1. cure for cancer (revision)
Tom and Reesha

2. Benign vs. Malignant BENIGN MALIGNANT Behaviour Macroscopic
BENIGN = cell growth within a compact mass
Growth restricted to site of origin
Cell phenotype unchanged
MALIGNANT = uncontrolled cell growth
Potential to invade and spread
Altered cell phenotype
BENIGN
MALIGNANT
Behaviour
No invasion
No metastasis
Retain cell function
Variable, often low, growth rate
Invade
Metastasise
Lose cell function
Variable, often high, growth rate
Macroscopic
Well defined edge
Capsule?
Irregular margin
Haemorrhage
Necrosis
Microscopic
Low mitotic count + normal mitoses
Retains cell specialisation
Minimal nuclear variation in size, chromasia and shape
Structural differentiation retained
Organised
Expansile cohesive growth
Low-high mitotic count + abnormal mitoses
Loss of cell specialisation
Minimal-marked nuclear variation I nsize, chromasia and shape
Altered structural differentiation
Unorganised
Local invasion beyond normal boundaries

3. Definitions Metaplasia Dysplasia Neoplasia
REVERSIBLE change from one adult cell type to another
Dysplasia
Abnormal cellular development / growth leading to abnormal functioning - reverses on stimulus removal
Neoplasia
Abnormal growth of cells which persists after initiating stimulus is removed 

4. Malignant Transformation
Neoplastic (cancer) cells = TRANSFORMED CELLS
They have acquired a serise of genetic changes which allow them to form tumours
These genetic changes must be NON-LETHAL + INHERITABLE (i.e. passed on to daughter cells)
Alterations can also be epigenetic – i.e. changes in cell phenotype not cause by change in DNA
A key feature of malignant tumours is CLONALITY:
Tumours = monoclonal population arising from single transformed cell
Usually malignant transformation involves genetic changes + exposure to key ENVIRONMENTAL FACTORS which promote malignant changes

5. Malignant Transformation
What is this process called?
CARCINOGENESIS
What are the stages of Carcinogenesis?
Initiation
Cellular exposure to a sufficient level of carcinogen causing permanent DNA mutation
Promotion
Induces tumours in initiated cells, but are non-tumourigenic by themselves
Environmental agents involved in tumourigenesis = CARCINOGENS
Name 4 types of carcinogens:
Viruses
Exogenous hormones
Radiation
Drugs inc. Tobacco and alcohol
Dyes
Asbestos
Chemicals

6. Important genes
Which 2 classes of genes are associated with malignant transformation of a cell?
Tumour suppressor genes and Oncogenes
Oncogenes:
EGF / EGFR
Her2
Ras
C-myc
Tumour suppressor genes:
Retinoblastoma
p53

7. Ras
Normally, Ras inactivated by the hydrolysis of GTP, but carcinogenic mutations in Ras lead to constitutive activation of the protein. This leads to continual downstream signaling, promoting cell proliferation

8. Retinoblastoma
Rb normally binds + inhibits E2F (gene transcription regulatory protein)
This complex = growth supressor
Phosphorylation of Rb releases E2F + promotes cell cycle progression (G1->S)
Mutation = inactive Rb
Therefore, E2F able to bind DNA + dysregulated cells are able progress through cycle
Overall outcome = decr. growth supression

9. P53 = Guardian of the genome
Normally acts at G1/S checkpoint 
stops cell cycle progression of damaged cells 
Induces gene transcription of DNA repair genes  + causes apoptosis in cells w/ non-repairable DNA damage
Mutation = cell cycle progression of cells with genetic instability and dysregulated functions leading to tumourigenesis

10. Hallmarks of Cancer Sustaining proliferative signals
Evading growth suppression
Activating invasion + metastasis
Enabling replecative immortality
Induction of angiogenesis
Resisting cell death
Avoiding immune destruction
Tumour promoting inflammation
Genome instability + mutation
Dergulating cellular energetics (Aerobic glycolysis inhibitors)

11. A few definitions What is invasion?
The ability of cells to break through normal barriers eg. BM and then spread
What is metastasis?
The ability of malignant cells to invade into lymphatic, blood vessels and cavities and spread to distant (non contiguous sites)
What are primary and secondary cancers?
Primary = the site where the original neoplasm arises
Secondary = metastatic site

12. Spread of tumours Transcoelomic
Imaging and histology locate a ovarian cancer in Mrs Biggs. 12 months later fresh imaging suggests that the tumour has spread to the liver. The two tumours are not continuous. What is the most likely route of transmission?
Transcoelomic
What are other 2 common routes for metastasis?
Haematogenous spread
Lymphatic spread

13. What are Integrins?
Integrins are a class of receptor molecule that tether the cell to the surrounding stroma. Like velcro. When integrins are expressed the cell is not motile, if switched off they can move
What are cadherins?
Cadherins are a Ca2+ dependant class of molecules that link cells with other cells. They also prevent detached cells from entering the cell cycle
Metalloproteases (MMPs)
MMPs are a class of proteases that can break down the extracellular stroma preparing a path for the cancer cells to move from a site through a BM and beyond.
Tissue inhibitors of metalloproteases (TIMPs)
TIMPs are like the antidote to MMPs that under normal conditions prevent MMPs from running riot and cells from eating the scaffold around them destroying everything

14. Metastasis – steps Steps for metastasis Invade BM (MMP/TIMP)
Passage through ECM (MMP/TIMP)
Intravasation (MMP/TIMP/altered integrins)
Immune interaction (↓ MHC Class 1)
Platelet adhesion (GF release)
Adhesion to endothelium/BM (CD44)
Extravasation (integrins/MMP/TIMP)
Angogenesis (angiogenic growth Factors)

15. Paraneoplastic syndromes
What Is a paraneoplastic effect?
A sign/ symptoms/ set of signs and symptoms mediated by humoral cytokines excreted by tumour cells that are a consequnce of a cancer that is not local to where the effects occur

16. The cell cycle G0 Resting
G1 Gap 1 – growth inpreparation for DNA synthesis
S Phase DNA replicates
G2 (Gap 2 – growth in preparation for M phase)
M Phase Nuclear & cytoplasmic division
M phase consists of prophase, metaphase, anaphase, telophase and cytokinesis in the classical cell cycle.
Between each stage of the cell cycle cells go through checkpoints.

17. What controls the checkpoints?
Cyclin dependant kinases
Regulate timely proteins, enzymes production, DNA synthesis + mitotic spindle formation
Cyclins
Regulate the CDKs and transition from one stage to the next
CDKI’s (inhibitors)
Shut down the operation if there is a problem or fault located by inhibiting the CDKs from activating the cellular machinery

18. How do cancers become resistant?
Alteration of drug target
Expression of drug pump
Expression of detoxification mechanisms
Reduced susceptibility to apoptosis
Increased ability to repair DNA damage
Altered proliferation

19. Tumour Staging (breast cancer)
TNM
T = tumour N = node M = metastasis
T1 = <2cm size
T2 = cm
T3 = skin and/ or chest wall involved
N0 = no axilliary nodes involved
N1 = mobile nodes involved
M0 = no metastases
M1 = demonstrable metastases

20. Tumour Grading Degree of differentiation e.g. Breast Cancer
How closely does it resemble normal tissue?
Well, moderately & poorly differentiated
e.g. Breast Cancer
degree of tubule formation
extent of nuclear variation
number of mitoses