Emily Hodgson

Hallmarks of CancerImmunology

DrugsMetastasis

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