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 NORMAL CELLS DNA DAMAGE
Viruses
Failure repair

Mutation in the
Genome of Somatic Cells

Activatiion of Alteration of Inactivation of

Growth Promoting Genes that Cancer Suppressor
Oncogenes Regulated Apoptosis Genes

Inheritaged Mutations in:

Genes Affecting DNA repair
Expresion of Altered Gene Product Genes Affecting Cell Growth
& Lost of Regulatory Gene Product 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-å
• 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) a_RAS (GTP)

GAP MAP kinase

PROLIFERATION
 Cyclin & Cyclin Dependent Kinase
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1

CYCLIN

CYCLIN
a_RB CDK 2
CDK 1 CDK 4
i_RB CDK 6

G2 S

CYCLIN
GROWTH
FACTOR
CDK 1
CDK 2
 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 β
Pathway
• Adenomatous Polyposis Coli β
Catenin Pathway
• TP 53 gene
 RB gene & Cell Cycle
CDKI_r21 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1

CYCLIN

CYCLIN
a_RB CDK 2
CDK 1 CDK 4
i_RB CDK 6

G2 S

CYCLIN
GROWTH
FACTOR
CDK 1
CDK 2
 RB gene & Cell Cycle

G1 S

a_RB i_RB

CYCLIN CDK 2
CDK 4
CDK 6
 Adenomatous Polyposis Coli
β Catenin Pathway
WNT reseptors WNT
E-cadherin

signals
APC
APC
β catenin
β catenin APC β catenin

No Proliferation Normal Proliferation

Proliferation
Normal Cell TP 53 gene AbNormal Cell
[TP 53 normal] [TP 53 AbNormal

DNA damage M G DNA damage

TP 53 activated G S TP 53 not activated

Transcriptional UpRegulation
G No Cell No DNA
Of Target Genes
Cycle Arrest Repair

DNA repair Mutant Cell

Expansion &
P21[CDK Inhib] BAX [Apoptosis gene] Additional
Mutation

Normal Cell Apoptosis Malignant Tumor

Selected Tumor Suppressor Genes Responsible for Familial Cancer Syndromes
Syndrome Gene Chromosome Tumors
Location
Basal cell nevus PTC 9q22.3 Basal cell cancer, jaw cysts, medulloblastoma
Familial breast/ovarian BRCA1 17q21 Breast, ovarian, colon, prostate cancer
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 EXT1 11p11-13 Exostoses, chondrosarcoma
exostoses
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 G0 CDKI_p15
CDKI_p16
CDKI_r27
CDKI_r52 CDKI_p18
CDKI_p19
M G1

CYCLIN

CYCLIN
a_RB CDK 2
CDK 1 TP53 check point
CDK 4
i_RB CDK 6

G2 S

CYCLIN
GROWTH
FACTOR
CDK 1
CDK 2
Normal Cell TP 53 gene AbNormal Cell
[TP 53 normal] [TP 53 AbNormal

DNA damage DNA damage

TP 53 activated TP 53 not activated

Transcriptional UpRegulation
No Cell No DNA
Of Target Genes
Cycle Arrest Repair

DNA repair Mutant Cell

Expansion &
P21[CDK Inhib] BAX [Apoptosis gene] Additional
Mutation

Normal Cell Apoptosis 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
FGF-1,2
Angiogenin
TGF β,α
VEGF TNF α
bFGF PDEGF
IL-8
Proliferin
Leptin

Malignant Cells
TP53

Plasminogen Angiostatin
Thrombospondin-1 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
 Normal Malignant
WNT reseptors WNT
E-cadherin

signals
APC
β catenin
β catenin APC

ECM

fibronectin
integrin
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
HORMONES
Human chorionic gonadotropin
Calcitonin
Catecholamines
ONCOFETAL ANTIGENS
Alphafetoprotein
Carcinoembryonic antigen
ENZYMES
Prostatic acid phosphatase
Neuron-specific enolase
Lactate dehydrogenase
TUMOR-ASSOCIATED PROTEINS
Prostate-specific antigen
Monoclonal immunoglobulin
CA-125
CA 19-9
CD30
CD25
Cancer
Gestational trophoblastic disease,
gonadal germ cell tumor
Medullary cancer of the thyroid
Pheochromocytoma
Hepatocellular carcinoma,
gonadal germ cell tumor
Adenocarcinomas of the colon,
pancreas, lung, breast, ovary
Prostate cancer
Small cell cancer of the lung,
neuroblastoma
Lymphoma, Ewing's sarcoma
Prostate cancer
Myeloma
Ovarian cancer, some lymphomas
Colon, pancreatic, breast cancer
Hodgkin's disease,
anaplastic large cell lymphoma
Hairy cell leukemia,
adult T cell leukemia/lymphoma
Non-Neoplastic Conditions
Pregnancy
Cirrhosis, hepatitis
Pancreatitis, hepatitis,
inflammatory bowel disease,
smoking
Prostatitis, prostatic hypertrophy
Hepatitis, hemolytic anemia,
Prostatitis, prostatic hypertrophy
Infection, MGUSa
Menstruation, peritonitis,
pregnancy
Pancreatitis, ulcerative colitis
æ
æ
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 Adult T cell leukemia/lymphoma
type I (HTLV-I)
Carcinogens and Associated Cancers or Neoplasms
Carcinogensa Associated Cancer or Neoplasm
Immunosuppressive agents Non-Hodgkin's lymphoma
(azathioprine, cyclosporine,
glucocorticoids)
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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