Cancer Ini Prom

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CANCER INITIATIONCANCER INITIATION

AND PROMOTIONAND PROMOTION

Concepts and MechanismsConcepts and Mechanisms

Salvador J. Diaz-CanoSalvador J. Diaz-Cano

[email protected] [email protected]



ObjectivesObjectives

•Tumor initiation. Cooperative DNAlesions 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 NeoplasmConcept 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 aBirth and Growth of a

TumorTumor• Which cells generate tumors? Stem cells

• Do tumors come from single or multiple progrenitorcells? 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 cancersEpidemiology of human cancers

indicates that development of cancerindicates that development of cancer

requires several mutationsrequires several mutations



Neoplasms Evolve inNeoplasms Evolve in

Multiple StepsMultiple Steps

• Initiation

• Promotion

• Progression



Initiation and PromotionInitiation and Promotion

(1) Concepts(1) Concepts

CANCER BIOLOGYCANCER BIOLOGY



Cancers originate in proliferatingCancers originate in proliferatingcellscells

Formation of differentiated blood cells fromhematopoietic stem cells in the bone marrow



MutationsMutations

TargetTargetSomaticSomaticStem CellsStem Cells



Slide 8.39



Initiation &Initiation &

PromotionPromotion

Time

No tumor

No tumor

No tumor

No tumor

Tumor Tumor

= Promoter = Initiator

Gr. 1

Gr. 2Gr. 3

Gr. 4

Gr. 5

Gr. 6



InitiationInitiation

•Irreversible DNA

damage in criticalgene(s)



PromotionPromotion

•Expansion of initiated cells

•Reversible, at least initially

•Repetitive process



Cell CycleCell Cycle



Balance of Tissue CellBalance of Tissue Cell

NumberNumber



Growth PopulationsGrowth Populations

in Tumorsin Tumors

G1

G2

M

S

G0

G1

G2

M

S

Cycling cellsPermanently arrested

cells

Dead

cells

Differ.

cellsReversibly

noncycling cells



Tumor Growth.Tumor Growth.“Depressing” Curve“Depressing” Curve

1

10

10 0

1000

10000

100000

1E+06

1E+07

1E+08

1E+09

1E+10

1E+11

1E+12

0 1 2 3 4 5 6 7 8 9

Numb

erof

celldoub

lings

40

30

20

10

0Numb

eroftumo r

cells

W

eightin

gr

ams

1

103

Time (arbitrary units)

Clinically detectabletumor

Latent

tumor



TumorigenesisTumorigenesis

DNA damagingDNA damagingagentsagents

NORMAL CELLNORMAL CELL

Cell Proliferation/ Cell Proliferation/ AlteredAltered

DifferentiationDifferentiation

MALIGNANT NEOPLASMMALIGNANT NEOPLASM

DNA damages

INITIATED CELLINITIATED CELL

Failure of

DNA repair

SuccessfulDNA repair

Cell DeathCell Death

PRENEOPLASTICPRENEOPLASTICCLONECLONE ProliferationProliferation

AdditionalAdditionalMutationsMutations

INITIATIONINITIATION

PROMOTIONPROMOTIONANDAND

PROGRESSIONPROGRESSION



Initiation and PromotionInitiation and Promotion

(2) Mechanisms(2) Mechanisms




Neoplastic Cells DONeoplastic Cells DO

NOT “Act” ProperlyNOT “Act” Properly

B i Bi l iB B



Basic BiologicBas c B o og cFeatures of Features of

NeoplasmsNeoplasms

Oncogenic LesionOncogenic Lesion

(e.g. RAS, MYC, E2F Activation)(e.g. RAS, MYC, E2F Activation)

Oncogenic LesionOncogenic Lesion

(e.g. RAS, MYC, E2F Activation)(e.g. RAS, MYC, E2F Activation)

DifferentiationAbnormal

ProliferationAngiogenesis Invasion

SenescenceApoptosis

P iP



ProgressiveProgress veAcquisition of Acquisition of

Neoplastic FeaturesNeoplastic Features

P i



ProgressiveProgressiveAccumulation of Accumulation of

MutationsMutations



Apoptosis andApoptosis andTumorigenesisTumorigenesis



Origen Clonal yOrigen Clonal yExpansión ClonalExpansión Clonal

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

n a onn a on



n a onn a onPromotionPromotion

Target GenesTarget Genes



DNA Repair DNA Repair

Tumor Tumor

Suppressor Suppressor GenesGenes

OncogenesOncogenes

Interstitial DeletionInterstitial Deletion

Inactivating MutationInactivating Mutation

HypermethylationHypermethylation

Gene AmplificationGene Amplification

Gene OverexpressionGene Overexpression

Activating MutationActivating Mutation

Genetic Instability: RER PhenotypeGenetic Instability: RER Phenotype

CANCERCANCER

Cancer: Target Genes &Cancer: Target Genes &Mechanisms of AlterationMechanisms of Alteration

G ti C t l fG ti C t l f



Genetic Control of Genetic Control of Neoplastic Initiation andNeoplastic Initiation and

PromotionPromotionGatekeeper genesGatekeeper genes

Caretaker genesCaretaker genes



Precancerous Lesions andPrecancerous Lesions and

Early NeoplasmsEarly Neoplasms




Precancerous LesionsPrecancerous Lesionsand Early Neoplasmsand Early Neoplasms

• Precede invasive neoplasms in time

• Without treatment, there is asignificant increase in tumor

incidence• May coexist with invasive neoplasms

• Hereditary or sporadic

• Relevant for epithelial neoplasms

• Risk markers



DysplasiaDysplasia

• Alterations in cell size andmorphology, with or without

disorganized growth pattern

M l i M h l i l



Multistep MorphologicalMultistep MorphologicalChanges during TumorChanges during Tumor

DevelopmentDevelopment• Cervical stratified squamous

epithelium

• Cutaneous squamous epithelium

•

Colonic mucosa• Barrett’s Esophagus



Normal Cells

High-grade dysplasia (H-SIL)

Invasive Squamous CellCarcinoma

Low-grade dysplasia (L-SIL)

Koilocytosis



DysplasiaDysplasiaSevere dysplasia (CIN 3) of the uterine cervix

Morphologic andMorp o og c an



Morphologic andMorp o og c anMolecular Progression inMolecular Progression in

NeoplasmsNeoplasms

Inflammatory BowelInflammatory Bowel



Inflammatory BowelInflammatory BowelDiaseaseDiasease

High-grade DysplasiaHigh-grade Dysplasia



Barrett’s EsophagusBarrett’s Esophagus

h



Esofageal adenocarcinoma

Barrett’s Esophagus:Barrett’s Esophagus:High-grade DysplasiaHigh-grade Dysplasia

High-grade

dysplasia inBarrett’s

Atypical DuctalAtypical Ductal



Atypical DuctalAtypical DuctalHyperplasia of theHyperplasia of the

PancreasPancreas

i i iC I i i i &



Cancer Initiation &Cancer Initiation &PromotionPromotion

• Neoplasms are genetic diseases(≠hereditary)

• Most tumors result from consecutive

and cooperative genetic lesions– Multistep tumorigenesis– Clonal evolution– Intratumor heterogeneity

•

Time required until irreversiblechange is variable• Diseases affecting cellular turnover

(kinetics) and differentiation



ObjectivesObjectives

•Tumor initiation. Cooperative DNAlesions as common final pathway

•Tumor promotion. Perpetuation of genetic lesions. Clonality

•Precancerous and incipientlesions

•Molecular targets. Oncogenes,

tumor suppressor genes & DNArepair genes

Cancer Ini Prom

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