© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 1 Human Disease Processes 1: Carcinogenesis This lesson aims to:  Describe the regulation of the cell cycle  Discuss the process of neoplasia  Describe the causes of carcinogenesis and DNA mutation  Describe the process of oncogenesis  Compare and contrast benign and malignant neoplasias  Describe the process of metastasis

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 2 Overview of the Normal Cell Cycle  Each cell has a basic cell cycle of growth and replication  The cell cycle has distinct phases including mitosis where it reproduces to a daughter cell  These phases are strictly regulated to ensure cells divide at periods appropriate to cellular size and DNA status  Cell replication is largely controlled by chemical factors (eg hormones) in the microenvironment which either stimulate or inhibit cell replication

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 3 The Cell Cycle S synthesis G1 Cell growth G2 Cell growth M mitosis G0 Resting state Differentiation No further division

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 4 Overview of the Normal Cell Cycle  Different cells complete the cell cycle in different times  Continuously dividing cells such as epithelial cells complete the cell cycle in a few hours  Quiescent (stable) cells have low levels of replication; cells can spend months on one cell cycle  Non-dividing cells have left the cell cycle and cannot further divide eg neurons, skeletal muscle

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 5 Overview of the Normal Cell Cycle  Control over the cell cycle is genetic and orchestrated via DNA.  Cells have varying degrees of specialisation and differentiation related to the cells function  When cells become disorganised or undifferentiated or their growth is uncontrolled their specialisation is lost as they lose control over the cell cycle

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 6 The Normal Cell Cycle and Ageing  Different cells have different life spans  Cellular aging occurs naturally and cells eventually enter apoptosis  The processes of cellular aging and the subsequent loss of cell control systems are not fully understood  Current theories focus on the presence of a programmed number of cell cycles (different for different cells) after which programmed cell death occurs  Normal mammalian cells are only able to undergo a finite number of cell divisions

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 7 Mutations  If the DNA is altered in the parent cell this is passed onto the daughter cell  This alteration or error in DNA replication is called a mutation  Changes in DNA (mutation) can alter cell structure and function or cause cell death  Mutations arise spontaneously during mitosis or can be induced through exposure to DNA damaging agents  Rapid rates of mitosis increase the chance of errors or mutations occurring  Seriously affected cells usually die or are destroyed by the immune system

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 8 The Causes of Cancer Damage to DNA occurs:  as a result of spontaneous mutation during mitosis  exposure to chemicals  exposure to viruses  exposure to radiation  exposure to other hazards such as trauma which increases mitotic rate and increases the risk of errors during DNA replication

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 9 Aetiology of Tumour Formation  Results from a sequence of changes over a relatively long period of time  Can be from a combination of factors or repeated exposure to a single factor  Some cancers have well established risk factors such as lung cancer and smoking  Often difficult to determine aetiology as multiple factors are involved and it takes many years to develop  Most mutations that arise occur in somatic genes and therefore not passed onto offspring however there are a few cancers where an inherited genetic predisposition occurs

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 10 Carcinogenesis  The generation of cancerous cells from normal cells (tumour formation)  Results in damage to DNA and loss of cell cycle control  Loss of cellular control results in a neoplasm (new growth)  Neoplastic cells are transformed (altered) as they continue to replicate ignoring normal cellular controls  In common medical terminology a neoplasm is often referred to as a tumour

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 11 Tumour Formation Carcinogenesis involves three step process:  Initiating factors- –cause the first irreversible change to the DNA  Promoters- –later exposure causes additional damage to the DNA  Additional changes to DNA and cell structure result in malignancy

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 12 Initiating Factors  The cell cycle normally has molecular checkpoints to prevent uncontrolled replication  Initiating factors in carcinogenesis cause damage to one or more of these checkpoints  This damage is the first irreversible damage to the DNA of the cell  Can be genetic or environmental exposure  This initial change does not result in an active neoplasia but instead generates an oncogene

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 13 Oncogenes  An oncogene is the term given to a gene that has been mutated to facilitate neoplastic growth  These are divided into two main types: –Loss of function of a tumour suppressor gene –Overactivity through the activation of a proto- oncogene

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 14 Tumour Suppressor Genes  proteins called tumour suppressor genes can act to prevent rapid mitosis from taking place  Tumour suppressor genes can, as a normal function, induce apoptosis of the cell to prevent the damage from being passed on to the daughter cell  A single mutation in a tumour suppressor gene is usually insufficient to initiate oncogene formation. A second mutation has to occur in the second copy of the gene  When these genes are damaged there is a loss of control over the cell cycle  When the function of tumour suppressor proteins is overcome through damage to the corresponding DNA this can be one way in which neoplasia begins to be initiated  One of the most common tumour suppressor genes is TP53 and is found to be damaged in over 50% of all human cancers

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 15 Proto-oncogenes  Mutations or the presence of additional copies of these genes results in overactivity  This overactivity is due to the fact that expression of these genes mimics persistent growth factor stimulation  Often proto-oncogenes involved in cell signalling or receptors  In animals a number of proto-genes are caused by retroviruses which carry activated oncogenes but this is not common in human cancers  Some human cancers are caused by viruses that induce mutation in the host cell- HPV ( human papilloma virus, herpes virus 8, and EBV (Epstein Barr virus)

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 16 Summary of Initiation  Damage has occurred to the DNA  This damage can result naturally or through exposure to damaging chemicals, radiations or infections  This damage activates a proto oncogene or inactivates a tumour suppressor gene resulting in decreased ability to control the rate of mitosis and the cell cycle

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 17 Promotion  Exposure to promoters results in further changes to the DNA  Results in less differentiation and an increased mitosis rate  Dysplasia or anaplasia may be present  Examples of promoters include: –Hormones (eg oestrogen) –Chemicals (eg food additives)  The prolonged time interval and multiple factors involved complicate efforts in identification of promoters and there specific relationship to cancer types  Continued exposure and changes in DNA result in a malignant tumour

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 18 First Hit-Initiation Irreversible damage Generation of oncogene UV, viral, radiation, inherited, spontaneous mutation Second Hit-Promotion Exposure to promoters Hormones, chemicals, Industrial factors Third Hit-Cancer Continued exposure to Damaging stimuli NEOPLASIA

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 19 Benign and Malignant Tumours  Benign: –not recurrent –Favorable for recovery  Malignant: –Tending to become progressively worse and to result in death –Having the properties of anaplasia, invasiveness and metastasis

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 20 Characteristic of Benign and Malignant Tumours BENIGN  Usually consist of undifferentiated cells that reproduce at a faster rate than normal  Often encapsulated  Expands but does not spread  Tissue damage results from compression of adjacent structures such as blood vessels  Not life threatening unless in delicate location such as brain where compression could cause serious damage MALIGNANT  Undifferentiated and non- functional cells  Cells reproduce more rapidly than normal  Tumour cells infiltrate or spread to surrounding tissue  Tumour cells detach or break off and spread to other organs and tissues  Can metastasise- spread to other parts of the body via the blood and lymphatics

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 21

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 22 Metastasis  Defined as the spread of the tumour to distant sites by the blood or lymphatics  Leads to the development of secondary implants (metastases) discontinuous with the primary tumour  Only a few tumour cells survive transfer but it only takes a few to start a new tumour  One or more methods of spread depending on the characteristics of the specific tumour

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 23 Mechanisms of Metastasis  Invasion- –local spread where tumour grows into adjacent tissue destroying normal cells  Metastasis- –spread to different sites via blood or lymphatics –usually to lymph node first then to blood and body organs  Seeding- –spread of cancer cells in body fluids or along membranes usually in body cavities –Production of secondary tumours which grow and spread –Leads to development of multiple tumours

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 24 Seeding

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 25 Metastasis Liver with multiple metastases

© Krejany and Morrison 2003 HDP1 Carcinogenesis Lesson 10 - Overhead 26 Human Disease Processes 1: Carcinogenesis By the end of this lesson students should be able to:  Understand the cell cycle and how it is regulated  Understand the process of neoplasia  Understand the causes of carcinogenesis  Understand the process of oncogenesis  Understand the difference between benign and malignant neoplasia  Understand the process of metastasis