cure for cancer (revision) Tom and Reesha

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

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 

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 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

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 Rb Therefore, 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 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)

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

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

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

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)

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) TNM T = tumour N = node M = metastasis T1 = <2cm size T2 = 2 - 5 cm T3 = skin and/ or chest wall involved N0 = no axilliary nodes involved N1 = mobile nodes involved M0 = no metastases M1 = demonstrable metastases

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