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 breastOther 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 organsGenerally harmless, bad effects ,if any ,are due to pressure
effects on surrounding tissues
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Once removed, they do not recurMalignant Tumors
Grow rapidly
Spread and invade the surrounding tissues as well as
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distant organsHave 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 supportDiminished 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 andcytoskeleton 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 tofeedback 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 anoxiaMitochondria in cancerous cell produce reactive
oxygen species which can damage the DNA
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Normal role of mitochondria in apoptosis may bealtered 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 CEAEtiology of Cancer
The exact etiology is not known
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No single agent or factor is responsible forcausing 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 cancerEven 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 cell2.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 intomalignant 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 mutationsThe 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 controlgenes)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 increasingmutation rates
Carcinogens
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Many agents can cause cancers are called carcinogensCarcinogens could be any of the following:
Physical Carcinogen
Radiations like X-rays,ultra-violet rays and -rays
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Chemical CarcinogenBiological Carcinogen:oncogenic viruses
Physical carcinogen
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Uv rays,x-rays and gamma-rays are mutagenic andcarcinogenic
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 andprobably contribute to carcinogenic effects of
radiation
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Exposure to UV radiation is common due to exposure tosunlight, 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 ofexposure, 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 carcinogenesisBoth 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 orderto 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 reactiveand 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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etcStages 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 cellPromotion
After initiation, cell undergoes the stage of promotion in which
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the cell division and malignant transformation of initiated cells isinduced
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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transformationExamples : 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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carcinogenesisHowever ,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 containingphorbolesters which act through protein kinase C and
influence in the cell signalling
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The exact mechanism of how promotors lead theinitiated 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 theirability 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 purposesA 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 beingable 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 RNAgenome 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 pathwaysresulting in cancers
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Oncogenes-Proto-oncogenesDNA 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, theproduct 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 proteinsMECHANISMS OF PROTO-ONCOGENE
ACTIVATION
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At least five mechanisms are known of proto-oncogene
activation
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1. Promoter insertion2.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 cDNAgets integrated in to host DNA
This integrated cDNA is called provirus
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cDNA is flanked on both sides by long terminal repeatIt 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 lymphocytesThe 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 geneEnhancer Insertion
It is seen that many times when a retrovirus genome,
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like the genome of avian leukaemia virus, is inserteddownstream 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 TranslocationChromosomal 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 thisis called reciprocal translocation
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Point mutationA 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 islost
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 transformationGene 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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transformationExamples 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 colonystimulating 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 associatedprotein that relay growth factor