Download MBBS Cancer Lecture PPT

BIOMEDICAL IMPORTANCE

Cancers constitute the second most common cause of

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death, after cardiovascular disease, in many countries

Humans of all ages develop cancer, and a wide variety

of organs are affected

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Worldwide, the main types of cancer accounting for

mortality are those involving

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lung,stomach,colon,rectum,liver and breast

Other type of cancers that lead to death include

cervical,esophageal and prostate cancer

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The incidence of many cancers increases with age
SOME GENERAL COMMENTS ON

NEOPLASM

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Tumor
Cellular mass formed due to uncontrolled proliferation of

cells is called a tumor

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Benign Tumors
Grow very slowly
Remain localized with well defined boundary
Do not invade the surrounding tissues

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Do not spread to distant organs
Generally harmless, bad effects ,if any ,are due to pressure

effects on surrounding tissues

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Once removed, they do not recur
Malignant Tumors
Grow rapidly
Spread and invade the surrounding tissues as well as

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distant organs

Have great propensity for recurrence even after

removal

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Cancer
Cancer refers to malignant tumors only

Properties of cancerous cell

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Loss of shape

Loss of contact inhibition

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Loss of anchor support

Diminished requirement of nutrients and growth

factors

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Cancer cells become immortal

Biochemical changes in Cancer Cells
Increased DNA replication and transcription

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Alteration in expression of cell surface molecules and

cytoskeleton components

Increased rate of anaerobic glycolysis even in the

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presence of oxygen could be due to :

1. cancer cell have less no of mitochondria and have an

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isoenzyme hexokinase II that does not respond to

feedback inhibition

2.Cancer cells are also known to have different pyruvate

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kinase isoenzyme called PK-2

3.Despite angiogenesis solid tumors have localized area of

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poor blood supply leading to anoxia
Mitochondria in cancerous cell produce reactive

oxygen species which can damage the DNA

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Normal role of mitochondria in apoptosis may be

altered due to damage

Alteration in antigen expression occurs with loss of

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some old ones and appearance of new antigens

Often foetal protein are expressed such as alpha-

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fetoprotein or CEA
Etiology of Cancer

The exact etiology is not known

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No single agent or factor is responsible for

causing the cancer

Many factors are involved in causation of

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cancer such as environmental, nutritional,

genetic ,etc.
DNA damage is central to the cancer

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development

All cancers originate from a single cell which becomes abnormal

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and goes on to proliferate indefinitely to produce cancer

Even though exact mechanisms leading to continued

proliferation of a cell resulting in a tumor formation is not

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known in all cancers, it is established that DNA damage is seen

in all cancers

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1.A cancerous cell divides and produces only a cancerous cell
2.Abnormal chromosomes have been demonstrated in some

cancers e.g. CML

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3.DNA from cancer cells can transform a normal cell into

malignant cell

4.DNA damaging agents have been shown to produce mutations

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leading to cancers
Genetic damage causing cancer can be due to acquired, or

inherited mutations

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Acquired mutations occur either by errors in DNA

replication or DNA repair, and are termed replication

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mutation, or by exposure to environmental mutations

The third major class of oncogenic mutation are termed

hereditary mutation; inherited mutations are derived from

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one or both parents

These mutations are found in specific genes (e.g. tumor

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suppressor genes; DNA repair genes,cell cycle control

genes)present in germ cells

Spontaneous mutations, some of which may predispose to

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cancer, occurs at a frequency of approximately 10-7 to 10-6

per cell per generation
This rate increases rapidly in dividing cells which

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accumulate with increasing age

Oxidative stress, generated as a result of enhanced

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production of ROS ,may also be a factor in increasing

mutation rates
Carcinogens

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Many agents can cause cancers are called carcinogens

Carcinogens could be any of the following:
Physical Carcinogen
Radiations like X-rays,ultra-violet rays and -rays

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Chemical Carcinogen

Biological Carcinogen:oncogenic viruses

Physical carcinogen

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Uv rays,x-rays and gamma-rays are mutagenic and

carcinogenic

Mutations in DNA,if not corrected, are thought to

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underlie the carcinogenic effect of radiation

Additionally x-rays and gamma-rays can induce

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formation of ROS,which are also mutagenic and

probably contribute to carcinogenic effects of

radiation

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Exposure to UV radiation is common due to exposure to

sunlight, which is its main source

Ample evidence shows that UV radiation is linked to cancer

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of skin

The risk of developing a skin cancer due to UV radiation

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increases with increase frequency and intensity of

exposure, and decreases with increasing melanin content

of skin.

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Individuals who have an inherited inability to repair DNA

have increased risk of developing a malignancy

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Chemical Carcinogen
The process by which chemical substances produce

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cancers is called chemical carcinogenesis

Both inorganic and organic molecules may be carcinogenic
Direct carcinogens
Those chemical carcinogens which are highly reactive and

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interact easily with target molecule like DNA to produce

cancers are called direct carcinogens

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They do not undergo any modification in the body in order

to cause cancer

For example,met-chlorethamine and beta-propionolactone

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are direct carcinogen
Pro-carcinogens and Proximate carcinogens
Pro-carcinogens are the chemicals which as such are not

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reactive and require prior metabolism to become reactive

and produce an ultimate carcinogen which result in cancer

The intermediates formed in between are called proximate

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carcinogens

Examples : A pro-carcinogen 2 acetylamino fluorine is

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converted in to ultimate carcinogen i.e sulphate ester of N-

hydroxy-AAF by undergoing chemical reactions in the

body

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Most ultimate carcinogens are electrophiles and attack

electron rich nucleophilic molecules like DNA,RNA,proteins

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etc

Stages of Chemical Carcinogenesis

Initiation is the stage which produces the irreversible change in

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the genome of the cell resulting in one or more mutation

Such a cell is predisposed or primed to become a cancerous cell

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but is yet not a cancerous cell

Promotion
After initiation, cell undergoes the stage of promotion in which

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the cell division and malignant transformation of initiated cells is

induced

Most promoting agents act by altering the signal transduction and

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gene expression

Either of two processes is incapable of producing malignant

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transformation
Examples : Benzopyrine and croton oil
Benzopyrene is a known chemical carcinogen which acts

as an initiating agent

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However, if it is painted once on the skin of an animal it

does not lead to cancers in animal but to the initiation of

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carcinogenesis

However ,if croton oil is applied several times after

benzopyrene ,often the animal develops tumors

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It is known that croton oil alone is also not capable of

causing tumor

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So croton oil is a promoting agent containing

phorbolesters which act through protein kinase C and

influence in the cell signalling

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The exact mechanism of how promotors lead the

initiated cell in to tumour forming cell remains

unknown

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Most direct carcinogens act as initiating as well as

promoting agent

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While some act only as promoting agent e.g.

saccharine,phenobrabitone or phenobarbital
Ames assay

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Chemical carcinogens can be identified by testing for their

ability to induce mutation

A simple way to do this is by using the Ames assay

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This relatively simple test, which detects mutations in the

bacterium salmonella typhimurium caused by

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chemicals,has proven very valuable for screening purposes

A refinement of the Ames test is to add an aliquot of

mammalian ER to assay, to make it possible to identify

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procarcinogens

Biological: Oncogenic Viruses

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Both DNA and RNA viruses have been identified as being

able to cause cancers in humans

In general, the genetic material of viruses is incorporated

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in to genome of host cell

In RNA viruses, only retroviruses can cause cancer because

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they have reverse transcriptase enzyme by which RNA

genome of the virus can be converted in to cDNA which is

then incorporated in to host genome

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Such integration of viral DNA to host DNA results in various

effect such as deregulation of cell cycle, inhibition of

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apoptosis and abnormalities of cell-signaling pathways

resulting in cancers

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Oncogenes-Proto-oncogenes

DNA sequence similar, but not identical ,to viral

oncogenes are also present in normal cells

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These have role in cellular growth and differentiation

and they are called proto-oncogenes

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An oncogene can be defined as an altered gene, the

product of which act in a dominant manner to

accelerate cell growth or cell division

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Oncogenes are generated by "activation" of normal

cellular proto-oncogenes,which encode growth

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stimulating proteins

MECHANISMS OF PROTO-ONCOGENE

ACTIVATION

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At least five mechanisms are known of proto-oncogene

activation

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1. Promoter insertion

2.Enhancer insertion

3. Chromosomal translocation

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4. Point mutation

5. Gene amplification
Promotor Insertion

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When a retrovirus infects a host,its double stranded cDNA

gets integrated in to host DNA

This integrated cDNA is called provirus

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cDNA is flanked on both sides by long terminal repeat
It is seen that when chicken B-lymphocytes are infected

by avian leukaemia virus, provirus is integrated near the C

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-MYC gene of lymphocytes

The LTR ,placed immediately upstream of C-MYC gene,

acts as promoter and initiates the transcription of C-MYC

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gene and ultimately produces the B-cell tumor

Human colorectal cancers also involve the activation of C-

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MYC gene

Enhancer Insertion
It is seen that many times when a retrovirus genome,

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like the genome of avian leukaemia virus, is inserted

downstream of C-MYC gene, still the activation of

MYC gene transcription occurs

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In such a situation, LTR of provirus act as an enhancer

and activate the transcription of C-MYC gene

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Chromosomal Translocation
Chromosomal translocation is a type of chromosomal

abnormality seen in some cancers like CML,Burkitt

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lymphoma etc.

A portion of chromosome is split off and joined to

another chromosome, resulting in activation of an

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oncogene at the site where insertion occurs

Usually there is an exchange of a chromosomal

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material between both the chromosomes, hence this

is called reciprocal translocation

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Point mutation
A classic example is a point mutation of the RAS oncogen

This result in the gene product, a small of G-protein

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(RAS),in which intrinsic GTPase activity of the protein is

lost

Loss of GTPase activity of this G-protein results in chronic

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stimulation of the activity of adenylyl cyclase and the

MAP kinase pathway, leading to cell proliferation and

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malignant transformation
Gene amplification
Abnormal multiplication of a gene occurs, resulting in

many copies and increased gene expression

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It has been shown that gene amplification of C-RAS

proto-oncogene has a role in a malignant

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transformation
Examples of oncogenes
SIS and INT-2 genes: These are located on

chromosome 22q13.1 and 11q13 respectively and

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encode growth factors to stimulate growth of

certain type of cells

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FMS and ERB encode receptors for colony

stimulating factor and epidermal growth factor

SRS and ABL which encodes non-receptor tyrosine

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kinase and are proteins involved in signal

transduction

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H-ras and K-ras which encode membrane associated

protein that relay growth factor