Carcinogenesis
Carcinogenesis
Carcinogenesis
DR. AYSER HAMEED
LEC.4
Carcinogenesis:
is a multistep process at
both
phenotypic & genetic levels.
Phenotypic level
includes:
I. Excessive growth.
II. Local invasion.
III. Metastasis.
These three criteria are called collectively
Tumor Progression
.
Genetic level
includes:
Six changes in normal cell physiology,
that results in cancer formation
These changes are included:
1. Autonomous growth:
This pattern of growth of cancer is under
the control of
Oncogenes
(genes
derived
from Protoncogenes).
These oncogenes produced
oncoproteins (growth factors), which
result in autonomous growth of
cancer
.
Mechanisms of action of oncoproteins:
By following steps:-
Step-I;
The
binding of growth factor
(Oncoproteins) to
specific receptors
on cell
membrane.
Malignant cells acquire autonomous
growth by followings:-
1. Acquiring the ability to synthesize the
same growth factors to which they responsive
(gene overexpression).
2. Pathological overexpression of normal
growth factor receptors,
Her2 receptors
are
overexpressed in 25- 30% of breast, lung
carcinoma.
Step- II; Growth factor & receptor
complex activate several proteins on
inner side of cell membrane
(transient
activation under normal state while
persistent activation under neoplastic
conditions).
Step- III;
Transmission of signals from
these proteins
along inner side of cell
membrane along the cytoplasm
to the
nucleus via secondary messenger.
Step- II & III: this is called (singling
pathway)
.
Two important genes that control this
pathway (
Ras
….increase cells proliferation
&
ABL…
……inhibit cell proliferation).
Cancer cells acquire autonomous growth is
by
mutation in these genes that
control the signaling pathway
(
transfer
of signal from inner side of cell membrane
to nucleus).
So
mutant Ras
is the most common
oncogene abnormalities in human tumors
Mutant Ras gene are present in 35% of
human cancers (carcinoma of colon,
carcinoma of pancreas……etc)
Model for action of
RAS
genes. When a normal cell is stimulated through a growth factor
receptor, inactive (GDP-bound) RAS is activated to a GTP-bound state. Activated
RAS recruits
RAF and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the
nucleus. The mutant RAS protein is permanently activated because of inability to
hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The
anchoring of RAS to the cell membrane by the farnesyl moiety is essential for its action.
Step- IV;
Activation of transcription inside the
nucleus
.
Mutations affect the genes that regulate
transcription of DNA may result in autonomous
growth of cancers.
e.g.
Myc gene
is commonly involved in human
tumors like in carcinoma of colon, breast, lung)..
Step- V;
Entry of cell into the cell cycle
& result in
cell division.
Normal cell cycle is consists of five phases (G
0
,G
1
,
S, G
2
, M).
All these phases are under control of proteins
(Cyclins & Cyclins dependent Kinase).
Cyclin D overexpression is seen in many cancers
(breast, esophagus & liver).
The chromosomal translocation and associated oncogenes in Burkitt lymphoma and
chronic myelogenous leukemia.
Amplification of the N-
MYC
gene in human neuroblastomas. The N-
MYC
gene, normally
present on chromosome 2p, becomes amplified and is seen either as extra
chromosomal
double minutes or as a chromosomally integrated, homogeneous staining region. The
integration involves other autosomes, such as 4, 9, or 13.
2. Insensitivity to inhibitory signals
(
disruption of tumor suppressor genes):
Disruptions of
tumor suppressor genes
make the
cells resistant to inhibition of
growth & increase their proliferation.
All tumor suppressor genes are caused
inhibition of cell growth by two pathways:
I. stimulate antigrowth signal, causing cells
to enter G
0
phase.
II. Prevent the cell to pass from phase G
1
to S phase.
Examples of Tumor suppressor genes:
1. RB gene:
This is the
first discovered suppressor
gene
,
loss of normal RB gene was
discovered initially in Retinoblastoma, but
recently proved it lost in many tumors
(breast cancer, bladder & lung cancer,
osteosarcoma).
Both alleles of RB gene most be
mutant
in order to regard this gene is
mutant.
Pathogenesis of retinoblastoma. Two mutations of the
RB
locus on chromosome 13q14 lead to neoplastic
proliferation of the retinal cells. In the familial form, all somatic cells
inherit one mutant
RB
gene from a
carrier parent. The second mutation affects the
Rb
locus in one of the retinal cells after birth. In the sporadic
form, on the other hand, both mutations at
the
RB
locus are acquired by the retinal cells after birth.
2. Adenomatous Polyposis coli (APC)
gene:
Loss of this gene can be seen in 70- 85%
of sporadic carcinoma of colon.
Individuals born with loss or mutant of one
of alleles of APC gene, they develop
hundreds to thousands of adenomatous
polyps in the colon which on second
decade of life one or more of these polyps
will undergo malignant transformation.
A,
The role of APC in regulating the stability and function of
-catenin. APC and
-catenin are components of the WNT signaling pathway. In
resting cells (not exposed to
WNT),
-catenin forms a macromolecular complex containing the APC protein. This complex leads to the
destruction of
-catenin, and intracellular levels of
-catenin are low.
B,
When
cells are stimulated by secreted WNT molecules, the
destruction
complex
is deactivated,
-catenin degradation does not occur, and cytoplasmic levels increase.
-catenin translocates to the
nucleus, where it binds to TCF, a transcription factor that activates several genes involved in the cell cycle.
C,
When
APC
is mutated or absent,
the destruction of
-catenin cannot occur.
-
Catenin translocates to the nucleus and coactivates genes that promote the cell cycle, and cells
behave as if they are under constant stimulation by the WNT pathway.
3. TP53:
It is one of most commonly mutated in human
cancers, it exert its
antiproliferative effects by
:-
I. Arrest cell cycle at late G
1
phase & remain the
cells in the G
0
phase (cell cycle pause) to allow a
time for DNA repair.
II. Stimulate Apoptosis.
III. Helping in repair of DNA.
•
More than 70% of malignant human tumor show
defect in functions of TP53
•
Most of mutations in TP53 are acquired & less
commonly they are inherited mutations like
Li-
fraumeni syndrome
(patient have many
cancers like sarcomas, breast cancer, leukemia,
brain tumors, adrenal tumors).
The role of
p53
in maintaining the integrity of the genome. Activation of normal
p53
by DNA-damaging agents or by
hypoxia leads to cell-cycle arrest in G1 and induction of
DNA repair, by transcriptional up-regulation of the cyclin-
dependent
kinase inhibitor
p21,
and the
GADD45
genes, respectively. Successful repair of DNA allows cells to proceed
with the
cell cycle; if DNA repair fails,
p53
-induced activation of the
BAX
gene promotes apoptosis. In cells with loss
or mutations of
p53,
DNA damage does not induce cell-cycle arrest or DNA
repair, and hence genetically damaged
cells proliferate, giving rise eventually to malignant neoplasms.
The multistep process of carcinogenesis at both phenotypic and genetic levels, including excessive growth, local invasion, and metastasis. Explore the six changes in normal cell physiology that result in cancer formation and the mechanisms of action of oncoproteins. Discover the role of important genes in controlling the signaling pathway and the model for action of RAS genes.
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Presentation Transcript
Carcinogenesis DR. AYSER HAMEED LEC.4
Carcinogenesis: is a multistep process at both phenotypic & genetic levels. Phenotypic level includes: I. Excessive growth. II. Local invasion. III. Metastasis. These three criteria are called collectively Tumor Progression.
Genetic level includes: Six changes in normal cell physiology, that results in cancer formation These changes are included: 1. Autonomous growth: This pattern of growth of cancer is under the control of Oncogenes (genes derived from Protoncogenes). These oncogenes produced oncoproteins (growth factors), which result in autonomous growth of cancer.
Mechanisms of action of oncoproteins: By following steps:- Step-I; The binding of growth factor (Oncoproteins) to specific receptors on cell membrane. Malignant cells acquire autonomous growth by followings:- 1. Acquiring the ability to synthesize the same growth factors to which they responsive (gene overexpression). 2. Pathological overexpression of normal growth factor receptors, Her2 receptors are overexpressed in 25- 30% of breast, lung carcinoma.
Step- II; Growth factor & receptor complex activate several proteins on inner side of cell membrane (transient activation under normal state while persistent activation under neoplastic conditions). Step- III; Transmission of signals from these proteins along inner side of cell membrane along the cytoplasm to the nucleus via secondary messenger. Step- II & III: this is called (singling pathway).
Two important genes that control this pathway (Ras .increase cells proliferation & ABL inhibit cell proliferation). Cancer cells acquire autonomous growth is by mutation in these genes that control the signaling pathway (transfer of signal from inner side of cell membrane to nucleus). So mutant Ras is the most common oncogene abnormalities in human tumors Mutant Ras gene are present in 35% of human cancers (carcinoma of colon, carcinoma of pancreas etc)
Model for action of RAS genes. When a normal cell is stimulated through a growth factor receptor, inactive (GDP-bound) RAS is activated to a GTP-bound state. Activated RAS recruits RAF and stimulates the MAP-kinase pathway to transmit growth-promoting signals to the nucleus. The mutant RAS protein is permanently activated because of inability to hydrolyze GTP, leading to continuous stimulation of cells without any external trigger. The anchoring of RAS to the cell membrane by the farnesyl moiety is essential for its action.
Step- IV; Activation of transcription inside the nucleus. Mutations affect the genes that regulate transcription of DNA may result in autonomous growth of cancers. e.g. Myc gene is commonly involved in human tumors like in carcinoma of colon, breast, lung).. Step- V; Entry of cell into the cell cycle & result in cell division. Normal cell cycle is consists of five phases (G0 ,G1 , S, G2 , M). All these phases are under control of proteins (Cyclins & Cyclins dependent Kinase). Cyclin D overexpression is seen in many cancers (breast, esophagus & liver).
The chromosomal translocation and associated oncogenes in Burkitt lymphoma and chronic myelogenous leukemia.
Amplification of the N-MYC gene in human neuroblastomas. The N-MYC gene, normally present on chromosome 2p, becomes amplified and is seen either as extra chromosomal double minutes or as a chromosomally integrated, homogeneous staining region. The integration involves other autosomes, such as 4, 9, or 13.
2. Insensitivity to inhibitory signals (disruption of tumor suppressor genes): Disruptions of tumor suppressor genes make the cells resistant to inhibition of growth & increase their proliferation. All tumor suppressor genes are caused inhibition of cell growth by two pathways: I. stimulate antigrowth signal, causing cells to enter G0 phase. II. Prevent the cell to pass from phase G1 to S phase.
Examples of Tumor suppressor genes: 1. RB gene: This is the first discovered suppressor gene, loss of normal RB gene was discovered initially in Retinoblastoma, but recently proved it lost in many tumors (breast cancer, bladder & lung cancer, osteosarcoma). Both alleles of RB gene most be mutant in order to regard this gene is mutant.
Pathogenesis of retinoblastoma. Two mutations of the RB locus on chromosome 13q14 lead to neoplastic proliferation of the retinal cells. In the familial form, all somatic cells inherit one mutant RB gene from a carrier parent. The second mutation affects the Rb locus in one of the retinal cells after birth. In the sporadic form, on the other hand, both mutations at the RB locus are acquired by the retinal cells after birth.
2. Adenomatous Polyposis coli (APC) gene: Loss of this gene can be seen in 70- 85% of sporadic carcinoma of colon. Individuals born with loss or mutant of one of alleles of APC gene, they develop hundreds to thousands of adenomatous polyps in the colon which on second decade of life one or more of these polyps will undergo malignant transformation.
A, The role of APC in regulating the stability and function of -catenin. APC and -catenin are components of the WNT signaling pathway. In resting cells (not exposed to WNT), -catenin forms a macromolecular complex containing the APC protein. This complex leads to the destruction of -catenin, and intracellular levels of -catenin are low. B, When cells are stimulated by secreted WNT molecules, the destruction complex is deactivated, -catenin degradation does not occur, and cytoplasmic levels increase. -catenin translocates to the nucleus, where it binds to TCF, a transcription factor that activates several genes involved in the cell cycle. C, When APC is mutated or absent, the destruction of -catenin cannot occur. - Catenin translocates to the nucleus and coactivates genes that promote the cell cycle, and cells behave as if they are under constant stimulation by the WNT pathway.
3. TP53: It is one of most commonly mutated in human cancers, it exert its antiproliferative effects by:- I. Arrest cell cycle at late G1 phase & remain the cells in the G0 phase (cell cycle pause) to allow a time for DNA repair. II. Stimulate Apoptosis. III. Helping in repair of DNA. More than 70% of malignant human tumor show defect in functions of TP53 Most of mutations in TP53 are acquired & less commonly they are inherited mutations like Li- fraumeni syndrome (patient have many cancers like sarcomas, breast cancer, leukemia, brain tumors, adrenal tumors).
The role of p53 in maintaining the integrity of the genome. Activation of normal p53 by DNA-damaging agents or by hypoxia leads to cell-cycle arrest in G1 and induction of DNA repair, by transcriptional up-regulation of the cyclin- dependent kinase inhibitor p21, and the GADD45 genes, respectively. Successful repair of DNA allows cells to proceed with the cell cycle; if DNA repair fails, p53-induced activation of the BAX gene promotes apoptosis. In cells with loss or mutations of p53, DNA damage does not induce cell-cycle arrest or DNA repair, and hence genetically damaged cells proliferate, giving rise eventually to malignant neoplasms.
