TumorigenesisTumorigenesis

Kastan MB. Cancer: Principles & Practice of Oncology. 5th ed. 1997;121-134.

Initialgenetic change

(eg, loss of function of pRb or overexpression of c-myc)

Decreasein apoptosiccell death

Subsequentgenetic change

Normalcell

Increase incell proliferationand apoptosic

cell death

Secondarygenetic change

(eg, dysfunction of p53or overexpression of bcl-2)

Further alterationsin phenotype(eg, invasivenessand metastasis)

Emergence of tumor cell heterogeneityEmergence of tumor cell heterogeneity

Primary NeoplasmPrimary Neoplasm MetastasesMetastases

TRANSFORMATIONTRANSFORMATION TUMOR EVOLUTIONTUMOR EVOLUTION METASTASISMETASTASIS TUMOR EVOLUTIONTUMOR EVOLUTIONAND PROGRESSIONAND PROGRESSION AND PROGRESSIONAND PROGRESSION

Anatomical factors

Organ microenvironment

Angiogenic factors

Immune response

Host influences on metastatic diseaseHost influences on metastatic disease

Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.

CANCER CELLSCANCER CELLS NORMAL CELLSNORMAL CELLS

Loss of contact inhibitionIncrease in growth factor secretionIncrease in oncogene expressionLoss of tumor suppressor genesNeovascularization

Oncogene expression is rare

Intermittent or coordinatedgrowth factor secretion

Presence of tumor suppressor genes

Frequentmitoses

Nucleus

Blood vessel

Abnormalheterogeneous cells

Normalcell

Fewmitoses

Cancer cells vs normal cellsCancer cells vs normal cells

Neoplasia (eg, prostatic intraepithelial neoplasia)

Polyps (eg, adenomatous polyps)

Carcinoma in situ

Precancerous conditionsPrecancerous conditions

Stedman’s Medical Dictionary. 26th ed. 1995;1182,1405, 279.

GrowthGrowthfactorfactor

Growth factorGrowth factorreceptorreceptor

Paracrine (adjacent cells)Paracrine (adjacent cells)

Growth factorGrowth factor and receptorand receptor synthesissynthesis

PostPostreceptor signalreceptor signaltransductiontransductionpathwayspathways

Gene activationGene activation

OncogenesOncogenes

Autocrine stimulation

Autocrine stimulationThe role of oncogenesThe role of oncogenes

PathogenesisPathogenesisTRANSFORMATION ANGIOGENESIS

MOTILITY & INVASION

Capillaries,Venules, Lymnphatics

ADHERENCE

ARREST INCAPILLARY BEDS EMBOLISM &

CIRCULATION

EXTRAVASATIONINTO ORGAN

PARENCHYMA RESPONSE TOMICROENVIRONMENT

TUMOR CELLPROLIFERATION

& ANGIOGENESIS

METASTASES

METASTASIS OFMETASTASES

TRANSPORT

Multicell aggregates(Lymphocyte, platelets)

AngiogenesisAngiogenesis

Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;135-147.

Establishment of a capillary network from the surrounding host tissue

A series of processes originating from microvascular endothelial cells

Mediated by multiple molecules released by both tumor and host cells [eg, fibroblastic growth factor (FGF), vascular endothelial growth factor (VEGF), vascular permeability factor (VPF), angiogenin, epidermal growth factor (EGF)]

Cell cycleCell cycle CELLCELLDIFFERENTIATIONDIFFERENTIATION

CELLCELLLIFE CYCLELIFE CYCLE

TIMETIME

CELLCELLDIVISIONDIVISION

GG22 PERIOD PERIOD

(CHROMOSOME REPLICATION) (CHROMOSOME REPLICATION) S-PHASES-PHASE

GG11 PERIOD PERIOD

The doubling processThe doubling process

NormalNormalcellcell

DividingDividing

MalignantMalignanttransformationtransformation

2 cancer2 cancercellscells

DoublingDoubling 4 cells4 cells

DoublingDoubling

8 cells8 cells

DoublingDoubling

16 cells16 cells

1 million cells1 million cells(20 doublings)(20 doublings)undetectableundetectable

1 billion cells1 billion cells(30 doublings)(30 doublings)lump appearslump appears

1 trillion cells1 trillion cells(40 doublings – 2 lb/1kg)(40 doublings – 2 lb/1kg)

41 – 4341 – 43doublingsdoublings— Death— Death

Tumor growth and detectionTumor growth and detection

10101212

101099

timetime

DiagnosticDiagnosticthresholdthreshold

(1cm)(1cm)

UndetectableUndetectablecancercancer

DetectableDetectablecancercancer

Limit ofLimit ofclinicalclinical

detectiondetection

HostHostdeathdeath

Nu

mb

er o

fN

um

ber

of

can

cer

cells

can

cer

cells

Malignant tumor cells can remain dormant yet viable for years

Emergence from dormancy can lead to disease recurrence

Possible mechanisms:◦ Cells may arrest in G0 phase

◦ Rate of cell death counterbalances rate of cell division

Dormancy of tumor cellsDormancy of tumor cells

Fidler IJ. Cancer: Principles & Practice of Oncology. 5th ed. 1997;141.