Emily Hodgson Hallmarks of Cancer Immunology Drugs Metastasis

HALLMARKS OF CANCER

Name as many hallmarks as you can? What happens first: – Genome Instability – Deregulating cellular energetics How does it survive (become ‘immortal’): – Self sustaining growth signals – Evade growth suppression – Limitless/endless replication – Avoid immune destruction – Resist cell death – Tumour promoting inflammation How does it thrive: – Invasion and metastasis – Angiogenesis

METASTASIS (AND INVASION)

What is invasion? Ability of cells to break through the normal barriers

How do cells invade? Malignant cells to not adhere as much as normal cells Change in the interaction with surrounding stroma Produce factors to help spread – increased motility and altered synthesis of enzymes which break down BM and stroma

What is a cadherin? Glycoproteins in the cell membrane Interact between cells and within the cells Reduced expression and alterations allow cells to move apart

What are integrins? Cell surface glycoproteins Receptors for different components of the BM Reduced expression in malignant cells modifies contact between cell and stroma

What enzymes are involved in BM break down? Matrix metalloproteinases Collagenases Gelatinases Stromelysins

What is metastasis? Ability of malignant cells to invade into lymphatics, blood vessels and cavities and spread to distant sites Not all circulating cells will settle

What are the steps of 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)

What is the difference between primary and secondary metastasis? Primary – site where the malignant neoplasm arises Secondary – metastasis e.g. carcinoma that has spread to another organ

What are the three main routes of metastasis? Lymphatics Blood vessels Coelomic spaces

IMMUNOLOGY

B-Lymphocytes APC present to B-cells in lymph nodes B cell >> Plasma cells Produce up to 10 million ab per hour

T-lymphocytes Helper cells – regulate Cytotoxic – destroy infected cells Viruses and cells transformed by cancer (not yet adapted to evade immune system) Need to recognize specific antigen bound to self-MHC

NK cells Attack cells lacking in self-MHC

Phagocytes Monocyte Macrophage Dendritic cell Neutrophil Eosinophil Mast cell Basophil

Immunity and Cancer Ag on surface change Shed ag into circulatory system Prompt action from cT cells, NK cells and macrophages Tumours develop when immune surveillance breaks down/overwhelmed

Immunotherapy Antibodies couples with toxins, drugs, radioactive substances Block receptors

CANCER DRUGS

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

Hormone therapy Herceptin – Trastuzumab – Amplification of HER2 – Anti-c-erbB2) Gefitinib or erlotinib – Activating mutation in the SGFR or HER1 Rituximab – Anti CD20 – Lymphoma