Download MBBS Cancer Lecture PPT

Download MBBS (Bachelor of Medicine and Bachelor of Surgery) Latest Cancer Lecture PPT


BIOMEDICAL IMPORTANCE

Cancers constitute the second most common cause of

death, after cardiovascular disease, in many countries

Humans of all ages develop cancer, and a wide variety

of organs are affected

Worldwide, the main types of cancer accounting for

mortality are those involving

lung,stomach,colon,rectum,liver and breast

Other type of cancers that lead to death include

cervical,esophageal and prostate cancer

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

NEOPLASM

Tumor
Cellular mass formed due to uncontrolled proliferation of

cells is called a tumor

Benign Tumors
Grow very slowly
Remain localized with well defined boundary
Do not invade the surrounding tissues
Do not spread to distant organs
Generally harmless, bad effects ,if any ,are due to pressure

effects on surrounding tissues

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

distant organs

Have great propensity for recurrence even after

removal

Cancer
Cancer refers to malignant tumors only

Properties of cancerous cell

Loss of shape

Loss of contact inhibition

Loss of anchor support

Diminished requirement of nutrients and growth

factors

Cancer cells become immortal

Biochemical changes in Cancer Cells
Increased DNA replication and transcription
Alteration in expression of cell surface molecules and

cytoskeleton components

Increased rate of anaerobic glycolysis even in the

presence of oxygen could be due to :

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

isoenzyme hexokinase II that does not respond to

feedback inhibition

2.Cancer cells are also known to have different pyruvate

kinase isoenzyme called PK-2

3.Despite angiogenesis solid tumors have localized area of

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

oxygen species which can damage the DNA

Normal role of mitochondria in apoptosis may be

altered due to damage

Alteration in antigen expression occurs with loss of

some old ones and appearance of new antigens

Often foetal protein are expressed such as alpha-

fetoprotein or CEA
Etiology of Cancer

The exact etiology is not known

No single agent or factor is responsible for

causing the cancer

Many factors are involved in causation of

cancer such as environmental, nutritional,

genetic ,etc.
DNA damage is central to the cancer

development

All cancers originate from a single cell which becomes abnormal

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

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

in all cancers

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

cancers e.g. CML

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

malignant cell

4.DNA damaging agents have been shown to produce mutations

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

inherited mutations

Acquired mutations occur either by errors in DNA

replication or DNA repair, and are termed replication

mutation, or by exposure to environmental mutations

The third major class of oncogenic mutation are termed

hereditary mutation; inherited mutations are derived from

one or both parents

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

suppressor genes; DNA repair genes,cell cycle control

genes)present in germ cells

Spontaneous mutations, some of which may predispose to

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

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

accumulate with increasing age

Oxidative stress, generated as a result of enhanced

production of ROS ,may also be a factor in increasing

mutation rates
Carcinogens

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
Chemical Carcinogen

Biological Carcinogen:oncogenic viruses

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

carcinogenic

Mutations in DNA,if not corrected, are thought to

underlie the carcinogenic effect of radiation

Additionally x-rays and gamma-rays can induce

formation of ROS,which are also mutagenic and

probably contribute to carcinogenic effects of

radiation
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

of skin

The risk of developing a skin cancer due to UV radiation

increases with increase frequency and intensity of

exposure, and decreases with increasing melanin content

of skin.

Individuals who have an inherited inability to repair DNA

have increased risk of developing a malignancy



Chemical Carcinogen
The process by which chemical substances produce

cancers is called chemical carcinogenesis

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

interact easily with target molecule like DNA to produce

cancers are called direct carcinogens

They do not undergo any modification in the body in order

to cause cancer

For example,met-chlorethamine and beta-propionolactone

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

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

carcinogens

Examples : A pro-carcinogen 2 acetylamino fluorine is

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

hydroxy-AAF by undergoing chemical reactions in the

body

Most ultimate carcinogens are electrophiles and attack

electron rich nucleophilic molecules like DNA,RNA,proteins

etc

Stages of Chemical Carcinogenesis

Initiation is the stage which produces the irreversible change in

the genome of the cell resulting in one or more mutation

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

but is yet not a cancerous cell

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

the cell division and malignant transformation of initiated cells is

induced

Most promoting agents act by altering the signal transduction and

gene expression

Either of two processes is incapable of producing malignant

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

as an initiating agent

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

carcinogenesis

However ,if croton oil is applied several times after

benzopyrene ,often the animal develops tumors

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

causing tumor

So croton oil is a promoting agent containing

phorbolesters which act through protein kinase C and

influence in the cell signalling
The exact mechanism of how promotors lead the

initiated cell in to tumour forming cell remains

unknown

Most direct carcinogens act as initiating as well as

promoting agent

While some act only as promoting agent e.g.

saccharine,phenobrabitone or phenobarbital
Ames assay

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

This relatively simple test, which detects mutations in the

bacterium salmonella typhimurium caused by

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

procarcinogens

Biological: Oncogenic Viruses

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

in to genome of host cell

In RNA viruses, only retroviruses can cause cancer because

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

Such integration of viral DNA to host DNA results in various

effect such as deregulation of cell cycle, inhibition of

apoptosis and abnormalities of cell-signaling pathways

resulting in cancers


Oncogenes-Proto-oncogenes

DNA sequence similar, but not identical ,to viral

oncogenes are also present in normal cells

These have role in cellular growth and differentiation

and they are called proto-oncogenes

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

Oncogenes are generated by "activation" of normal

cellular proto-oncogenes,which encode growth

stimulating proteins

MECHANISMS OF PROTO-ONCOGENE

ACTIVATION

At least five mechanisms are known of proto-oncogene

activation

1. Promoter insertion

2.Enhancer insertion

3. Chromosomal translocation

4. Point mutation

5. Gene amplification
Promotor Insertion
When a retrovirus infects a host,its double stranded cDNA

gets integrated in to host DNA

This integrated cDNA is called provirus
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

-MYC gene of lymphocytes

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

acts as promoter and initiates the transcription of C-MYC

gene and ultimately produces the B-cell tumor

Human colorectal cancers also involve the activation of C-

MYC gene

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

like the genome of avian leukaemia virus, is inserted

downstream of C-MYC gene, still the activation of

MYC gene transcription occurs

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

and activate the transcription of C-MYC gene

Chromosomal Translocation
Chromosomal translocation is a type of chromosomal

abnormality seen in some cancers like CML,Burkitt

lymphoma etc.

A portion of chromosome is split off and joined to

another chromosome, resulting in activation of an

oncogene at the site where insertion occurs

Usually there is an exchange of a chromosomal

material between both the chromosomes, hence this

is called reciprocal translocation


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

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

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

lost

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

stimulation of the activity of adenylyl cyclase and the

MAP kinase pathway, leading to cell proliferation and

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

many copies and increased gene expression

It has been shown that gene amplification of C-RAS

proto-oncogene has a role in a malignant

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

chromosome 22q13.1 and 11q13 respectively and

encode growth factors to stimulate growth of

certain type of cells

FMS and ERB encode receptors for colony

stimulating factor and epidermal growth factor

SRS and ABL which encodes non-receptor tyrosine

kinase and are proteins involved in signal

transduction

H-ras and K-ras which encode membrane associated

protein that relay growth factor

This post was last modified on 30 November 2021