Robbins Basic Pathology ,7ed

Kumar, Cotran, Robbins

CARCINOGENESIS
THE MOLECULAR BASIS OF CANCER

Dr.Fairuz Quzwain, SpPA,M.Kes

Fundamental Principles
Non lethal genetic damages lies at the heart of
carcinogenesis
Four classes of normal regulatory
genes :

Growth promoting protooncogenes

Growth inhibiting cancer supressor genes
Genes that regulated apoptosis
Genes that repaired damage DNA

Carcinogenesis is a multistep process at both

phenotypic & genetic levels.

Success repair

DNA damaging agent:

Chemical
Radiation
Viruses

NORMAL CELLS

DNA DAMAGE
Failure repair

Mutation in the
Genome of Somatic Cells

Inactivation of
Activatiion of
Alteration of
Cancer Suppressor
Growth Promoting
Genes that
Genes
Oncogenes
Regulated Apoptosis

Expresion of Altered Gene Product

& Lost of Regulatory Gene Product

Inheritaged Mutations in:

Genes Affecting DNA repair
Genes Affecting Cell Growth
or Apoptosis

Clonal expansion
Additional Mutation
Heterogenecity

Malignant Neoplasm

6 Fundamental Changes
in Cell Physiology

Self sufficiency in Growth Signals

Insensitivity in Growth Inhibitory Signals
Evasion of Apoptosis
Limitless Replicative Potential
Sustained Angiogenesis
Ability to Invade/Metastasize

Self sufficiency in Growth Signals

Growth Factors
PDGF, TGF-

Growth Factor Receptors

ERBB1 (EGF), ERBB2

Signal Transducing Proteins

RAS, ABL

Nuclear Transcription Factor

MYC,MYB,JUN,FOS,REL

Cyclin & Cyclin Dependent

Kinase

Signal Transducing Proteins

GF

GF + reseptor
i_RAS (GDP)

GAP

a_RAS (GTP)

MAP kinase

PROLIFERATION

Cyclin & Cyclin Dependent Kinase

CDKI_r21
CDKI_r27
CDKI_r52

G0
M

CDKI_p15
CDKI_p16
CDKI_p18
CDKI_p19

G1
a_RB

CDK 1

CDK 2
CDK 4

i_RB

S
CDK 1
CDK 2

CYCLIN

G2

CDK 6

CYCLIN

CYCLIN

GROWTH
FACTOR

6 Fundamental Changes
in Cell Physiology
Self sufficiency in Growth Signals

Insensitivity in Growth
Inhibitory Signals

Evasion of Apoptosis
Limitless Replicative Potential
Sustained Angiogenesis
Ability to Invade/Metastasize

Insensitivity in Growth Inhibitory

Signals
RB gene & Cell Cycle
Transforming Growth Factor
Pathway
Adenomatous Polyposis Coli
Catenin Pathway
TP 53 gene

RB gene & Cell Cycle

CDKI_r21
CDKI_r27
CDKI_r52

G0
M

CDKI_p15
CDKI_p16
CDKI_p18
CDKI_p19

G1
a_RB

CDK 1

CDK 2
CDK 4

i_RB

S
CDK 1
CDK 2

CYCLIN

G2

CDK 6

CYCLIN

CYCLIN

GROWTH
FACTOR

RB gene & Cell Cycle

S

G1
a_RB

i_RB
CYCLIN

CDK 2
CDK 4
CDK 6

Adenomatous Polyposis Coli

Catenin Pathway
WNT

WNT reseptors
E-cadherin

APC

signals

APC

catenin
catenin

No Proliferation

APC

Normal
Proliferation

catenin

Proliferation

Normal Cell
[TP 53 normal]

TP 53 gene

DNA damage

TP 53 activated

Transcriptional UpRegulation
Of Target Genes

Normal Cell

DNA damage
TP 53 not activated

No Cell
Cycle Arrest

No DNA
Repair

Mutant Cell

DNA repair
P21[CDK Inhib]

AbNormal Cell
[TP 53 AbNormal

BAX [Apoptosis gene]

Apoptosis

Expansion &
Additional
Mutation
Malignant Tumor

Selected Tumor Suppressor Genes Responsible for Familial Cancer Syndromes

Syndrome

Gene

Chromosome
Location

Tumors

Basal cell nevus

PTC

9q22.3

Basal cell cancer, jaw cysts, medulloblastoma

Familial breast/ovarian
cancer

BRCA1

17q21

Breast, ovarian, colon, prostate cancer

Familial breast cancer

BRCA2

13q12-13

Breast cancer, male breast cancer

Familial melanoma

p16

9p21

Melanoma, pancreatic cancer

Familial polyposis coli

APC

5q21

Intestinal polyposis, colorectal cancer

Familial retinoblastoma

RB

13q24

Retinoblastoma, osteosarcoma

Familial Wilms' tumor

WT1

11p13

Wilms' tumor, WAGRa

Hereditary multiple
exostoses

EXT1

11p11-13

Exostoses, chondrosarcoma

Li-Fraumeni

p53

17q13

Sarcomas, breast cancer

Neurofibromatosis type 1

NF1

17q11.2

Neurofibroma, neurofibrosarcoma, brain tumor

Neurofibromatosis type 2

NF2

22q12

Acoustic neuroma, meningioma

Tuberous sclerosis

TSC2

16p13.3

Angiofibroma, renal angiomyolipoma

Von Hippel-Lindau

VHL

3p25-26

Renal cell cancer, pheochromocytoma, retinal

angioma, hemangioblastoma

a WAGR, Wilms' tumor, aniridia, genitourinary abnormalities, and mental retardation.

6 Fundamental Changes
in Cell Physiology
Self sufficiency in Growth Signals
Insensitivity in Growth Inhibitory Signals

Evasion of Apoptosis
Limitless Replicative Potential
Sustained Angiogenesis
Ability to Invade/Metastasize

Limitless Replicative Potential

Most Normal Human Cells,
have 60-70 doublings
Telomeres Shortening
Active RB & TP53
Active CDKN2A

RB gene & Cell Cycle

CDKI_r21
CDKI_r27
CDKI_r52

G0
M

CDKI_p15
CDKI_p16
CDKI_p18
CDKI_p19

G1
a_RB
TP53 check point

CDK 1

CDK 4
i_RB

S
CDK 1
CDK 2

CYCLIN

G2

CDK 2
CDK 6

CYCLIN

CYCLIN

GROWTH
FACTOR

Normal Cell
[TP 53 normal]

TP 53 gene

AbNormal Cell
[TP 53 AbNormal
DNA damage

DNA damage

TP 53 not activated

TP 53 activated
Transcriptional UpRegulation
Of Target Genes

No Cell
Cycle Arrest

Mutant Cell

DNA repair
P21[CDK Inhib]

Normal Cell

No DNA
Repair

BAX [Apoptosis gene]

Apoptosis

Expansion &
Additional
Mutation
Malignant Tumor

Sustained Angiogenesis
Tumors cannot enlarge beyond 1-2mm
unless they are vascularized
Dual effect of new vascularization
To growth
To spread

Angiogenic vs antiangiogenic factor

Angiogenic Factors
Hypoxia
VEGF
bFGF

FGF-1,2
Angiogenin
TGF ,
TNF
PDEGF
IL-8
Proliferin
Leptin

Malignant Cells
TP53

Thrombospondin-1

Plasminogen Angiostatin
Collagen
Vasculostatin
Transthyretin Endostatin

Other Cells
Platelet F 4
Interferon Alpha
IL-12
Troponin
Maspin

Antiangiogenic Factors

Ability to Invade/Metastasize
Invasion of Extra Cellular Matrix
Detachment of tumor cells from each
other
Attachment of tumor cells to matrix
component
Degradation of ECM
Migration of Tumor Cells

Vascular Dissemination & Homing

of Tumor Cells

WNT reseptors

Normal

Malignant

WNT

E-cadherin

signals

APC

catenin
catenin

A PC

APC
cat
enin

ECM

integrin

fibronectin
laminin

 Individuals born w/ such a inheritage mutations

of DNA repair Protein are the greatly increase
risk of developing Cancer
Each cancer, must result from accumulation of
multiple mutations.
Despite the fact that most malignant tumor are
monoclonal in origin, by the tumor they clinically
evident, their constituent cells are extremely
heterogenous

Tumor Markers

Cancer

Non-Neoplastic Conditions

Human chorionic gonadotropin

Gestational trophoblastic disease,

gonadal germ cell tumor

Pregnancy

Calcitonin

Medullary cancer of the thyroid

Catecholamines

Pheochromocytoma

HORMONES

ONCOFETAL ANTIGENS
Alphafetoprotein

Hepatocellular carcinoma,
gonadal germ cell tumor

Cirrhosis, hepatitis

Carcinoembryonic antigen

Adenocarcinomas of the colon,

pancreas, lung, breast, ovary

Pancreatitis, hepatitis,
inflammatory bowel disease,
smoking

Prostatic acid phosphatase

Prostate cancer

Prostatitis, prostatic hypertrophy

Neuron-specific enolase

Small cell cancer of the lung,

neuroblastoma

Lactate dehydrogenase

Lymphoma, Ewing's sarcoma

ENZYMES

Hepatitis, hemolytic anemia,

TUMOR-ASSOCIATED PROTEINS
Prostate-specific antigen

Prostate cancer

Prostatitis, prostatic hypertrophy

Monoclonal immunoglobulin

Myeloma

Infection, MGUSa

CA-125

Ovarian cancer, some lymphomas

Menstruation, peritonitis,
pregnancy

CA 19-9

Colon, pancreatic, breast cancer

Pancreatitis, ulcerative colitis

CD30

Hodgkin's disease,
anaplastic large cell lymphoma

CD25

Hairy cell leukemia,

adult T cell leukemia/lymphoma

Carcinogens and Associated Cancers or Neoplasms

Carcinogensa

Associated Cancer or Neoplasm

Alkylating agents

Acute myelocytic leukemia, bladder cancer

Androgens

Prostate cancer

Aromatic amines (dyes)

Bladder cancer

Arsenic

Cancer of the lung, skin

Asbestos

Cancer of the lung, pleura, peritoneum

Benzene

Acute myelocytic leukemia

Chromium

Lung cancer

Diethylstilbestrol (prenatal)

Vaginal cancer (clear cell)

Epstein-Barr virus

Burkitt's lymphoma, nasal T cell lymphoma

Estrogens

Cancer of the endometrium, liver

Ethyl alcohol

Cancer of the liver, esophagus, head and neck

Helicobacter pylori

Gastric cancer

Hepatitis B or C virus

Liver cancer

Human immunodeficiency virus

Non-Hodgkin's lymphoma, Kaposi's sarcoma,

squamous cell carcinomas (especially of the urogenital
tract)
Human papilloma virus

Human T cell lymphotropic virus

type I (HTLV-I)

Adult T cell leukemia/lymphoma

Carcinogens and Associated Cancers or Neoplasms

Carcinogensa

Associated Cancer or Neoplasm

Immunosuppressive agents
(azathioprine, cyclosporine,
glucocorticoids)

Non-Hodgkin's lymphoma

Nitrogen mustard gas

Cancer of the lung, head and neck, nasal sinuses

Nickel dust

Cancer of the lung, nasal sinuses

Phenacetin

Cancer of the renal pelvis and bladder

Polycyclic hydrocarbons

Cancer of the lung, skin (especially squamous cell

carcinoma of scrotal skin)

Schistosomiasis

Bladder cancer (squamous cell)

Sunlight (ultraviolet)

Skin cancer (squamous cell and melanoma)

Tobacco (including smokeless)

Cancer of the upper aerodigestive tract, bladder

Vinyl chloride

Liver cancer (angiosarcoma)

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