patologia bilogia del cancer
TRANSCRIPT
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.