CANCER INITIATION

AND PROMOTION

Concepts and Mechanisms

Salvador J. Diaz-Cano
s.j.diaz-cano@qmul.ac.uk
 Objectives
• Tumor initiation. Cooperative DNA
lesions as common final pathway
• Tumor promotion. Perpetuation of
genetic lesions. Clonality
• Precancerous and incipient lesions
• Molecular targets. Oncogenes, tumor
suppressor genes & DNA repair genes
 Concept of Neoplasm
“… is an abnormal mass of tissue, the growth of
which exceeds and is uncoordinated with that of
the normal tissues, and persists in the same
excessive manner after cessation of the stimuli
which evoked the change”

Willis, 1952
 Birth and Growth of a
Tumor
• Which cells generate tumors? Stem cells
• Do tumors come from single or multiple
progrenitor cells? Single = Monoclonality
• Needs of neoangiogenesis
• Initiation, promotion, and progression
• How fast do tumors grow? Volume doubling time,
% replicating cells, cell loss

• Key factor: Cells capable of dividing

 Epidemiology of human cancers
indicates that development of cancer
requires several mutations
Neoplasms Evolve in Multiple
Steps
• Initiation

• Promotion

• Progression
CANCER BIOLOGY

Initiation and Promotion

(1) Concepts
Cancers originate in proliferating
cells

Formation of differentiated blood cells from

hematopoietic stem cells in the bone marrow
 Mutations
Target Somatic
Stem Cells
Slide 8.39
 Initiation & Promotion
= Initiator = Promoter
Gr. 1 No tumor
Gr. 2 Tumor
Gr. 3 Tumor
Gr. 4 No tumor
Gr. 5 No tumor
Gr. 6 No tumor

Time
 Initiation

• Irreversible DNA damage in

critical gene(s)
 Promotion

• Expansion of initiated cells

• Reversible, at least initially
• Repetitive process
Cell Cycle
Balance of Tissue Cell
Number
 Growth Populations in
Tumors
Permanently arrested
Cycling cells
cells
M
G2
M G1
G2 S

G1 Dead
cells
S
G0 Differ.
Reversibly
noncycling cells cells
Tumor Growth. “Depressing”
Curve
Number of cell doublings

40 1E+12 103
Number of tumor cells

1E+11 Clinically detectable

1E+10 tumor

Weight in grams
30 1E+09 1
1E+08
1E+07
20 1E+06
100000
10000 Latent
10 1000
tumor
100
10
0 1
0 1 2 3 4 5 6 7 8 9

Time (arbitrary units)

 Tumorigenesis
DNA damaging NORMAL CELL
agents
Successful
DNA repair
INITIATION DNA damages Cell Death
Failure of
DNA repair
INITIATED CELL

Cell Proliferation/
Altered
PROMOTION Differentiation
AND
PROGRESSION PRENEOPLASTIC
CLONE Proliferation
Additional
MALIGNANT NEOPLASM Mutations
CANCER BIOLOGY

Initiation and Promotion

(2) Mechanisms
Neoplastic Cells DO NOT
“Act” Properly
 Basic Biologic Features of
Neoplasms
Abnormal
Differentiation Angiogenesis Invasion
Proliferation

Oncogenic
OncogenicLesion
Lesion
(e.g.
(e.g.RAS,
RAS,MYC,
MYC,E2F
E2FActivation)
Activation)

Apoptosis Senescence
Progressive Acquisition of
Neoplastic Features
Progressive Accumulation of
Mutations
Apoptosis and
Tumorigenesis
Origen Clonal y Expansión
Clonal

Diaz-Cano et al. Diagn Mol Pathol 2001; 10: 24-33

Initiation & Promotion
Target Genes
 Cancer: Target Genes &
Mechanisms of Alteration
Genetic Instability: RER Phenotype

DNA Repair

CANCER

Tumor
Oncogenes
Suppressor
Genes
Interstitial Deletion Gene Amplification
Inactivating Mutation Gene Overexpression
Hypermethylation Activating Mutation
Genetic Control of Neoplastic
Initiation and Promotion

Gatekeeper genes

Caretaker genes
CANCER BIOLOGY

Precancerous Lesions and

Early Neoplasms
 Precancerous Lesions and
Early Neoplasms
• Precede invasive neoplasms in time
• Without treatment, there is a significant
increase in tumor incidence
• May coexist with invasive neoplasms
• Hereditary or sporadic
• Relevant for epithelial neoplasms

• Risk markers
 Dysplasia
• Alterations in cell size and morphology,
with or without disorganized growth
pattern
 Multistep Morphological
Changes during Tumor
Development
• Cervical stratified squamous epithelium

• Cutaneous squamous epithelium

• Colonic mucosa

• Barrett’s Esophagus
 Normal Cells Low-grade dysplasia (L-SIL)
Koilocytosis

Invasive Squamous Cell

High-grade dysplasia (H-SIL) Carcinoma
 Dysplasia
Severe dysplasia (CIN 3) of the uterine cervix
Morphologic and Molecular
Progression in Neoplasms
Inflammatory Bowel Diasease
High-grade Dysplasia
Barrett’s Esophagus
Barrett’s Esophagus: High-
grade Dysplasia
Esofageal adenocarcinoma

High-grade dysplasia in
Barrett’s esophagus
Atypical Ductal Hyperplasia of the
Pancreas
 Cancer Initiation & Promotion
• Neoplasms are genetic diseases (≠hereditary)
• Most tumors result from consecutive and
cooperative genetic lesions
– Multistep tumorigenesis
– Clonal evolution
– Intratumor heterogeneity
• Time required until irreversible change is
variable
• Diseases affecting cellular turnover (kinetics)
and differentiation
 Objectives
• Tumor initiation. Cooperative DNA
lesions as common final pathway
• Tumor promotion. Perpetuation of
genetic lesions. Clonality
• Precancerous and incipient lesions
• Molecular targets. Oncogenes, tumor
suppressor genes & DNA repair genes