Cancer

Uncontrolled- growth at the usual rate, but

then keep growing when other cells would
normally stop- ignore stopping signals, or
grow w/o added signals.
Invasive
Immortal- normal cells undergo
senescence
Chromosomal abnormalities- aneuploid
Well-behaved-
stop growing
when they cover
the dish.
Not well-
behaved- keep
growing after
they cover the
dish.
Normal Cells Cancer Cells
DCC = deleted in colorectal carcinoma
APC = Adenomatous polyposis coli
RAS = Rat Sarcoma
TP53 = Tumour Protein 53
 Apoptosis
Apoptosis or programmed cell death, is carefully
coordinated collapse of cell, protein degradation ,
DNA fragmentation followed by rapid engulfment of
corpses by neighbouring cells. (Tommi, 2002)

Essential part of life for every multicellular organism

from worms to humans. (Faddy et al.,1992)

Apoptosis plays a major role from embryonic

development to senescence.
Apoptosis

Cell death by injury

-Mechanical damage
-Exposure to toxic chemicals
Cell death by suicide
-Internal signals
-External signals
Why should a cell commit suicide?

Apoptosis is needed for proper development

Examples:
The formation of the fingers and toes of the fetus
The sloughing off of the inner lining of the uterus
The formation of the proper connections between neurons in the
brain
Apoptosis is needed to destroy cells
Examples:
Cells infected with viruses
Cells of the immune system
Cells with DNA damage
Cancer cells
What makes a cell decide to commit
suicide?
Withdrawal of positive signals
examples :
growth factors for neurons
Interleukin-2 (IL-2)

Receipt of negative signals

examples :
increased levels of oxidants within the cell
damage to DNA by oxidants
death activators :
Tumor necrosis factor alpha (TNF-)
Lymphotoxin (TNF-)
Fas ligand (FasL)
STAGES OF APOPTOSIS

Induction of apoptosis related genes, signal transduction

Sherman et al., 1997

 APOPTOSIS: Morphology

organelle
reduction
membrane
blebbing &
changes
cell
mitochondrial
shrinkage
leakage

nuclear
fragmentation chromatin
condensation

Hacker., 2000
Two Caspase Pathways

Extrinsic Pathway

Death Ligand

Death Receptors

Caspases

Cell Death
Two Caspase Pathways

Intrinsic Pathway
BAX
BAK
BOK Mitochondria
BCL-Xs
BAD

BID
B IK
Cytochrome C
BIM
NIP3
BNIP3 Apoptosome
Complex

Caspases

Cell Death
 Oncogenes
Oncogene: onco (cancer) gene
J. Michael Bishop and Harold Varmus (1989) Nobel
Prize in Medicine or Physiology: The Discovery of
the Cellular Origin of Retroviral Oncogenes
Proto-oncogenes: normal cellular genes usually
involved in cell growth and/or cell division
Oncogenes: a proto-oncogene that has been
activated by mutation or overexpression. Results
in a dominant gain of function phenotype
Growth Factors, Growth Factor Receptors, G-
proteins, Kinases, Gene Regulatory Proteins
 Oncogene Activation

Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian;
Raff, Martin; Roberts, Keith; Walter, Peter. New York and London: Garland Science;
c2002
 Retroviruses

Retroviruses are members of one family of RNA viruses

that cause cancer in variety of animals and humans.
The Retrovirus is made of 3 main genes gag, pol & env that
are required for virus replication but not play role in cell
transformation.
a retrovirus can transform cells from normal to cancer if
they include a specific gene that is capable of inducing cell
transformation this gene is known as Oncogene.

Retrovirus

Cancerous
Retrovirus Oncogene
Retrovirus oncogene
Two main types of oncogenes:
Viral oncogene: gene from the retrovirus itself
Non-Viral oncogene (Cellular oncogene): genes derived
from the genes of the host cell that are in an inactive form
usually. Occasionally if the gene incorporates with the viral
genome will form a highly oncogenic virus.
Proto-oncogenes: are the form of cellular genes that
inactive normally but can incorporate with the viral
genome to produce a highly oncogenic virus.
 Proto-Oncogene Oncogene
The proto-oncogene become oncogene by:
1. Mutation:
Example: mutation in Ras gene Continuous
activation of Ras by (constitutively in the GTP-bound
conformation) Unregulated cell proliferation
Cell transformation.
 Proto-Oncogene Oncogene
2. Abnormal Activity:
Example: Removal of the Regulatory domain in the Raf gene
and replaced by gag gene Raf kinase domain
consciously active Cell transformation

Raf Proto-oncogene
Regulatory Domain Protein Kinase Domain

Raf oncogene
gag Protein Kinase Domain
Proto-Oncogene Oncogene
3. Gene translocation:
Example: c-myc gene is
translocated from
chromosome 8 to the IgH
on the chromosome 14
resulting in abnormal
c-myc expression
Cell transformation
Functions of oncogene
1. Growth Factor (example, Epithelium growth factor EGF ,
and platelet derived growth factor PDGF)
2. Growth Factor Receptor (Example; PDGFR)
3. Signal transudation (example; Ras, Raf, & MEK)
4. Transcription Factor (example; Jun, Fos, Elk-1 & myc)
Oncogenes
Oncogene causes cancer by affecting:
1. Cell Proliferation: (example; Ras, Raf, EGF)
2. Cell differentiation (example, PML/RAR that inhibits
the differentiation of promyelocyte to granulocyte which
will maintain the cell in its active proliferate state)
3. Cell Survival (example; Pl-3/AKT which will activate
BCL-2 inhibit Apoptosis & maintain cell
survival.
MYC Oncogene
Myc (c-Myc) is a regulator gene that codes for transcription
factor
A mutated version of Myc is found in many cancers, which
causes Myc to be constitutively expressed
Normal nondividing cells
Myc levels are low but responsive to growth signals from
the cellular environment
Dividing cells
Myc levels constantly maintained at an intermediate level
throughout cell cycle
Oncogenic MYC
Point mutation prevents MYC degradation allows for
accumulation of high levels of MYC
Increased transcriptional activity
 Common Human
Oncogenes

The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000
Tumour Suppressor Genes
Tumour Suppressor genes: are genes that act to
inhibit cell proliferation and tumour development.

If Tumor Suppresor Gene was

Mutated OR Inactivated

It will lead to cell transformation

 Tumor Suppressor Genes
Genes that are normally involved in the inhibition of
cell growth and proliferation.
Tumor suppressor genes act in a recessive manner
Need loss of both alleles to progress towards cancer

Molecular Biology of the Cell. Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin;
Roberts, Keith; Walter, Peter. New York and London: Garland Science; c2002
Common Human Tumor Suppressor Genes

The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.;
c2000
Retinoblastoma (Rb) Tumor Suppressor
Gene

The Cell - A Molecular Approach. Cooper, Geoffrey M. Sunderland (MA): Sinauer Associates, Inc.; c2000

Rb prevents E2F transcription factor from transcribing genes

inappropriately

Loss of Rb allows for unregulated gene transcription

 Tumour Suppressor Genes

Mutation of the tumour suppressor gene will

cause cancer.
Example; deletion of Rb gene will cause
retinoblastoma. The development of retinoblastoma
can be either:
Hereditary: a defective copy of Rb gene is inherited from
the affected parents.
Nonhereditary: in which 2 normal Rb genes are inherited
and develop mutation during life.
Retinoblastoma is developed if 2 somatic mutations
inactivate both copies of Rb in the same cell.
p53 Tumor Suppressor Gene

p53 is the single most

common target for genetic
insults leading to cancer

DNA damage stabilizes p53

and allows for p53 accumulation

p53 induces p21 (CDKN1A, CIP1,

WAF1) to cause cell cycle arrest

Robbins & Cotran Basic Pathology 7th ed

Tumour Suppressor Genes
Inactivation of Tumour suppressor gene will cause cancer.
If the Rb gene interact with DNA tumour virus (SV40) it will
induce cell transformation.

SV40
Function of Tumour Suppressor gene

1. Antagonize the action of oncogene. (ex. PTEN which

converts PIPIII to PIPII because PIPIII will activate Pl-
3/AKT which will activate BCL-2 that will inhibit apoptosis
and induce cell transformation)

PTEN
PIPII PIPIII
PI-3
AKT

BCL-2

Inhibit apoptosis & induce

cell transformation
Function of Tumour Suppressor gene

2. Transcription factors
Repressor transcription factors: example; WT1 is a
repressor that appears to suppress transcription factor
( Insulin like growth factor) which will contribute in the
development of tumour.
Activator transcription factors: example; SMAD family
that are activated by TGF-, leading to inhibition of cell
proliferation.
Function of Tumour Suppressor gene

3. Regulate cell cycle:

Rb gene: that inhibits the cell cycle in the G1 phase
decrease cell proliferation.
INK-4 gene: that produces P16 that inhibits
cdk4/cyclin D action ( to phosphorylate Rb gene to
inactivate its action)
P53: that produces P21 that has the same action of P16 in
inhibiting the action of cdk4/cyclin D
Regulate cell cycle
P16
P
Cdk4/cyclin D
Rb Rb
Rb inactive

G1
G1 S
S

M G2 M G2

Cell Cycle Blocked Cell Cycle Proceeds

Function of Tumour Suppressor gene

4. Induce apoptosis:
P53 release will increase Bax form
holes in the mitochondria release cytochrom c
activate apoptosis
In Males
Male
In Females
 Breast/Ovarian Cancer
BRCA1 was first linked to chromosome 17q21 and subsequently
isolated in 1994.
BRCA1 encode large proteins of 1863 a. acids
BRCA1 may also play a role in transcription regulation, cell cycle
control, and development
BRCA2, on chromosome 13q12
BRCA2 encode large proteins of 3350 a. acids
BRCA1 or BRCA2 mutation may be running in a family include:
Early-onset breast cancer (before menopause) in several relatives over
different generations;
Ovarian cancer in addition to breast cancer among relatives;
Relatives who have breast cancer in both breasts;
Relatives who have had both breast and ovarian cancer;
BRCA1 or BRCA2 mutation have a significantly increased risk of
developing breast and ovarian cancer during their lifetime
LUNG CANCER
Adenocarcinoma Of Lung
Non-small Cell Lung Cancer
Gene map locus
17q21.1, 12p12.1, 11q22-q24, 11p15.5, 10p11.2, 7q34, 7p12.3-p12.1, 6q25.
2-q27,
3p22-p21.3
including SLC22A1L, TP53, KRAS2, BRAF, and EGFR, can be involved
in the pathogenesis of lung cancer.
Official Symbol: DLEC1
Official Full Name: deleted in lung and esophageal cancer 1
Gene type: protein coding
Summary: This gene contains 37 exons, spans approximately 59-kb, and is
located in the 3p22-p21.3 chromosomal segment that is commonly deleted
in various carcinomas. Several alternatively spliced transcripts have been
observed that contain disrupted coding regions and likely encode
nonfunctional proteins. Aberrant transcription of this gene may be involved
in carcinogenesis of the lung, esophagus, and kidney.
Official Symbol: SLC22A18
Official Full Name: solute carrier family 22 (organic cation
transporter
Gene type: protein coding
Summary: This gene is one of several tumor-suppressing sub
transferable fragments located in the imprinted gene domain of
11p15.5, an important tumor-suppressor gene region.
Alterations in this region have been associated with the Wilms
tumor, adrenocortical carcinoma, and lung, ovarian, and breast
cancer. This gene may play a role in malignancies and disease
that involve this region as well as the transport of chloroquine-
and quinidine-related compounds in the kidney.