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
cells
noncycling 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
 Low-grade dysplasia (L-
Normal Cells SIL)
Koilocytosis

Invasive Squamous Cell

High-grade dysplasia (H- Carcinoma
SIL)
 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
 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