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