© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 1 Human Disease Processes 1: Carcinogenesis This lesson aims to: Describe the regulation

© Krejany and Morrison 2003© Krejany and Morrison 2003HDP1 Carcinogenesis HDP1 Carcinogenesis

Lesson 10 - Overhead Lesson 10 - Overhead 11

Human Disease Processes 1:Human Disease Processes 1:CarcinogenesisCarcinogenesis

This lesson aims to:This lesson aims to: Describe the regulation of the cell cycle Describe the regulation of the cell cycle Discuss the process of neoplasiaDiscuss the process of neoplasia Describe the causes of carcinogenesis and DNA Describe the causes of carcinogenesis and DNA

mutationmutation Describe the process of oncogenesisDescribe the process of oncogenesis Compare and contrast benign and malignant Compare and contrast benign and malignant

neoplasiasneoplasias Describe the process of metastasisDescribe the process of metastasis



Overview of the Normal Cell CycleOverview of the Normal Cell Cycle

Each cell has a basic cell cycle of growth and Each cell has a basic cell cycle of growth and replicationreplication

The cell cycle has distinct phases including The cell cycle has distinct phases including mitosis where it reproduces to a daughter cellmitosis where it reproduces to a daughter cell

These phases are strictly regulated to ensure These phases are strictly regulated to ensure cells divide at periods appropriate to cellular size cells divide at periods appropriate to cellular size and DNA statusand DNA status

Cell replication is largely controlled by chemical Cell replication is largely controlled by chemical factors (eg hormones) in the microenvironment factors (eg hormones) in the microenvironment which either stimulate or inhibit cell replicationwhich either stimulate or inhibit cell replication



The Cell CycleThe Cell Cycle

Ssynthesis

G1Cell growth

G2Cell growthM

mitosisG0Resting state

DifferentiationNo further division




Different cells complete the cell cycle in different Different cells complete the cell cycle in different timestimes

Continuously dividing cells such as epithelial cells Continuously dividing cells such as epithelial cells complete the cell cycle in a few hourscomplete the cell cycle in a few hours

Quiescent (stable) cells have low levels of Quiescent (stable) cells have low levels of replication; cells can spend months on one cell replication; cells can spend months on one cell cyclecycle

Non-dividing cells have left the cell cycle and Non-dividing cells have left the cell cycle and cannot further divide eg neurons, skeletal musclecannot further divide eg neurons, skeletal muscle




Control over the cell cycle is genetic and Control over the cell cycle is genetic and orchestrated via DNA. orchestrated via DNA.

Cells have varying degrees of specialisation and Cells have varying degrees of specialisation and differentiation related to the cells functiondifferentiation related to the cells function

When cells become disorganised or When cells become disorganised or undifferentiated or their growth is uncontrolled undifferentiated or their growth is uncontrolled their specialisation is lost as they lose control their specialisation is lost as they lose control over the cell cycleover the cell cycle



The Normal Cell Cycle and AgeingThe Normal Cell Cycle and Ageing

Different cells have different life spansDifferent cells have different life spans Cellular aging occurs naturally and cells Cellular aging occurs naturally and cells

eventually enter apoptosiseventually enter apoptosis The processes of cellular aging and the The processes of cellular aging and the

subsequent loss of cell control systems are not subsequent loss of cell control systems are not fully understoodfully understood

Current theories focus on the presence of a Current theories focus on the presence of a programmed number of cell cycles (different for programmed number of cell cycles (different for different cells) after which programmed cell death different cells) after which programmed cell death occursoccurs

Normal mammalian cells are only able to undergo Normal mammalian cells are only able to undergo a finite number of cell divisionsa finite number of cell divisions



MutationsMutations

If the DNA is altered in the parent cell this is passed If the DNA is altered in the parent cell this is passed onto the daughter cellonto the daughter cell

This alteration or error in DNA replication is called a This alteration or error in DNA replication is called a mutationmutation

Changes in DNA (mutation) can alter cell structure Changes in DNA (mutation) can alter cell structure and function or cause cell deathand function or cause cell death

Mutations arise spontaneously during mitosis or can Mutations arise spontaneously during mitosis or can be induced through exposure to DNA damaging be induced through exposure to DNA damaging agentsagents

Rapid rates of mitosis increase the chance of errors or Rapid rates of mitosis increase the chance of errors or mutations occurringmutations occurring

Seriously affected cells usually die or are destroyed by Seriously affected cells usually die or are destroyed by the immune systemthe immune system



The Causes of CancerThe Causes of Cancer

Damage to DNA occurs:Damage to DNA occurs: as a result of spontaneous mutation during as a result of spontaneous mutation during

mitosismitosis exposure to chemicalsexposure to chemicals exposure to virusesexposure to viruses exposure to radiationexposure to radiation exposure to other hazards such as trauma exposure to other hazards such as trauma

which increases mitotic rate and increases which increases mitotic rate and increases the risk of errors during DNA replication the risk of errors during DNA replication



Aetiology of Tumour FormationAetiology of Tumour Formation

Results from a sequence of changes over a Results from a sequence of changes over a relatively long period of timerelatively long period of time

Can be from a combination of factors or repeated Can be from a combination of factors or repeated exposure to a single factorexposure to a single factor

Some cancers have well established risk factors Some cancers have well established risk factors such as lung cancer and smokingsuch as lung cancer and smoking

Often difficult to determine aetiology as multiple Often difficult to determine aetiology as multiple factors are involved and it takes many years to factors are involved and it takes many years to develop develop

Most mutations that arise occur in somatic genes Most mutations that arise occur in somatic genes and therefore not passed onto offspring however and therefore not passed onto offspring however there are a few cancers where an inherited there are a few cancers where an inherited genetic predisposition occursgenetic predisposition occurs



CarcinogenesisCarcinogenesis

The generation of cancerous cells from normal The generation of cancerous cells from normal cells (tumour formation)cells (tumour formation)

Results in damage to DNA and loss of cell cycle Results in damage to DNA and loss of cell cycle controlcontrol

Loss of cellular control results in a neoplasm (new Loss of cellular control results in a neoplasm (new growth)growth)

Neoplastic cells are transformed (altered) as they Neoplastic cells are transformed (altered) as they continue to replicate ignoring normal cellular continue to replicate ignoring normal cellular controlscontrols

In common medical terminology a neoplasm is In common medical terminology a neoplasm is often referred to as a tumouroften referred to as a tumour



Tumour FormationTumour Formation

Carcinogenesis involves three step process:Carcinogenesis involves three step process: Initiating factors- Initiating factors-

– cause the first irreversible change to the DNAcause the first irreversible change to the DNA Promoters- Promoters-

– later exposure causes additional damage to later exposure causes additional damage to the DNA the DNA

Additional changes to DNA and cell Additional changes to DNA and cell structure result in malignancy structure result in malignancy



Initiating FactorsInitiating Factors

The cell cycle normally has molecular checkpoints The cell cycle normally has molecular checkpoints to prevent uncontrolled replicationto prevent uncontrolled replication

Initiating factors in carcinogenesis cause damage Initiating factors in carcinogenesis cause damage to one or more of these checkpointsto one or more of these checkpoints

This damage is the first irreversible damage to This damage is the first irreversible damage to the DNA of the cellthe DNA of the cell

Can be genetic or environmental exposureCan be genetic or environmental exposure

This initial change does not result in an active This initial change does not result in an active neoplasia but instead generates an oncogeneneoplasia but instead generates an oncogene



OncogenesOncogenes

An oncogene is the term given to a gene that has An oncogene is the term given to a gene that has been mutated to facilitate neoplastic growthbeen mutated to facilitate neoplastic growth

These are divided into two main types:These are divided into two main types:– Loss of function of a tumour suppressor geneLoss of function of a tumour suppressor gene– Overactivity through the activation of a proto-Overactivity through the activation of a proto-

oncogeneoncogene



Tumour Suppressor GenesTumour Suppressor Genes

proteins called tumour suppressor genes can act to prevent rapid proteins called tumour suppressor genes can act to prevent rapid mitosis from taking placemitosis from taking place

Tumour suppressor genes can, as a normal function, induce Tumour suppressor genes can, as a normal function, induce apoptosis of the cell to prevent the damage from being passed on apoptosis of the cell to prevent the damage from being passed on to the daughter cellto the daughter cell

A single mutation in a tumour suppressor gene is usually A single mutation in a tumour suppressor gene is usually insufficient to initiate oncogene formation. A second mutation has insufficient to initiate oncogene formation. A second mutation has to occur in the second copy of the gene to occur in the second copy of the gene

When these genes are damaged there is a loss of control over the When these genes are damaged there is a loss of control over the cell cyclecell cycle

When the function of tumour suppressor proteins is overcome When the function of tumour suppressor proteins is overcome through damage to the corresponding DNA this can be one way in through damage to the corresponding DNA this can be one way in which neoplasia begins to be initiatedwhich neoplasia begins to be initiated

One of the most common tumour suppressor genes is TP53 and is One of the most common tumour suppressor genes is TP53 and is found to be damaged in over 50% of all human cancersfound to be damaged in over 50% of all human cancers



Proto-oncogenesProto-oncogenes

Mutations or the presence of additional copies of these Mutations or the presence of additional copies of these genes results in overactivitygenes results in overactivity

This overactivity is due to the fact that expression of This overactivity is due to the fact that expression of these genes mimics persistent growth factor these genes mimics persistent growth factor stimulationstimulation

Often proto-oncogenes involved in cell signalling or Often proto-oncogenes involved in cell signalling or receptorsreceptors

In animals a number of proto-genes are caused by In animals a number of proto-genes are caused by retroviruses which carry activated oncogenes but this retroviruses which carry activated oncogenes but this is not common in human cancersis not common in human cancers

Some human cancers are caused by viruses that Some human cancers are caused by viruses that induce mutation in the host cell- HPV ( human induce mutation in the host cell- HPV ( human papilloma virus, herpes virus 8, and EBV (Epstein Barr papilloma virus, herpes virus 8, and EBV (Epstein Barr virus) virus)



Summary of InitiationSummary of Initiation

Damage has occurred to the DNADamage has occurred to the DNA

This damage can result naturally or This damage can result naturally or through exposure to damaging chemicals, through exposure to damaging chemicals, radiations or infectionsradiations or infections

This damage activates a proto oncogene This damage activates a proto oncogene or inactivates a tumour suppressor gene or inactivates a tumour suppressor gene resulting in decreased ability to control the resulting in decreased ability to control the rate of mitosis and the cell cyclerate of mitosis and the cell cycle



PromotionPromotion

Exposure to promoters results in further changes to Exposure to promoters results in further changes to the DNAthe DNA

Results in less differentiation and an increased mitosis Results in less differentiation and an increased mitosis raterate

Dysplasia or anaplasia may be present Dysplasia or anaplasia may be present Examples of promoters include:Examples of promoters include:

– Hormones (eg oestrogen)Hormones (eg oestrogen)– Chemicals (eg food additives)Chemicals (eg food additives)

The prolonged time interval and multiple factors The prolonged time interval and multiple factors involved complicate efforts in identification of involved complicate efforts in identification of promoters and there specific relationship to cancer promoters and there specific relationship to cancer typestypes

Continued exposure and changes in DNA result in a Continued exposure and changes in DNA result in a malignant tumourmalignant tumour



First Hit-InitiationIrreversible damage

Generation of oncogeneUV, viral, radiation,

inherited, spontaneous mutation

Second Hit-PromotionExposure to promotersHormones, chemicals,

Industrial factors

Third Hit-CancerContinued exposure to

Damaging stimuli

NEOPLASIA



Benign and Malignant TumoursBenign and Malignant Tumours

Benign: Benign: – not recurrentnot recurrent– Favorable for recoveryFavorable for recovery

Malignant:Malignant:– Tending to become progressively worse Tending to become progressively worse

and to result in deathand to result in death– Having the properties of anaplasia, Having the properties of anaplasia,

invasiveness and metastasisinvasiveness and metastasis



Characteristic of Benign and Characteristic of Benign and Malignant TumoursMalignant Tumours

BENIGNBENIGN Usually consist of Usually consist of

undifferentiated cells that undifferentiated cells that reproduce at a faster rate reproduce at a faster rate than normalthan normal

Often encapsulatedOften encapsulated Expands but does not Expands but does not

spreadspread Tissue damage results Tissue damage results

from compression of from compression of adjacent structures such adjacent structures such as blood vesselsas blood vessels

Not life threatening unless Not life threatening unless in delicate location such as in delicate location such as brain where compression brain where compression could cause serious could cause serious damagedamage

MALIGNANTMALIGNANT Undifferentiated and non-Undifferentiated and non-

functional cellsfunctional cells Cells reproduce more Cells reproduce more

rapidly than normalrapidly than normal Tumour cells infiltrate or Tumour cells infiltrate or

spread to surrounding spread to surrounding tissuetissue

Tumour cells detach or Tumour cells detach or break off and spread to break off and spread to other organs and tissuesother organs and tissues

Can metastasise- spread to Can metastasise- spread to other parts of the body via other parts of the body via the blood and lymphatics the blood and lymphatics





MetastasisMetastasis

Defined as the spread of the tumour to Defined as the spread of the tumour to distant sites by the blood or lymphaticsdistant sites by the blood or lymphatics

Leads to the development of secondary Leads to the development of secondary implants (metastases) discontinuous with implants (metastases) discontinuous with the primary tumourthe primary tumour

Only a few tumour cells survive transfer Only a few tumour cells survive transfer but it only takes a few to start a new but it only takes a few to start a new tumourtumour

One or more methods of spread depending One or more methods of spread depending on the characteristics of the specific on the characteristics of the specific tumourtumour



Mechanisms of MetastasisMechanisms of Metastasis

Invasion-Invasion- – local spread where tumour grows into adjacent tissue local spread where tumour grows into adjacent tissue

destroying normal cellsdestroying normal cells Metastasis-Metastasis-

– spread to different sites via blood or lymphatics spread to different sites via blood or lymphatics – usually to lymph node first then to blood and body usually to lymph node first then to blood and body

organsorgans Seeding-Seeding-

– spread of cancer cells in body fluids or along spread of cancer cells in body fluids or along membranes usually in body cavitiesmembranes usually in body cavities

– Production of secondary tumours which grow and spreadProduction of secondary tumours which grow and spread– Leads to development of multiple tumours Leads to development of multiple tumours



SeedingSeeding



MetastasisMetastasis

Liver with multiple metastases



Human Disease Processes 1:Human Disease Processes 1:CarcinogenesisCarcinogenesis

By the end of this lesson students should be able By the end of this lesson students should be able to:to:

Understand the cell cycle and how it is regulatedUnderstand the cell cycle and how it is regulated Understand the process of neoplasiaUnderstand the process of neoplasia Understand the causes of carcinogenesisUnderstand the causes of carcinogenesis Understand the process of oncogenesisUnderstand the process of oncogenesis Understand the difference between benign and Understand the difference between benign and

malignant neoplasiamalignant neoplasia Understand the process of metastasisUnderstand the process of metastasis

Documents

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 1 Human Disease Processes 1: Carcinogenesis This lesson aims to: Describe the regulation