Lecture 5: Cancer Flashcards
What type of mutations cause cancer and description
- Point mutations:The mutation of one or a small number ofbaseswithin agene. Changes in the codons of the DNA can affect whichamino acidsare linked together to make proteins, and so can affect the whole cell.
- Chromosomal mutations:Changes in the positions of the genes within a chromosome – the genes may be duplicated, deleted or their positions may be changed around.All of these mutations have the potential to produce problems in the individual, because they may result in the formation of a different protein that does not function properly in the cell.
- Whole chromosome mutations:These usually occur in meiosis, when a whole chromosome is lost or duplicated in the gametes.
- Damage toDNAcaused by harmful substances in the environment, such as the chemicals in tobacco smoke andultravioletrays from the sun
5.Inherited
Factors increasing risk of cancer development
Smoking Chemicals UV Viruses Cell dividing Genetic
Cell division steps
- G1 = duplication of cell contents (except chromosomes)
2.S = duplication of chromosomes to form 2 sister chromatids for every chromosome
3.G2 = double checking and any repair if errors
4.Mitosis
PPMATC
Prophase = chromosome condense, spindle fibres appear Prometaphase = chromosome condense and spindle fibres attach metaphase= chromosomes allign anaphase = sister chromatids diverge to opposite ends of cell Telophase = chromosome decondense, spindle fibres disappear, nuclear membrane forms Cytokinesis = cytoplasm divides
What is the restriction point?
occurs in the G1 phase. Metabolic changes prepare the cell for division. At a certain point - the restriction point - the cell is committed to division and moves into the S phase.
MItosis vs meiosis main difference
mitosis is the process of making new body cells to form two identical daughter cells. Meiosis is the type of cell division that creates egg and sperm cells.
Cell division process with the specific cyclins and CDKS in each step with the restriction points
G1 to S = Cyclin E/CDK2
S to G2 = Cyclin A/CDK2
G2 to M = Cyclin B/ CDK1
M to G1 = Cyclin D/CDK2
Restriction sites:
End of G1
End of G2 and before cell division in mitosis.
Purpose of restriction points
and the the examples of three restriction points with specific cyclins and CDK’s
DRAW DIAGRAM
This is where the complexes of cyclin and CDK bind together and allow the cell to continue through the cell cycle.
G1 = Cyclin E/CDK2 bound G2= Cyclin B/ CDK1 (mitotic cyclin and mitotic CDK M = anaphase -promoting complex
2 major roles of regulator
- detecting and repairing damaged DNA
2. preventing uncontrolled cell division.
two key classes of regulatory molecules
Cyclin (regulator subunit) and CDK (catalytic subunit)
Is cyclin OR CDK synthesised in cell and have catalytic activity?
and their overall function once bound together
Cyclins are synthesized in the cell cycle and have no catalytic activity.
CDKs are found within the cell and only active once bound with cyclins.
Cyclins and CDKs work together to phosphorylate and activate (or inactivate) target proteins in the following steps of the cell cycle.
Function of S cyclin-CDK complex
S cyclin-CDK complexes ..
1. phosphorylate proteins in pre-replication complexes, therefore activating them
- prevent new unwanted complexes from forming
- ensure only one copy of each genome
Function of mitotic cyclin-CDK complex
Mitotic cyclin-CDK complexes
- initiate mitosis by stimulating the proteins involved in the processes of mitotic spindle creation and chromosome condensation
Function of Cyclin D and CDK2
phosphorylate retinoblastoma (Rb). When this happens, the Rb protein breaks away from the Rb/E2F pathway and activates E2F.
Function of Cyclin E and CDK2
move the cell from the G1 to the S phase of the cell cycle. Promote expression of S cyclins and enzymes that DNA replication requires and degrade S phase inhibitors via ubiquitination
Function of Cyclin B and CDK1
move it from the G2 to the M phase, and also cause the breakdown of the nuclear envelope so that mitosis can begin.
What are the role and example of regulatory inhibitors
Inhibitory proteins include CDK inhibitory proteins (the CIP family) and kinase inhibitory proteins (the KIP family).
They alter the G1 phase of the cell cycle by inactivating cyclin-CDK complexes.
More inhibitors include the INK4a/ARF family (which bond to CDK-4, preventing degradation and halting the G1 phase)
Define Proto-oncogene, oncogene and tumor suppressor gene
Proto-oncogene:
A gene which regulates cell proliferation, growth and differentiation. It codes for proteins which promote cell cycle progression, eg RAS and MYC.
oncogene: A mutated form of a proto-oncogene which causes the production of proteins which cause the cell to multiply all the time (hyperactive proteins, eg RAS creating too many cyclins and MYC promotes too much cell growth, surivival and activity). POS regulator of cell cycle
Tumor suppressor gene:
Code for proteins which allow for cell arrest, DNA repair and cell apoptosis. NEG regulator of cell cycle
2 ways in which Proto-oncogene, oncogene and tumor suppressor gene cause CANCER
Low tumor suppressor genes
High oncogenes
Describe RAS and MYC functions as proto-oncogenes and oncogenes and the effects of this
RAS:
The RAS gene is located in cell DNA and creates the protein RAS located below plasma membrane next to the growth factor receptor. If a cell goes through the cell cycle it releases growth factor. This binds to the growth factor receptor and activates the RAS protein. This creates a series of intracellular phosphorylation reactions and forms a transciption protein. This binds to the DNA and transcribes the DNA to formulate cell growth proteins (cyclins and CDK’s). These RAS proteins are inactive and only active when the growth factor is present.
IF mutated then the RAS gene makes RAS proteins which are always activated and thus constant intracellular phosphorylation reactions and transciption proteins and thus overproducing these CDK and cyclins causing the cell to bypass the restriction points
MYC:
This gene codes for proteins that aid in cell growth, activity and survival. SO mutation to MYC gene means that the cell has MORE growth, activity and survival making it more cancerous
THESE mutated forms cause the proto-oncogenes to oncogenes causing uncontrolled cell growth
Tumour suppressor genes function as proto-oncogenes and ongogenes
If a cell is damaged at a checkpoint (G1) then the cells DNA releases p53 proteins which act as transcription factor. This makes proteins for cell arrest (proteins that inhibit cyclins and CDK’s thus inhibiting cell cycle to allow for DNA repairs to be completed), apoptosis (if DNA can not be fixed), repairs DNA.
IF MUTATED
Then these proteins can not occur and there is no arrest of damaged DNA in cells causing these cells to proliferate and the checkpoitns to be irrelevant
Types of cancers
Carcinomas
A carcinoma begins in the skin or the tissue that covers the surface of internal organs and glands.
They are the most common type of cancer. Examples of carcinomas includeprostate cancer,breast cancer,lung cancer, andcolorectal cancer.
Sarcomas
Asarcomabegins in the tissues that support and connect the body. A sarcoma can develop in fat, muscles, nerves, tendons, joints, blood vessels, lymph vessels, cartilage, or bone.
Leukemias
Leukemia is a cancer of the blood.
4 main types of leukemia areacute lymphocytic leukemia,chronic lymphocytic leukemia,acute myeloid leukemia, andchronic myeloid leukemia.
Lymphomas.
Lymphoma is a cancer that begins in the lymphatic system.
There are 2 main types of lymphomas:Hodgkin lymphoma andnon-Hodgkin lymphoma
Tumor antigens examples and description
- Self antigens (on healthy tissues)
- Tumor assosciated antigens (Overexpression of self antigens, differientation antigens and cancer testis antigens) Antigens derived from genes overexpressed in tumours comprise a class of normal self-proteins which are minimally expressed by healthy tissues but constitutively overexpressed in cancer cells as a result of their malignant profile.
- Tumor specific Antigens
(neoanitgens, oncoviral antigens)
Tumour antigen examples: Viral, differentiation, cancer-germline, overexpressed and mutated
Viral antigens are only expressed in virus-infected cells.
Differentiation antigens are encoded by genes with tissue-specific expression.
Cancer germline genes are expressed in tumours or germ line cells owing to whole-genome demethylation.
Some genes are overexpressed in tumours as a result of increased transcription or gene amplification. The resulting peptides are upregulated on these tumours but also show a low level of expression in some healthy tissues.
However, mutated genes may yield a mutant peptide (neoantigen), which is recognized as non-self by immune cells.
Immune response to tumour main roles
Protect the host from virus-induced tumours by eliminating or suppressing viral infections
Specifically identify and eliminate tumour cells on the basis of their expression of tumour-specific antigens or molecules induced by cellular stress in timely manner
Cancer immunoediting process
Ehrlich, 1909
The immune system regulates cancer development and protects the host from neoplastic diseases.
Burnet and Thomas
Introduced cancer immunosurvalliance hypothesis. The interface between cancer and immune system
Dual effects of the immune system
Protect against tumor development and capacity to promote tumour growth.
3 steps of immunoediting and description
1) . Elimination represents cancer immunosurveillance (thymus dependent cells of the body constantly surveyed host tissues for nascently transformed cells)
2) equilibrium is the period of immune-mediated latency after incomplete tumour destruction in the elimination phase
3) escape refers to the final out- growth of tumours that have outstripped immunological restraints of the equilibrium phase.
Describe the elimination phase
Original concept:
The immune system detects and eliminates tumour cells
Complete
When all tumour cells are successfully eradicated
Incomplete:
When only some of the tumour cells are eradicated and this causes dynamic equilibrium that can develop between the immune system and the developing tumour.
Describe the equilibrium phase
Dynamic Phase
Immune cells and their cytokines exert relentless selection pressure on the tumour cells
Is it enough?
Many of the original tumour cell variants are eliminated but new variants may arise which carry new mutations
Resistance to immune attack:
tumour cells eventually resist the hosts immunological seige and a new tumour cell population emerges
Describe the escape phase
Immune system is no longer able to constrain tumour growth and there is progressive tumour growth
The ability of cancer to evade the protective network of the immune system is often considered a hallmark of cancer
The multitude of mechanisms which cancer uses to the evade the immune system is wide
Cancer immunoediting is now considered a process composed of 3 phases:
elimination, or cancer immune surveillance;
equilibrium, a phase of tumor dormancy where tumor cells and immunity enter into a dynamic equilibrium that keeps tumor expansion in check;
escape, where tumor cells emerge that either display reduced immunogenicities or engage a large number of possible immunosuppressive mechanisms to attenuate antitumor immune responses leading to the appearance of progressively growing tumors
Example of a mechanism of ‘escape’
These variants may eventually evade the immune system by a variety of mechanisms, expanding in an uncontrolled manner and becoming clinically detectable in the escape phase. Other factors that may contribute to escape is T cell exhaustion, in which they have increased expression of inhibitory moleculaes such as PD-1 on their surface. In addition, tumour cells may have increased expression of PD-L1 which bind to PD-1 and thus shutting down the T cell response.
Immune evasion mechanisms of tumor cells
Reduced immunogenecity
Resistance to immune mediated killing
subversion of the immune response
