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Flashcards in Neoplasia 2 Deck (28):
1

MARKERS OF DIFFERENTIATION

1. CELL MORPHOLOGY- usually lost in neoplastic cells; any recognisable gross/histologic features are lost.
2. CELL FUNCTION- usually lost in malignant tumours. Regulatory mechanisms are lost.
3. CELL BEHAVIOUR- increasingly aggressive with loss of differentiation and function.

2

CELL MORPHOLOG- HISTOLOGICAL FEATURES OF MALIGNANCY

Neoplastic cells have a LARGE nucleus with a prominent nucleolus- open faced/vesicular nucleus.

Anisocytosis and anisokaryosis are seen.

May see multiple NUCLEOLI within cells.

Neoplastic cells show increased mitosis and abnormal mitotic figures- aysmmetric etc.

'Bizarre' cells.

3

RATE OF GROWTH IN NORMAL CELLS

There is a baseline population of stem cells, which can undergo differentiation to cells with a specific function.
They can proliferate, or undergo apoptosis.

Proliferation in normal tissues follows the cell cycle G1 -> S -> G2 -> M, with appropriate checkpoints (G1-S and G2-M).
There is a balance between permanent, stable and labile cells.
Cells can enter G0 where they are quiescent.

4

RATE OF GROWTH IN TUMOUR CELLS

PROLIFERATIVE ACTIVITY:
-Tumour cells spend little time in G0
-They do not undergo cell cycle arrest
-Checkpoints do not work properly- DNA damage is not detected, so damaged cells can go on to divide.

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MECHANISMS OF TUMOUR GROWTH

1. Altered proliferation potential:
-Cell cycle can be SHORTENED.
-Quiescent cells can be converted to DIVIDING cells.

2. NEOPLASTIC CELLS:
-Escape normal limits of cell division
-Are independent of external growth factors.
-Are not susceptible to apoptotic factors- they avoid apoptosis.

3. REEXPRESSION OF TELOMERASE- telomerase is an enzyme allowing replication and expansion of telomeres. It is important in immortality.

6

TELOMERASE

Embryonic cells express telomerase, which allows telomere replication.

The extreme ends of DNA templates are not replicated on cell division (telomeres)- very short telomeres mean that division cannot happen.

Neoplastic cells often REGAAIN THE ABILITY TO EXPRESS TELOMERASE. This allows indefinite replication- immortality.

7

MECHANISMS OF TUMOUR GROWTH- GROWTH MODULATION

In normal tissue, growth modulation is seen due to a constant transfer of information between cells.
stimulatory factors/inhibitory factors/hormones

Neoplastic cells LOSE DEPENDENCE.
They are not responsive to the needs of the whole organism.
The DRIVE THEIR OWN REPLICATION.

8

APOPTOSIS

Many neoplastic cells are resistant to apoptosis.
FUNCTIONAL INACTIVATION OF p53 GENE IS SEEN.
The overall growth rate is increased.

This activates survival signalling pathways.
This protects the neoplastic cells- they are independent of exogenous survival factors.

Death factor signalling pathways are INACTIVATED, allowing evasion of apoptosis and increase in cell number.

9

NORMAL APOPTOSIS

Normally, apoptosis allows tissue homeostasis.

Pathologically induced apoptosis:
-Withdrawal of survival factors
-Binding of death factors (Fas ligand, TNF-a)
-Hypoxia
-DNA damage (p53 gene)
-Cytotoxic immune cells (T lymphocytes, NK cells)
-CASPASES (intracellular proteases) are final effectors.

10

MORPHOLOGICAL MARKERS OF APOPTOSIS

1. Margination of chromatin
2. Condensation and fragmentation of nucleus.
3. Condensation of cells, with preservation of organelles (membrane bound remnants do not alert immune system)

Tingible body macrophages are often seen histologically with apoptosis; apoptotic cells and cell fragments are phagocytosed by macrophages.

11

TUMOUR GROWTH

A high number of cells are proliferating. There are some control mechanisms.

As the tumour cell population expands, a higher percentage of cells leave the replicative pool by reversion to G0, differentiation, and death.

12

CARCINOGENESIS

Tumours arise from clonal growth of cells which have mutations in four classes of genes:
1. Cell growth regulators- PROTOONCOGENES (increase tumour growth)
2. Cell growth regulators- TUMOUR SUPPRESSOR GENES (decrease tumour growth normally)
3. APOPTOSIS REGULATORS- may respond to p53.
4. DNA REPAIR REGULATORS.

Multiple mutations on multiple genes are generally required for carcinogenesis (malignant tumour formation)

13

DETERMINATION OF TUMOUR GROWTH

Tumour growth is a balance between PROLIFERATION, DIFFERENTIATION, and CELL DEATH BY APOPTOSIS.

14

SUBCLONES

Provide tumour heterogeneity.
Tumour cell variants are clonally expanded to form a solid malignancy.
The variants that survive may have characteristics that aid tumour growth eg. nonantigenic, invasive, metastatic, require fewer growth factors.

15

LATENCY PERIOD

Tumours have a latency period. Often by the time a solid tumour becomes clinically apparent, it is already serious.
There is rapid progression of transformed cells.
1g = smallest detectable clinical mass, seen after 30 doublings of tumour cell.
1kg = largest mass compatible with life in most species. Seen after 10 doublings of 1g mass. (10^9 to 10^12 cells)

16

OTHER IMPORTANT FACTORS IN TUMOUR GROWTH

-Blood supply
-Extrinsic growth regulating factors eg. hormones
-Efficacy of host immune response
-Emergence of subpopulations of aggressive tumour cells (subclones of variant cells)

17

TUMOUR PROGRESSION

Original transformed cell undergoes several mutations, leading to new subclones.
With progression, the tumour is enriched with 'nastier' variants.
eg. More aggressive, more evasive of host immune system.
Variant subclones give the tumour HETEROGENEITY.

18

SIX HALLMARKS OF CANCER

1. Self sufficiency in growth signals
2. Insensitivity to antigrowth signals
3. Tissue invasion and metastasis
4. Limitless replicative potential
5. Sustained angiogenesis
6. Evasion of apoptosis.

19

TUMOUR EVOLUTION

STEPWISE TUMOUR DEVELOPMENT:
1. Initiation
2. Promotion
3. Progression

20

INITIATION

IRREVERSIBLE genetic change is introduced in to basal cells of skin by an initiator.
This initiator is a chemical or physical (eg. UV radiation) carcinogen.
DNA lesions are introduced.
DNA lesion mispairing during subsequent replication FIXES the mutation.

INITIATED CELLS are morphologically normal and can possibly remain quiescent for years.

21

PROMOTION

OUTGROWTH OF STIMULATED CELLS IN RESPONSE TO SELECTED STIMULI.
-Promoters alter gene expression.
-Initiated cells have a growth advantage.
-Promotion does not involve mutation, so it is reversible.
-A PRENEOPLASTIC LESION/BENIGN TUMOUR is produced.

22

PROGRESSION

BENIGN becomes MALIGNANT becomes METASTATIC.
Involves genetic (irreversible) and epigenetic changes.
Increasingly malignant subclones are selected.

23

EPIGENETIC CHANGES

These are reversible, heritable changes in gene expression that occur without mutation.
eg. Hypermethylation of promoter sequence -> stops tumour suppressor genes.

24

MECHANISMS OF INVASION

1. CELLS DETACH FROM MASS
2. CELLS ATTACH TO BASEMENT MEMBRANE
3. BASEMENT MEMBRANE DEGRADED
4. CELLS PENETRATE BASEMENT MEMBRANE AND ENTER ECM

25

1. CELLS DETACH FROM MASS

Desmosomes dismantled and cadherin function lost.
This makes cells more mobile.
Intracellular junctions are loosened.

26

2. CELLS ATTACH TO BASEMENT MEMBRANE

Cells attach via laminin receptors and secrete proteolytic enzymes:
-Type IV collagenases
-Plasminogen activator
These destroy the basement membrane enzymatically to allow the cell to enter the ECM.

27

3. BASEMENT MEMBRANE DEGRADED

Type IV collagen is cleaved by Type IV collagenase and plasmin degrades plasma proteins.

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4. CELLS PENETRATE BASEMENT MEMBRANE AND ENTER ECM

Alteration of cytoskeleton allows entry to ECM.
Contact with ECM components is established- fibronectin, laminin, collagen etc.

The initial mechanisms of invasion are very similar to the initial mechanisms of metastasis.