly checkpoint monitors attachment between the spindle and chromosomes
APC/C is the main effector of the spindle assembly checkpoint
When chromosomes are incorrectly attached, APC/C is inactivated prevents anaphase initiation and mitotic exit.
Describe extrinsic regulation of cell division in normal cells.
Mitogens are small secreted proteins that directly stimulate cell division by activating cyclin-Cdks for example epidermal growth factor
The mitogen binds to a cell surface receptor and stimulates a signal cascade that stimulates expression of genes including G1 and S cyclins.
Growth factors and mitogens promote passage through the restriction point
Growth factors stimulate increase in cell size - regulated by TOR kinase - increases rate of protein synthesis.
