CURE FOR CANCER (REVISION)

Tom and Reesha

Benign vs. Malignant

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 phenotypeBENIGN MALIGNANT

Behaviour

No invasionNo metastasisRetain cell functionVariable, often low, growth rate

InvadeMetastasiseLose cell functionVariable, often high, growth rate

Macroscopic

Well defined edgeCapsule?

Irregular marginHaemorrhageNecrosis

Microscopic

Low mitotic count + normal mitosesRetains cell specialisationMinimal nuclear variation in size, chromasia and shapeStructural differentiation retainedOrganisedExpansile cohesive growth

Low-high mitotic count + abnormal mitosesLoss of cell specialisationMinimal-marked nuclear variation I nsize, chromasia and shapeAltered structural differentiationUnorganisedLocal invasion beyond normal boundaries

Definitions

MetaplasiaREVERSIBLE change from one adult cell type to another

DysplasiaAbnormal cellular development / growth leading to abnormal functioning - reverses on stimulus removal

NeoplasiaAbnormal growth of cells which persists after initiating stimulus is removed 

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

Malignant Transformation

1. InitiationCellular exposure to a sufficient level of carcinogen causing permanent DNA mutation

2. PromotionInduces tumours in initiated cells, but are non-tumourigenic by themselves

What is this process called?

CARCINOGENESIS

What are the stages of Carcinogenesis?

Environmental agents involved in tumourigenesis = CARCINOGENSName 4 types of carcinogens:• Viruses• Exogenous

hormones• Radiation

• Drugs inc. Tobacco and alcohol• Dyes • Asbestos• Chemicals

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

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

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 RbTherefore, E2F able to bind DNA + dysregulated cells are able progress through cycle

Overall outcome = decr. growth supression

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

Hallmarks of Cancer

1. Sustaining proliferative signals 2. Evading growth suppression3. Activating invasion + metastasis 4. Enabling replecative immortality 5. Induction of angiogenesis 6. Resisting cell death

7. Avoiding immune destruction 8. Tumour promoting inflammation 9. Genome instability + mutation 10.Dergulating cellular energetics (Aerobic glycolysis

inhibitors)

A few definitions

What is invasion?

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?

What is metastasis?

The ability of cells to break through normal barriers eg. BM and then spread

Primary = the site where the original neoplasm arises Secondary = metastatic site

Spread of tumours

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 spreadLymphatic spread

What are Integrins?

What are cadherins?

Tissue inhibitors of metalloproteases (TIMPs)

Metalloproteases (MMPs)

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

Cadherins are a Ca2+ dependant class of molecules that link cells with other cells. They also prevent detached cells from entering the cell cycle

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.

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

Metastasis – steps

Steps for metastasis

1. Invade BM (MMP/TIMP)2. Passage through ECM (MMP/TIMP)3. Intravasation (MMP/TIMP/altered

integrins)4. Immune interaction (↓ MHC Class 1)5. Platelet adhesion (GF release)6. Adhesion to endothelium/BM (CD44)7. Extravasation (integrins/MMP/TIMP)8. Angogenesis (angiogenic growth

Factors)

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

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.

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

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

Tumour Staging (breast cancer)

TNMT = tumour N = node M = metastasis

T1 = <2cm size T2 = 2 - 5 cm T3 = skin and/ or chest wall involvedN0 = no axilliary nodes involvedN1 = mobile nodes involvedM0 = no metastasesM1 = demonstrable metastases

Tumour Grading

• Degree of differentiation

• 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