Cancer Biology

[Link] ZAKI HAMDAN

Introduction
❑ Any living cell committed to die, and it devotes its
entire life towards the germ cells (Sperm or ovum).

❑ Germ cells is the only cells that have the ability to

give rise to another living creature.
Cont.

❑ Forsuch sacrifices multicellular organisms

have to cooperate and coordinate their
behaviour, needs, growth for the good of
the organism.

❑ Thisis occur through set of orders and

socially environment telling each cell how
to act, die, …
What is (tumor) Neoplasm?

❑ Is
group of cells that its growth is out of
control.
❑ It can be Benign or Malignant tumor.
Characteristics of cancer cells

1. Cancer cell and its progeny can divide

without any restrictions as compared to
normal cells (uncontrolled growth).
2. Cancer cell invades and colonize territories
normally reserved for other cells (Metastases).
Metastases occurs through direct invasion,
blood vessels, lymphatic vessels.
Cont.

3. Cancer cells are immortal they can resist

apoptosis signals.

4. Cancer cells can resist growth suppression

signals.
Cont.

3. Cancer cells develop its own blood

supply vessels (Induces angiogenesis).

4. Release and activates itself by secreting

growth factors (autocrine).
Angiogenesis

❑ Formation
of
New blood
vessels.
❑ These blood
vessels usually
fragile and liable
to rupture.
What causes cancers?
❑ Cancers can arise from single abnormal cell
that contains mutation(s). This abnormal cell
must pass its abnormality to its progeny.
❑ It
is needed to know whether the genetic
mutations is the leading cause of cancer or
an epigenetic error is the major cause?
❑ In fact both lead to cancers.
What leads to genetic mutations?

❑ Genetic mutations causes includes:

❑ Acquired causes (environmental).
❑ Inherited
mutations (Inherited gene mutations).
E.g BRCA1, BRCA2, DNA repair genes, non
polyposis colon cancer. These mutations present
in germ cells therefore inherited and occurs later
in life.
Carcinogenesis (generation of cancer)

❑ It clearly linked with mutagenesis (production of

change in DNA sequences (mutation)).
❑ Agents that cause mutations named mutagens.
1. Chemical carcinogens.
2. Ionizing radiation carcinogens.
3. Biological carcinogens (viruses insert foreign DNA).
Chemical carcinogens
❑ Makes local changes to nucleotide sequences
(local mutation).
❑ Aromaticamines (Aromatic amines are widely
used as precursor to pesticides,
pharmaceuticals, dyes and benzene).
❑ Nitrosamines (balloons, latex, food, tobacco).
❑ Mustard
gas ( chemical weapons that used by
German in first world war).
 Mustard Gas victims
❑ Itcauses skin
burning and blisters
in acute exposure.
❑ Itcauses squamous
cell carcinoma in
later life if patient
survive.
Cont.
❑ Cyclophosphomide (cytotoxic drug).
❑ Diethylstilbestrol
(prescribed to pregnant ladies
to prevent abortion).
❑ AflatoxinB (poison secreted by peanut fungi
aspergillus flavus cause hepato cellular
carcinoma).
Cont.

❑ Chemical carcinogens are either already

ready to exert its carcinogenesis effect or
need prior activation (procarcinogen) by
P450 cytochrome enzyme.
How chemical carcinogen act?

❑ Chemical carcinogen acts through two

stages:
❑ Initiation.
This step includes irreversible damage to the
DNA.
❑ Promotion.
This step includes abnormal cell growth and
division.
Ionizing radiation carcinogens
❑ Ionizingradiation like X-ray, UV ray, Gamma
rays are carcinogenic.
❑ They lead to DNA damages by the following
mechanisms:
1. Makes single or double Chromosomal breaks
and translocation.
2. Formation of Pyrimidine dimer (UV-light).
3. Formation of apurinic or apyrimidinic site by
eliminating the corresponding bases.
Cont.

4. Dicentric and ring chromosomes, chromated

and chromosome breaks, acentric fragments,
translocations, and micronuclei (Nuclear
radiations).
Chernobyl Nuclear Plant Disaster 1986
Types of cancers resulted by
Chernobyl disaster
❑ Breast cancer.
❑ Brain cancer.
❑ Leukemia.
❑ Skin cancer.
❑ Thyroid cancer.
Cont.
❑ Both gamma and X-rays can induce oxidative
stress damage which is damaging to the DNA.

❑ UV-rays
emitted form the Sun and it causes skin
cancers. Specially for those with less developed
melanin pigment or those suffering from failure
of DNA repair mechanisms.
Biological carcinogens
❑ Both DNA and RNA viruses can cause cancers
and the cause is insertion of foreign DNA to the
human DNA.
❑ This foreign DNA causes one of the following:
1. Deregulation of the cell cycle.
2. Inhibition of apoptosis.
3. Abnormalities of cell signaling pathways.
What exactly the mutation do in the
DNA?
❑ Lets
discuss the concept of protoncogenes and
Tumor suppressor genes.
❑ Protoncogene:
Genes encoding proteins that promote cell divisions
are known as oncogenes.
❑ Tumor suppressor gene:
On the contrary genes encode proteins that inhibit
cell divisions.
Cont.
❑ The
acquired mutations usually cause one of
two outcomes:

❑ Gaining new function or losing specific

function.
Proto-oncogens
❑ This is the non-mutaed form of the gene. If it
is being mutated it is named oncogene.
Cont.

❑ Proto-oncogenes includes:
❑ MYC:
Avian myelocytomatosis viral oncogene
homology.
❑ It encodes proteins that promotes cell growth,
DNA replication and cell cycle progression.
Activation of MYC gene by avian
leukemia virus promoter region
Activation of MYC gene by
translocation (Burkitt’s Lymphoma)
Burkitt’s lymphoma
RAS oncogene
❑ Thisis a down stream signaling protein linked
to GTPase.
❑ Itis linked to the activation of proteins that
involved in cell growth.
❑ Persistentactivation of these genes due to
mutations contributes to the development of
a variety of cancers.
Decreases lipolysis
Decreases gluconeogenesis
Increases lipogenesis
Increase protein synthesis and
decreases protein degradation
Tumor suppressor genes
❑ Includes:
❑ P53:
This protein usually mutated in over 50% of the
cancer cases.
It induces cell cycle arrest, apoptosis, senescence,
DNA repair and is involved in
some aspects of regulation of cellular metabolism.
❑ It has been named “the guardian of the
genome”.
Cont.

❑ P53
act as a tumor suppressor as it promotes
apoptosis.
❑ Luckyenough we have two copies of P53.
Therefore in case of losing one copy, the
another will compensate for that loss. But if we
loose both copies then we are stuck in a
trouble.
Retinoblastoma protein

❑ Itrepresses the transcription of various genes

involved in the S phase of the cycle.
❑ Mutation of the RB gene is the cause of
retinoblastoma, but it is also involved in the
genesis of certain other tumors .
D 4 6

Retinoblastoma
E2F

DNA
Retinoblastoma
Gatekeeper and Caretaker tumor
suppressor genes
❑ Gatekeeper genes are genes that control
the cell cycle, apoptosis and cell
proliferation.
❑ Caretakergenes are genes that concern by
recognizing and correcting the damaged
DNA.
Oncogenes Vs. Tumor Suppressor Genes
What’s new?
❑ Due to recent advances in genetic
sequencing and molecular biology era,
whole genome sequencing and exome
sequencing revealed many new genes that
involved in the cancer formations.
❑ There
are about 33 new genes resulting in 33
new proteins have linked to cancer
formations.
Cont.
❑ These proteins function summarized as the
following:
1. Genome stability
2. Epigenetic/chromatin gene regulation.
3. Immune evasion
4. Proliferation
5. Apoptosis
6. RNA processing
7. Protein homeostasis
Cont.
❑ Which of these proteins is the hub protein
and which of these gene mutation is a driver
mutations and which is a Passenger
mutations ?
Answering these questions will add a lot to
the field of cancer biology and era of its
therapeutics and diagnosis.
Deadly pancreatic cancer

❑ Pancreatic cancer is the most deadly cancer

world widely.
❑ It
is uncertain whether it is lethal due to its
aggressiveness or late diagnosis?
❑ Datafrom genome sequencing for pancreatic
cancers revealed the following:
Cont.

❑ 61
known cancer-related mutations were
detected in each metastasis.
❑ Byusing specific techniques named
“molecular clock” scientist able to calculate
the exact time that is needed by the
malignant cell to became metastasize
malignant in the pancreatic cancers.
Molecular clock
Cont.
❑ The result is shocking.
❑ Morethan 10 years needed to generate by the
non-metastatic primary tumor cell to possess the
mutations that found in the metastatic cells.
❑ Morethan 5 years is needed to gain metastatic
potentials.
❑ After
2 years the tumor became metastasis and
death occurs.
Cont.

❑ Thisshows that pancreatic cancer is slowly

progressed cancer and not that aggressive.
So the problem is late diagnosis.
❑ Hope in the coming future early diagnostic
tools for the pancreatic cancer will be
available (Blood biomarker or stool samples
that carry the mutated genes).
Altered metabolism in cancer cells

❑ Cancers cells express an odd behavior

regarding the metabolism of all nutrients.
❑ This
facts is consolidated more after the
exome sequencing.
❑ In 1924 Warburg and his college notice that
cancer cells uptake glucose in high amounts
and oxidized it to lactate instead of pyruvate,
in spite presence of oxygen (Warburg effect).
Dr Ottoo Warburg
Nobel Prize winner in Medicine 1931
Cont.
❑ Warburg postulate two hypothesis:
❑ Thereis a defect in the mitochondria
which unable to cope with high aerobic
glycolysis rate.
❑ Perhaps the cancers cells prefer to
proliferate in the presence of low oxygen
tension.
❑ Such
effect is owing to the cancer cells
tumorigenesis ability.
Cont.
❑ The evidence showed that the
mitochondria has been hijacked and
reprogrammed to do so.
❑ This
reprogramming though to be directly
caused by the influences of :
❑ Self-sustaining proliferative growth factor.
❑ Geneticchanges in specific metabolic
enzyme-encoding genes and other genes.
Some genetic variants
❑ Genetic variants induce alternative splicing for
specific genes like pyruvate kinase/PKM,
phosphofructokinase/PFKFB3, glutaminase/GLS.
❑ The result of these alterations is the productions
of what is named oncometabolites these
metabolites altered the epigenetics control of
gene expression and affect the affinity of the
cell to utilize of glucose aerobically.
Cont.
❑ Another approach:
❑ Anaerobic glycolysis leads to production
of lactic acids which lowering the pH
locally.
❑ Acidic pH may lead to more easy cellular
invasions.
❑ On the other hand, this may be an
approach for a possible treatment
strategy.
Cont.

❑ Ifwe could inhibit anaerobic glycolysis

inside the tumor cells invasions will be
difficult.
❑ Scientist develops some chemicals that
inhibit glycolysis key enzymes in cancer
cells selectively.
Potentials chemical for inhibiting
glycolysis
Tumor Biomarkers

❑ Some cancer cells expressed unusual

amounts of proteins, enzymes, hormones
that may be detected in the urine , blood
samples and other biological fluids.
❑ These named as tumor biomarkers.
Cont.

❑ Manyof these biomarkers are not specific for

cancer.
❑ For example, PSA is not expressed in prostate
cancer only, it can be expressed in
inflammatory prostate conditions.
❑ Biomarker
is useful in follow-up of the patients
and to check whether there is recurrence of
the cancer after cure or not.
Cont.

❑ Afterthe exome sequencing and the advances

in proteomic field, future is widely open for
developing new diagnostic biomarker.
Can we avoid cancer?

❑ Ifyou know that, you have the mutated

form of the genes, that have the
increased susceptibility to specific cancer
what are you going to do?
Organs removal strategy
50% of the cancer risk can be
avoided if modifiable risk factor are
avoided
Cont.

❑ If all risk factors are avoided and not

exposed to any oncogenes, still there is a
risk of cancer development.
❑ Thisis attributed to, every single gene has
a probability of wrong replication about
10 power -6/ DNA replication.
Cancer treatment strategies

❑ Cancers has been treated for a long time

by what is named cytotoxic drugs which
are also known as chemotherapeutic
agents.
❑ Theexact actions of these drugs is to
decrease the rate of cell divisions or arrest
the DNA replication.
New strategies

❑ Development of inhibitors of signal

transductions proteins (tyrosine kinase
inhibitros). This is could be by:
❑ Specific
antibodies toward the tyrosine
kinase enzyme.
❑ Specificantibodies toward the tyrosine
kinase receptor domain.
Cont.

❑ Another
strategies is development of anti-
angiogenesis agents.
❑ Gene therapy.
❑ Oncolytic viruses.
❑ Telomerase inhibitors.
❑ Selectively targeting cancer stem cells.
 Cancer cells resist
the drugs through
these mechanisms.
Personalized anti-cancer therapy

❑ Empirical
use of anti-cancer lead to
development of drug resistance and
development of severe side effects.
❑ Molecular profiling of the cancer in every
patients allows oncologist to select the
best drug for that patient.
Thank You