Give du’a before start, carcinogenesis derived from 2 words, Carcinogen-a substance capable of causing cancer in living tissueGenesis- the origin or mode of formation of something.Carcinogenesis - The production of cancer
1. Al hadith : Narrated by ibn abbas and reported by Al hakim, Kitab Al Mustadrak Ala As-Sohihain, (read in arabic and definition in english)2. Ithis hadith is very special for this presentation, because it give the reason on why we should be thankful for everything that Allah have give us. the health and strength
1. (Read first then) All 3 carries same definition2. Normal cell are developed into abnormal cell by reprogram to undergo uncontrolled cell division.3. the modus operandi of carcinogenesis is disturbed the normal regulation of tissue cell
2 factor induce carcinogenesisOncogene, a mutated proto oncogenDefect of tumor suppressor gene
1. Proto oncogene codes for protein toCell growth. This process occur in G1 and G2 phase of cell cycle.Cell Differentiation or mitogenic process in mitosis process of cell cycle2. Any mutation hit to proto oncogen, will start carcinogenesis by oncogene which causes the tumor develpment
1. Oncogene exist when the mutation hit to the proto oncogene2. Its responsible for hyperproliferate of cells and also cause the effected cells to become immortal.3. Reported by Carlo M. Croce, that a single genetic change is rarely sufficient for the development of a malignant tumor but it requires multistep process of sequential alterations in several, often many, oncogenes, tumor-suppressor genes, or microRNA genes in cancer cells
1. This is a schematic presentation of the balance between growth promoting pathways and intrinsic tumor suppressor pathways in relationship with normal cell balance, 2. At my left, growth promoting pathways consist of proliferation and cell survival3. E2F isoenzyme family is a type of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins. Example of E2F is CDK and cyclin4. At my right, cell cycle arrest and apoptosis make the intrinsic tumor suppressor pathways.5. For maintaining the development of tissue, both proliferation and programme cell death are closely maintain by E2F family.6. Mutation to protooncogene causes the disturbance of growth promoting pathways or intrinsic tumor suppressor pathways.7. Oncogene on the above act as culprit to either hyperproliferate the cell development, increase the survivality of the cells, undo the cell cycle arrest or develop the cell to resist the apoptosis. 8. For example, if there are altered growth promoting pathways, the cell will begin to hyperproliferate and leads to development of cancerous cell, and vice versa.
This is a presentation in point of analogy regards theory by Carlo M. Croce about the development of cancerous cell. The image showing the normal cell, tumor suppressor genes, proto oncogene and in relation with carcinogenesis Let say the car is a cell with proto-oncogene and the handbrake is tumor suppressor gene. In the upper row, it is a normal cell development. Usually, a normal development by proto oncogene of cell is actually in very small way leads to development of cancerous cell, but with presence of tumor suppressor gene, hyperproliferation are avoided.In the second row, mutation takes place in proto oncogene, causes acceleration of the cell proliferation, but still not develop into malignant tumorIn the third row, on the 2nd hit of mutation, suppose tumor suppressor gene are effected, the cell development are uncontrolled and lead to carcinogenesis
Loss of cell regulation, (refer to seesaw picture), the disturbance to the proliferation and tumor suppresor geneHigh amount of protein producedThe cells codes for protein (it might be RNA or hormone) Induce to develop more highly immortality rate of and prolonged the existance and activity of a cellIncreased gene expression not at precise timeIncrease of enzymatic reactionKIV
1. Tumor suppressor gene or also known as p53, have 2 functionArrest the cell cyclePromote apoptosis2. This gene is fundamental for maintaining and balance the cell growth development
Other sub function of tumor suppressor gene areKIV
This slide shows a schematic presentation of DNA strand and its components upon the DNA replication in the S phase of the cell cycle and relationship between the repression of gene and the cell survivalityThis is very technical slide, insyaAllah, i will present it step by stepThis is DNA strand (show), consist of promoter, operator and lac Z, Lac Y and lac APolymerase trigger the formation of mRNA by attach to promoter and move along the DNA strand. KIVWhen the repressor happen to attach to active site of operator, it will inhibit the process of DNA replicationIn presence of lactose, it act to attach other active site of repressor, and automatically inhibit the function, and the replication is happened
Carcinogenesis happened when the are adjustment made to the gene which byMutationEpimutation
Mutation is a permenent change to DNA sequenceFor example, this is a DNA strand that consist of multiple codon. This is codon (show)Each codon has 3 nucleotides (show)Any removal, addition, etc either it is involving the codon or only nucleotide are known as mutation
There are several types of mutation, This is substitutionAs we can see, the nucleotide A are replace by G, in the second codonThe example from this types of mutation is sickle cell anemia. This is a blood film prepared with Romanowsky stains method.There are no clear WBC happen to appear, the blueish small phragment appear might be the plateletAlong side with the normal red blood cell, which appear in biconcave shape, there are a semi-creascent shape of RBC also known sickle cell RBC.Sickle cell anemia is inherited form of anemia, from the schematic illustration, as we can see there are abnormal form of RBC present in this blood film (show).
1. This is other kind of mutation, insertion2. In this slide shows insertion of whole new codon (show) in between original one.3. Example from this type of mutation is, Huntington’s disease4. This is coronal plane of view of cerebrum, in my right shows normal anatomy of cerebrum and my left shows effected cerebrum with Huntington’s disease5. It is results from genetically programmed degeneration of brain cells6. Clear difference here is, in the left brain, we can see the washed out brain tissue compared to right one.
This is the 3rd type of mutation, deletionThere are removal of of one nucleotide from both codon (show)Example from this type of mutation is Cry Du Cat syndromeCri Du Chat syndrome is cause by chromosome 5p deletionIt is characterised with, cry of affected infants, which is similar to that of a meowing kitten, due to problems with the larynx and nervous system.severe cognitive, speech, and motor delays;behavioral problems such as hyperactivity, aggression, tantrums, and repetitive movements;unusual facial features which may change over time;excessive drooling;small head and jaw;wide eyes;
This is another type of mutation, frameshiftFrom the slide, the codon is being shifted from letter T for the first codon, to letter H and the rest follows to form 1 codon that consist of 3 nucleotideOne example that can be shown here is, Crohn’s diseaseCrohn's disease is a form of inflammatory bowel disease (IBD). It usually affects the intestines, but may occur anywhere from the mouth to the end of the rectum (anus). Ulcerative colitis is a related condition.
1. KoujiBanno et. al describe epimutation as repression of usually active gene and activation usually repress gene2. Epimutation is the starting of the
This is a schematic illustration of epimutation. There are attachment, in this case, methyl group, attach to any nucleotide and cause either activation of usually repress gene or/and repression of usually active gene of function.
Mutation can be subdivided into 2, large scale and small scale,While epimutation consist of addition or removal of any alkyl group (methyl group, acetyl group, or phosphoryl group) or alteration of histones.
Mutation and epimutation may acquired either exogenously or endogenously. For example, exogenous agent might be smoking, exposure of radioactive or might be infection by viruses and bacteria. As for endogenous agent, it is develop within the patient body itself or inherited from their parents affected gene.
There are two categories of cancer which are (look slide)Non sporadic cancer is also known to have hereditary componentSporadic cancer is also known as non hereditary cancer
This is a comparison of non sporadic and sporadic cancerFrom the first point, we noted that non sporadic cancer are detected earlier than sporadicFrom the second row, non sporadic passes the effected gene to its progeny and sporadic acquired from the environmentLastly, the non sporadic gene will cause the affected patient to have multiple cancer, and sporadic gene having less of risk of having cancer.
In normal cell, proliferation and apoptosis are closely maintain with aid of growth factor. For example CDK and cyclin, p27 and p53.
For carcinogenesis, there are disturbance of either apoptosis and proliferationFor example, mutation of p53 causes the disturbance of apoptosis and cell repair
This is a schematic presentation of comparison between normal cell and cancerous cellIn diagram A, shows normal replication of cell, Initiation of replication by growth factor originate from outside the cell.When a cell are happen to be mutated, the p53 take action by lead the effected cell to either cell arrest and repair or apoptosis.In diagram B, shows abnormal proliferation of cancerous cellThe mutated cell have the self sufficiency ability. This means that the cell are allows it grows without aid of growth factor. For example in cell cycle, a cell requires suitable CDK and cyclin complex to move to another stage, but in this case, no CDK and cyclin needed.The cell is immune to the anti-growth signal and continue to develop even more The cell loss its capacity to senescent and apoptosis, causing the survivality of cells increase, and continues to replicate.
This is a schematic presentation of angiogenesis during carcinogenesis. It is a continuation from previous slideAt the diagram flows, shows that the integrity of the blood vessel is strong and even develop to supply the needed of the cancer mass. The cancerous cell secrete angiopoietin to induce neovasculature.Hanahan and Weinberg also stated that the cancer cell will invade the neighbouring cells and trigger of formation of cancer of the new cells.
Lastly, the cancerous cells take advantages from the blood vessels to metastases to other organ and create multiple cancer disease.
“Take benefit of five before five: Your
youth before your old age, your health before
your sickness, your wealth before your poverty,
your free time before you are preoccupied, and
your life before your death”
(Narrated by Ibn Abbas and reported by Al
Carcinogenesis = oncogenesis = tum
It is a process by which
normal cells are transformed into
Reprogram a cell to undergo
uncontrolled cell division, forming a
Cancer is disease of regulation of
A proto-oncogene code for proteins that
help to regulate cell growth and
Often involved in signal transduction and
execution of mitogenic signals, usually
through their protein products.
proto-oncogene mutation oncogene (tumorinducing agent).
The proto-oncogene can become
an oncogene by small modification of its
An oncogene is a gene that, when
mutated or expressed at high
levels, helps turn a normal cell into a
Activated oncogenes cause cells to
survive and proliferate instead of
programmed form of death
Oncogenes require an additional
step, such as mutations in another
gene, or environmental factors, such
as viral infection, to cause cancer.
A oncogene can cause
◦ a loss of regulation
◦ increase in protein concentration, caused by
an increase of protein expression (through misregulation)
an increase of protein (mRNA) stability, prolonging its
existence and thus its activity in the cell
a gene duplication (one type
of chromosome abnormality), resulting in an increased
amount of protein in the cell
A chromosomal translocation (another type of
chromosome abnormality), causing
an increased gene expression in the wrong cell type or at wrong
the expression of a constitutively active ''hybrid protein''. This
type of aberration in a dividing stem cell in the bone
marrow leads to adult leukemia
◦ an increase in protein (enzyme) activity
Tumor suppressor gene
Also called antioncogene protects
a cell from develop into cancer cell.
Tumor-suppressor genes code
proteins to dampening or repressive
the cell cycle or promote apoptosis,
and sometimes do both.
Cont. Tumor suppressor gene
The functions of tumor-suppressor
proteins fall into several categories
including the following:
◦ Repression of genes
◦ Coupling the cell cycle to DNA damage.
◦ Involved in cell adhesion prevent tumor
cells from dispersing, block loss of contact
inhibition, and inhibit metastasis.
Repression of genes
• that are essential for the continuing of the
cell cycle. If these genes are not expressed,
the cell cycle does not continue, effectively
inhibiting cell division.
Caused by mutation and epimutation
of the genetic material of normal cells,
which upsets the normal balance
between proliferation and cell death
◦ A mutation is a permanent change in the
DNA sequence of a gene.
◦ alter the amino acid sequence of the
protein encoded by the gene.
The sun was hot but the old man did not get
Types of mutation
◦ CTG GAG
◦ Example : sickle cell anemia
◦ CTG GAG
◦ Example : Cri du chat
◦ The fat cat sat
hef atc ats at
Example : Crohn’s Disease
◦ Epimutation is abnormal transcriptional
repression of active genes and/or
abnormal activation of usually repressed
genes caused by errors in epigenetic
◦ Epimutation arises in somatic cells and
the germline, and constitutional
epimutation may also occur.
◦ Epimutation is the first step of
tumorigenesis and can be a direct cause
Mutation and epimutation
Large-scale mutations involve the
deletion or gain of a portion of a
Small-scale mutations include point
mutations, deletions, and insertions
Epimutations include methylations,
phosphorylation or other alterations to
DNA damages can arise from
◦ Exogenous agents
◦ Endogenous agent
Category of cancer
Non sporadic cancers (30%), do have
Sporadic cancers (70%), have no
Non-sporadic vs sporadic
Hereditary cancer often occur
earlier than the sporadic - experts
often recommend different
screening, at a younger age for
people with hereditary cancer in their
Occur late than non sporadic
Hereditary cancers are caused in part
by gene changes passed on from
parents to their children. Other blood
relatives may share these same gene
Sporadic cancers are believed to arise
from gene damage acquired
from environmental exposures, dietary
factors, hormones, normal aging, and
other influences. Most acquired gene
changes are not shared among
relatives or passed on to children.
Individuals who have inherited a gene
change may be at a higher risk for
more than one type of cancer.
Less risk of having multiple cancer
Normal circumstances, the balance
between proliferation and
programmed cell death (apoptosis)
maintained by tightly regulating both
processes to ensure the integrity of
organs and tissues
The uncontrolled and often rapid
proliferation of cells can lead to benign
tumors; some types of these may turn
into malignant tumors (cancer).
Hanahan and Weinberg were summarized the biological properties
of malignant tumor cells as follows:
Acquisition of self-sufficiency in growth signals, leading to unchecked
Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
Loss of capacity for apoptosis, in order to allow growth despite genetic
errors and external anti-growth signals.
Loss of capacity for senescence, leading to limitless replicative potential
Acquisition of sustained angiogenesis, allowing the tumor to grow beyond
the limitations of passive nutrient diffusion.
Acquisition of ability to invade neighbouring
tissues, the defining property
of invasive carcinoma.
Acquisition of ability to build metastases
at distant sites, the classical property of
malignant tumors (carcinomas or others).