Outline of disease process 1-2

Learning Outcomes:

• Describe the principles of ‘staging’ in cancer.

• Explain the importance of genetic changes in cancer.

• Describe modalities of therapy currently available

-What is Cancer PT1

Disease of the genome

Cancer is a disease of the genome occurring as a result of unregulated cell growth

UK Statistics: •1 IN 2 PEOPLE BORN AFTER 1960 WILL DEVELOP CANCER IN THEIR LIFETIME

•A NEW DIAGNOSIS IS MADE EVERY 2 MINUTES

•CANCER CAUSES MORE THAN 1 IN 4 OF ALL DEATHS

Types of cancer cells

-epithelial cells

squamous (flat)

cuboidal

columnar

85% of cancers

Carcinomas

-mesoderm cells

bone

muscle

Sarcomas

-glandular cells

glandular cells e.g. breast, oesophagus, lung

Adenocarcinomas

The hallmarks of cancer

Sustaining proliferative signalling

GROWTH SIGNAL AUTONOMY = LACK OF REGULATION OF GROWTH FACTOR SIGNALLING

NORMAL CELLS REQUIRE AN EXTERNAL GROWTH SIGNAL TO DIVIDE

CANCER CELLS BYPASS NORMAL GROWTH FACTOR PATHWAYS LEADING TO UNREGULATED GROWTH

OCCURS AS RESULT OF ACQUIRED MUTATIONS

* MUTATION = ANY CHANGE IN DNA SEQUENCE OF A CELL

Evasion of inhibitory growth signals

Inhibitory growth signals maintain homeostasis within the tissue

Cells are not continuously dividing as a result

Cancer cells ignore these signals - enabled by acquired mutations and gene silencing

* Gene silencing = interruption or suppression of gene expression at transcriptional or translational level

Avoiding Immune Destruction

Immune system can recognise and remove cancer cells

However some cancer cells are able to avoid detection by not initiating an immune response

cancer cells hijack immune checkpoints and modulate immune response via Sting

What is an immune checkpoint? built in control mechanisms that maintain self tolerance during an immune response

Unlimited Replicative Potential

Normal cells have a counting device (telomeres) that monitor and adjust the number of cell doublings

Once cell numbers have reached this finite number they enter senescence

Cancer cells maintain telomere length - replication overdrive begins

Tumour Promoting Inflammation

All tumours have inflammatory immune cells

Inflammatory cells provide growth factors that promote angiogenesis and invasion

Cell death by necrosis gives rise to inflammation4

Necrotic cells release bioactive regulatory factors IL - 1

Inflammatory cells can release radical oxygen species that give rise to mutations

Invasion and Metastasis

Cancer cells develop the ability to migrate to other areas

Formation of metastasis is a major cause of death in cancer

Mutations within the genome may affect the enzymes involved in cell- cell adhesion e.g. E-cadherin

Angiogenesis

Creation of new blood vessels by the tumour

Provides supply of oxygen and nutrients

New blood vessels are friable leading to tumour cell escape

Many drugs have been developed to target angiogenesis

Genomic Instability

Alterations in DNA lead to instability

Faulty DNA repair pathways or hereditary predisposition contribute to the development of DNA alterations (mutations)

Single point and large chromosomal abnormalities can be found in tumour DNA

Accumulation of mutations over a period time explains why cancer is more frequent in the ageing population

Evasion of cell death

Normal cells undergo cell death in response to extracellular factors or Physical damage

Cell death is either regulated (programmed)=Apoptosis or unregulated = Necrosis

Cancer cells evade death as a result of mutations within the Apoptosis pathway

Caspases play central role in apoptosis therefore mutations in this family will allow cancer cells to pass through unchecked

Cell death occurs in physiological conditions e.g. Menstruation/ embryogenesis and in pathological conditions e.g. DNA damage

Deregulating Cell Energetics

This is reprogramming energy metabolism

Aerobic glycolysis - used by cancer cells to redirect energy

Allows cancer cell to fuel cell growth and division

PET scanning was developed using FDG (glucose analogue) to trace the activity of cancer cells throughout the body

Genes

somatic mutations - most common and is acquired

Germline mutations - hereditary

Gene = composed of DNA, everyone has 2 copies of each gene

All cells have the ability to become oncogenic

Oncogene = mutated gene giving rise to tumour formation in a dominant fashion

Tumour suppressor gene = inhibits tumour formation

Mutations can occur within tumour suppressor genes - usually recessive

The Cell Cycle

G0- Resting phase

G1 - Cells grow larger and copy organelles

S - Cells make a complete copy of DNA

G2 - Further cell growth

M - 4 phases of mitosis

Invasive Cancer-PT2

Tumour Spread

• Organs are well defined by basement membranes

• Basement membrane is made up of extracellular matrix proteins

Theories of Spread- en route theory

-seed and soil

-pre- metastatic niche

Extracellular Matrix

Extracellular Matrix (ECM) - complex meshwork of proteins and carbohydrates

Major component of ecm is collagen/proteoglycans - gives structural integrity to tissues

ECM is directly connected to the cells it surrounds- it is the interface between the cell and other surrounding structures like blood vessels

It is by penetration of this matrix that cancer cells can move into the blood stream and ultimately around the body

Cadherins are a type of cell adhesion molecule (cam) - these bind cells to each other and the ECM

E -cadherin is involved in cell-cell adhesion of epithelial cells

Epithelial cancers frequently show downregulation and mutation of e-cahderin

Mechanisms of Metastasis

Spread of tumour cells from the primary tumour is not clonal

Primary tumour is composed of cells that are subcloncal

2 Different Mechanisms >monoclonal >polyclonal

2 Different Patterns >Linear >Branched

Epithelial Mesenchymal Transition (EMT)

Cells must acquire migratory characteristics

EMT is the conversion of closely connected epithelial cells becoming independent mesenchymal cells with the ability to move and invade their local environment

This is a reversible process

EMT usually occurs in embryogenesis however this also occurs in cancer metastasis

Journey to metastasis: invasion

EMT begins with signals from tumour stroma (HGF, TGF-beta) stimulate kinase receptors (EFGR) & trigger MAPK pathway

Multiple components involved in invasion

Cell Adhesion Molecules - Cadherins ( calcium dependent transmembrane proteins) & Catenins (protein inducing gene expression)

Integrins - enable cells to “break free” becoming mobile

Proteases - make the pathway through ECM, Matrix Metalloproteins contribute to loss of cell junctions

Journey to metastasis: intravasation

Intravasation = entry into blood or lymphatics

Tumour cell attaches to stromal side of basement membrane

MMPs and serin proteases help to degrade basement membrane

Tumour cell passes between the endothelial cells and off into the bloodstream (transendothelial migration)

Journey to metastasis: transport

Tumour cells in bloodstream = circulating tumour cells (CTCs)

Solo travellers vs. Clumps - unidirectional

Certain cancers have favoured metastatic sites - first pass organ

Journey to metastasis: extravasation

Exit of tumour cells from bloods vessels into distant tissues

Tumour cells become trapped in capillaries

Reverse of intravasation

Endothelial side of blood vessel - degrade basement membrane -migrate into stroma

E- Selectin is a calcium dependent receptor which enables attachment of the cancer cell to the endothelium surface of blood vessels and passage through the endothelium (transendothelial migration)

Journey to metastasis: colonisation

Site of metastasis is determined by the point of extravasation but also the microenvironment

Environment must be favourable - for the tumour to grow it must create new blood vessels (angiogenesis) for nutrients and oxygen

Cells can spread but not colonise - dormant (micrometastases)

Angiogenesis

Angiogenesis = formation of new blood vessels

Angiogenic switch - dependent on inhibitors and inducers

Anti - angiogenic factors:

Angiostatin

Endostatin

Prolactin

Protein 53 (p53)

Thrombospondin 1 & 2

Pro - angiogenic factors:

VEGF

Fibroblast growth factor

Hepatocyte growth factor

Epidermal growth factor

Platelet derived growth factor

Angiogenic Inducers

VEGF is the Star player ** (vascular endothelial growth factor)

VEGF family = A -D and placental growth factor

Signals are transmitted via VEGF Receptors 1-3

VEGFR must be phosphorylated to be become activated

Tumour cells can also stimulate nearby cells to produce VEGF and in turn promote angiogenesis

Angiogenic Inhibitors

Inhibitors help to regulate angiogenesis

Plasminogen is cleaved to form angiostatin

Endostatin blocks the MAPK pathway thus inhibiting gene expression

Concomitant resistance - enabling growth in distant metastases

Angiogenic switch is controlled by hypoxia

Tumours create a hypoxic environment activating HIF1 alpha & beta subunit triggering VEGF

Many drugs have been developed to inhibit angiogenesis e.g TKI Afatanib