Document

Ontstaan
– Neoplasieën ontstaan waarschijnlijk uit
stamcellen of immature precursoren.
– De meeste zijn monoclonaal
– Men neemt aan dat een cel neoplastisch wordt
door beschadiging van het DNA
– Voor de geboorte
» Beschadigd sperma of eicel
» Tijdens de embryonale ontwikkeling
– Na de geboorte
» Door een externe factor
» Tijdens het delen
Oorzaak van DNA beschadiging
“De”oorzaak van DNA beschadiging, die aanleiding geeft
tot een neoplasie, bestaat niet; meestal bestaat deze DNA
beschadiging uit meerdere afzonderlijke beschadigingen
die elk het gevolg kunnen zijn van meerdere factoren
= multifactoriëel
Sommige van de factoren die in verband gebracht worden
met het ontstaan van kanker kunnen we zelf controleren (bvb omgevingsfactoren)
- andere niet
The Lancet, 360:861_868, 2002
Figure 1: Age-adjusted incidence rates of the most common cancers
HEPATOCELLULAIR CARCINOOM
Genen en kanker
• Poortwachter genen  betrokken bij celgroei
– Oncogenen
– Tumorsuppressorgenen
– Telomerase
• Opzichter genen  betrokken bij DNA herstel
– o.a. Mismatch repair genen
Bij afwijking: te veel of te weinig microsatelliet sequenties
= Microsatelliet instabiliteit of MSI
Figure 1. Molecular pathways involved in tumour cell progression. (S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art.)
•
Figure 2. Molecular pathways involved in microenvironment interactions (intercellular, and stromal, neoangiogenesis, and invasion)
(S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art)
Figure 3. Molecular pathways involved in the tumour cell acquired capability of self-maintained proliferation.
(S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art)
•
Figure 4. Molecular pathways involved in the tumour cell acquired capability of extended cell survival.
(S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art)
Figure 5. Molecular pathways involved in the tumour cell acquired capability of genetic instability – DNA damage and repair
(S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art)
Figure 6. Molecular pathways involved in the tumour cell acquired capability of modifications of chromatin, transcription and
epigenetic changes. (S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art)
Figure 7. Molecular pathways involved in the tumour cell acquired capability of mobilization of cellular resources – ribosomes (protein synthesis).
(S.J. Diaz-Cano Histopathology 2008, 53, 1-19 )
Figure 8. Molecular pathways involved in the tumour cell acquired capability of mobilization of cellular resources – mitochondria (ATP synthesis,
•
apoptosis, reactive oxygen species and damage). (S.J. Diaz-Cano Histopathology 2008, 53, 1-19 art)
Carcinogene factoren
• Chemisch
• Fysisch
• Biologisch
• Chemische factoren
Genotsmiddelen
Voeding
Hormonen
Chemische beroepsblootstelling
Chemotherapie
• Fysische factoren
UV stralen
loniserende stralen :
röntgen stralen
radium
medisch
Hiroshima-Nagasaki
Tsjernobyl
Fysisch trauma
• Biologische factoren
Chemische factoren
Genotsmiddelen
Voeding
Hormonen
Chemische beroepsblootstelling
Chemotherapie
Fysische factoren
UV stralen
loniserende stralen :
röntgen stralen
radium
medisch
Hiroshima-Nagasaki
Tsjernobyl
Fysisch trauma
Biologische oorzaken van kanker
Chemische factoren
Genotsmiddelen
Voeding
Hormonen
Chemische beroepsblootstelling
Chemotherapie
Fysische factoren
UV stralen
loniserende stralen :
röntgen stralen
radium
medisch
Hiroshima-Nagasaki
Tsjernobyl
Fysisch trauma
Biologische oorzaken van kanker
The Lancet, 360:861_868, 2002
Dietary risk factors, dietary protective factors, and other major risk factors for the common cancers
Cancer
Dietary and diet-related
risk factors
Dietary protective factors
Other major risk factors
Oral cavity, pharynx,
and oesophagus
Alcohol
Very hot drinks
Obesity (adenocarcinoma of
the oesophagus)
Chinese-style salted fish
(nasopharyngeal cancer)
Probably high intake of saltpreserved foods and salt
Obesity
Possibly red and processed
meat
High alcohol intake
Foods contaminated with
aflatoxins
None established
Alcohol
None established
Obesity after menopause
Alcohol
Obesity
None established
None established
Obesity
Probably fruit and vegetables
Smoking
Probably fruit and vegetables
Infection by Helicobacter pylori
Probably fruit, vegetables, and
other plant foods rich in fibre
None established
Sedentary lifestyle
None established
None established
Possibly fruit and vegetables
None established
Smoking
Smoking
Smoking
Reproductive and hormonal factors
None established
None established
None established
None established
Low parity
Human papillomavirus
None established
None established
Stomach
Colorectum
Liver
Pancreas
Larynx
Lung
Breast
Endometrium
Cervix
Prostate
Kidney
Hepatitis viruses
Chemische factoren
Genotsmiddelen
Voeding
Hormonen
Chemische beroepsblootstelling
Chemotherapie
Fysische factoren
UV stralen
loniserende stralen :
röntgen stralen
radium
medisch
Hiroshima-Nagasaki
Tsjernobyl
Fysisch trauma
Biologische oorzaken van kanker
Tot hier
Chemische factoren
Genotsmiddelen
Voeding
Hormonen
Chemische beroepsblootstelling
Chemotherapie
Fysische factoren
UV stralen
loniserende stralen :
röntgen stralen
radium
medisch
Hiroshima-Nagasaki
Tsjernobyl
Fysisch trauma
Biologische oorzaken van kanker
Maligne Melanoom
Chemische factoren
Genotsmiddelen
Voeding
Hormonen
Chemische beroepsblootstelling
Chemotherapie
Fysische factoren
UV stralen
loniserende stralen :
röntgen stralen
radium
medisch
Hiroshima-Nagasaki
Tsjernobyl
Fysisch trauma
Biologische oorzaken van kanker
VIRUSSEN
Virchows Archiv maart 2000
Biologische oorzaken van kanker
• Bacteriën
– HP:
• Maaglymfoom
• Maagadenocarcinoom
• Parasieten
– Schistosoma
• Blaas: plaveiselcelcarcinoom
Papilloom van het plaveiselepitheel (HPV)
HPV - geassocieerde papillomen
Verruca vulgaris
TUMOREN
- Definities
- Ontstaan & evolutie
Oorzaken
Precancereuze condities
Metastasering
- Verdediging
- Labo-technieken (Morfologische diagnose)
carcinogenese
ONCOGEN
ACTIVATIE
DOMINANT
TUMOR SUPPRESSORGEN
DESACTIVATIE
RECESSIEF
NORMALE CEL
Gecontroleerde groei
Ongecontroleerde groei
-turn on oncogenen (groeipromotie)
-turn off tumorsupressor genen( verlies groei-inhibitie)
neoplasie
Oncogenen
1. Groeifactoren
•
c-sis gen
2. Groeifactor receptoren
•
C-erb-b2 (neu)
3. Cyclische nucleotide bindende eiwitten
•
•
•
HRAS
KRAS
NRAS
4. Tyrosine fosforylerende kinases
•
•
ABL
SRC
5. Nucleaire transcryptiefactoren
•
MYC
Tumor suppressorgenen
•
•
•
•
•
•
RB
P53
NF
VHL
APC
………
Telomerase
• Telomeren
Repetitieve sequenties van niet coderend DNA aan
uiteinde van de chromosomen
Bij elke celdeling gaat stukje telomeer DNA verloren
Eens het telomeer DNA te kort is kan geen celdeling
meer plaatsgrijpen
Te korte telomeren worden hersteld door telomerase, maar
telomerase komt fysiologisch enkel voor in stamcellen
en germinatieve cellen.
In grote meerderheid van tumoren is telomerase
geactiveerd
Late chromosomale veranderingen
Door ontregeling van de celdeling kunnen uiteindelijk
cellen ontstaan waarbij volledige chromosomen of
grote stukken chromosomen ontbreken of
vermenigvuldigen
Virchows arch 2004, 444:131-323
Negative and positive regulators of the normal cell cycle. Signals promoting and inhibiting the different phases of
the cell cycle as well as checkpoints monitoring the proper completion of every phase of the cell cycle are
indicated. In the centre of the cycle, the CDK/cyclin complexes driving the respective phase are shown. For
details, see the text
Virchows arch 2004, 444:131-323
Upregulation of cell-cycle activators
downregulation of cell-cycle inhibitors
Deregulation of the cell cycle in cancer. Upregulation of cell-cycle activators and downregulation of cell-cycle inhibitors are both involved in promoting the
transformation of a normal cell into a continuously proliferating cell, which is independent of growth-promoting signals and resistant to growth-inhibiting signals. When
this transformation is supported by other mechanisms, such as angiogenesis as well as evasion of apoptosis and immune surveillance, it will create the clonogenic
malignant cell. For every alteration of cell-cycle regulators, only one example of an associated human malignancy is given. The two-dimensional representation is
clearly simplifying the complex interdependence of all participating factors. For further details, see the text and references therein
Nature, vol 432, 18 nov 2004:316-323
Figure 4 Schematic representation of two main steps that contribute to a spectrum of mutations leading to cancer development. If DNA damage is repaired efficiently,
the likelihood of tumour development is low. If cells have mutations in DNA-damage-response signalling pathways — either sporadic or inherited — this will lead to
enhanced genomic abnormalities. Cells with damaged DNA frequently arrest or do not survive, thus reducing the probability that they will progress to malignancy.
Mutations in apoptosis pathways, DNA-damage, DNA-repair or mitotic-checkpoint pathways can permit the survival or continued growth of cells with genomic
abnormalities, thus enhancing the likelihood of malignant transformation.
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of growth
control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of
inhibition of cell proliferation that allows DNA repair
p53
Overexpression of growth factor receptors (such as
epidermal growth factor, or EGF) making cells more
sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocatiion of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation prevents
apoptosis
bcl-2
Growth Promotion
Limitation of Apoptosis
TUMOREN
- Definities
- Ontstaan & evolutie
Oorzaken
Precancereuze condities
Metastasering
- Verdediging
- Labo-technieken (Morfologische diagnose)
Precancereuze condities
Precancereuze condities:
1) Genetische predispositie : in sommige families
komt kanker méér voor dan in andere.
2) Afwijkingen in het orgaan zelf : thv sommige
letsels ontwikkelt zich meer frequent een
neoplasie; nl thv
- metaplasie
- dysplasie
- GA tumoren
- Chronische inflammatie
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of growth
control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of
inhibition of cell proliferation that allows DNA repair
p53
Overexpression of growth factor receptors (such as
epidermal growth factor, or EGF) making cells more
sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocatiion of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation
prevents apoptosis
bcl-2
Growth Promotion
Limitation of Apoptosis
Genetische predispositie
Gevolg van mutatie thv een tumorsuppressorgen
Het bestaan van tumor-suppressorgenen werd
vermoed door het bestuderen van de tumor:
“retinoblastoom”
2 vormen : hereditair en sporadisch
hereditaire vorm: jonge leeftijd; kan bilateraal
sporadische vorm: volwassen leeftijd;unilateraal
Retinoblastoom
RETINOBLASTOOM
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of growth
control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through
lack of inhibition of cell proliferation that allows
DNA repair
p53
Overexpression of growth factor receptors (such as
epidermal growth factor, or EGF) making cells more
sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocatiion of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation
prevents apoptosis
bcl-2
Growth Promotion
Limitation of Apoptosis
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of
growth control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of
inhibition of cell proliferation that allows DNA repair
p53
Overexpression of growth factor receptors (such as
epidermal growth factor, or EGF) making cells more
sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocatiion of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation
prevents apoptosis
bcl-2
Growth Promotion
Limitation of Apoptosis
Poliepen van de darm
Adenomateuze poliposis coli - M-13jaar
Germ-line mutaties in tumorsuppressorgenen
Syndrome
Tumour caused
Defect
MEN syndromes
Multiple tumours in
endocrine organs
Mutations on
chromosomes 10 and 11
Polyposis coli
(APC)
Adenomata and
carcinomas of the
colon
Absent tumour
suppressor gene
Li-Fraumeni
(P53)
Breast cancer and
sarcomas
Mutated tumour
suppressor gene
Familial
retinoblastoma (RB)
Malignant tumour of
the retina
Absent tumour
suppressor gene
Neurofibromatosis
type 1 (NF)
Benign and malignant
tumours of peripheral
nerves
Abnormal tumour
suppressor gene
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of growth
control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of
inhibition of cell proliferation that allows DNA repair
p53
Overexpression of growth factor receptors (such as
epidermal growth factor, or EGF) making cells more
sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocatiion of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation
prevents apoptosis
bcl-2
Growth Promotion
Limitation of Apoptosis
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of growth
control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of
inhibition of cell proliferation that allows DNA repair
p53
Overexpression of growth factor receptors
c-erb-B2
Growth Promotion
(such as epidermal growth factor, or EGF) making cells
more sensitive to growth stimuli
Limitation of Apoptosis
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocation of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation
prevents apoptosis
bcl-2
C-erb-B2 oncogen werkt via vermenigvuldigen van het normaal protooncogen; dit leidt tot de overproductie van een proteine dat
ongecontroleerde celgroei veroorzaakt. Dit proteine wordt
gedetecteerd door een immunoperoxidase kleuring;
c-erb-B2 immuunhistochemie in borst carcinoma
Oncogenesis= afwijking genoom
Mechanism
Action
Example
Loss of Tumor Suppressor Gene
Function
Loss of normal growth inhibition
BRCA-1
Lack of regulation of cell adhesion with loss of growth
control through cell interaction
APC
Loss of down-regulation of growth promoting signal
transduction
NF-1
Loss of regulation of cell cycle activation through
sequestration of transcriptional factors
Rb
Loss of regulation of cell cycle activation through lack of
inhibition of cell proliferation that allows DNA repair
p53
Overexpression of growth factor receptors (such as
epidermal growth factor, or EGF) making cells more
sensitive to growth stimuli
c-erb-B2
Increased growth factor signal transduction by an
oncogene that lacks the GTPase activity that limits GTP
induction of cytoplasmic kinases that drive cell growth
ras
Overexpression of a gene product by stimulation from an
oncogene (such as ras)
c-sis
Lack of normal gene regulation through translocatiion of a
gene where it is controlled by surrounding gene to a place
where it is no longer inhibited
c-abl
Binding of oncogene product to the nucleus with DNA
transcriptional activation to promote entry into the cell cycle
c-myc
Overexpression of gene, activated by translocation
prevents apoptosis
bcl-2
Growth Promotion
Limitation of Apoptosis
bcl-2 oncogen overexpressie leidt tot inhibitie van apoptose en
vermenigvuldiging van de lymfocyten. De tumorale lymfocyten in de
lymphoiede follikels en de interfollicular gebieden worden gekleurd.
Immuunhistochemie voor bcl-2
Precancereuze condities
Precancereuze condities:
1) Genetische predispositie : in sommige families
komt kanker méér voor dan in andere.
2) Afwijkingen in het orgaan zelf : thv sommige
letsels ontwikkelt zich meer frequent een
neoplasie; nl thv
- metaplasie
- dysplasie
- GA tumoren
- Chronische inflammatie
Precancereuze letsels
1.
2.
3.
4.
Metaplasie
Dysplasie
Goedaardige tumoren
Chronische inflammatie
Metaplasie
Definitie :
Vervanging van de cel door een cel
met een andere (normaal) fenotype
die in een andere localisatie thuishoort
Metaplasie
Oorzaken : chronische inflammatie = meest
frequent
- Respiratoir : pseudo-meerlagig
trilhaarepitheel vervangen door
plaveiselepitheel bij chronische bronchitis
- maagepitheel vervangen door dundarm
epitheel bij chronische gastritis.
Nomenclatuur metaplasie
1) Het vervangend weefsel wordt genoemd gevolgd
door het woord “metaplasie” gevolgd door het
orgaan, vb. : plaveisel-metaplasie van de bronchus,
intestinale-metaplasie van de maag, kraakbeenmetaplasie van de long.
2) Meer specifiek :
 leukoplakie = macroscopisch begrip = wit worden
van weefsel dat normaal niet wit is.
- plaveisel-metaplasie van een cylinderepitheel (vb.
cervix mucosa)
- verhoorning-metaplasie van niet-verhoornd
plaveiselepitheel (vb. mond mucosa)
 Barrett oesofagus : maag- of intestinale
metaplasie van de distale oesofagus wordt Barrett
oesofagus genoemd.
Kliniek metaplasie
Meestal weinig gevolgen
– kan dit letsel CA geven ? Het is het gevolg
van celbeschadiging en vele kankers zijn dit
eveneens. De ontwikkeling van kanker kan
dus door een stadium van metaplasie gaan
Precancereuze letsels
1.
2.
3.
4.
Metaplasie
Dysplasie
Goedaardige tumoren
Chronische inflammatie
Dysplasie
Definitie :
Abnormale schikking en oriëntatie
van cellen, gepaard met cel- en
kernafwijkingen en een toegenomen
aantal mitosen.
Dysplasie:
Meestal tgv chronische irritatie en
inflammatie
• gepaard met metaplasie
• volgend op metaplasie
• de novo
Morfologie dysplasie :
1. Kern/plasma (K/P) verhouding stijgt.
2. Hyperchromatose van de kern en/of grote
nucleolen en/of verdikte chromatine.
3. Neiging tot anaplasie.
Anaplasie = verminderen van de differentiatie,
bvb. verlies aan kenmerken eigen aan de cel
(vb. mucusproductie, afplatting van bovenste
cellen in plaveiselepitheel, verlies paraplucellen).
4. Mitosen op abno plaats
bvb: hoger dan basale cellaag in plaveiselepitheel
hoger dan onderste 1/2 crypten in colon
Gradering :
* Lichte dysplasie
* Matige dysplasie
* Zware dysplasie of carcinoma in situ (C.I.S) = maligne letsel
C.I.S. wordt gebruikt als synoniem voor zware dysplasie van een
epitheel.
Men spreekt ook van intra-epitheliale neoplasie,
Nu ook gebruikt voor lichte en matige dysplasie:
bvb. : CIN
= cervical intra-epithelial neoplasia.
CIN I
= lichte dysplasie
CIN II
= matige dysplasie
CIN III = zware dysplasie of CIS
Naar analogie wordt deze naamgeving ook voor andere organen
gebruikt (prostaat=PIN, vagina=VIN enz...)
Laatste evolutie: laagradig (I) en hooggradig (II & III)
Dysplasie cervix epitheel
Dysplasie cervix epitheel
Dysplasie cervix epitheel
Plaveiselepitheel
Normaal
Dysplasie
Plaveiselepitheel dysplasie
Plaveiselepitheel dysplasie
Carcinoma in situ
Invasief carcinoom cervix
Invasief carcinoom cervix
Invasief carcinoom cervix
Invasief carcinoom cervix
Invasief carcinoom cervix
Overgang naar kanker bij darmepitheel
Normaal epitheel / dysplastisch epitheel
Klierepitheel met lichte dysplasie
Adenoom darm
matige dysplasie epitheel
Klierepitheel met matige dysplasie
Klierepitheel:zware dysplasie
Klierepitheel: zware dysplasie
Klierepitheel zware dysplasie
Invasief adenocarcinoom colon
Precancereuze letsels
1.
2.
3.
4.
Metaplasie
Dysplasie
Goedaardige tumoren
Chronische inflammatie
Chronische inflammatie
Vooral toen er geen behandeling was
voor chronische ontsteking
 Lupus vulgaris
 Osteomyelitis
 Chronische gastritis
 Levercirrose
 RCUH
Nature, vol 432, 18 nov 2004:324-331
Figure 2 Model for carcinogenesis resulting from persistence of a state of injury repair. A, Cellular events of epithelial repair. a, Resting epithelium with several differentiated
cell phenotypes (brown, orange, and yellow) derived from tissue stem cells, now quiescent (red). Pathways such as Hh and Wnt signalling pathways that have a role in the
renewal of stem cells are not active. b, Epithelial defect resulting from acute injury. Loss of epithelial continuity activates a repair program which is driven by Hh or Wnt
signalling. This program results in the acquisition by epithelial cells of a more mesenchymal phenotype, including flattening and movement of cells (straight arrow) to cover
the wound, activation (green), and expansion of stem cells through renewal divisions (curved arrows). c, The wound is repaired, first by rapid cell movement, and then by
restoration of cell numbers resulting from the amplification of stem cells and the differentiation of their progeny. Subsequently, either epithelial continuity and patterning is
restored, Hh and Wnt signalling ceases, and the stem cell compartment returns to quiescence (a); or oncogenic event(s) may trap a stem cell in an activated state of continuous
renewal, which is driven by autonomous Wnt or Hh signalling (d). Further genetic or epigenetic change in such a persistently activated stem cell (curved red arrows) might
produce a cancer stem cell (green) which is capable of aggressively propagating a cancer (e). This may result from enhanced proliferation and production of more cancer stem
cells as well as from differentiated cancer cells (blue). B, Stem cells cycle between quiescence and activity as a consequence of Hh/Wnt driven responses to injury. Oncogenic
event(s) may trap activated stem cells in a permanent state of Hh/Wnt driven activity, resulting in cancer stem cells.
TUMOREN
- Definities
- Ontstaan & evolutie
Oorzaken
Precancereuze condities
Metastasering
- Verdediging
- Morfologische diagnose (labotechnieken)
Lancet 2007; 369
Metastasiëring: theorieën
1. Clonale selectie
2. Gepredetermineerde tumorcellen
3. Gastheer factoren
Lancet 2007; 369
Lancet 2007; 369
Lancet 2007; 369
The process of metastasis begins before cells migrate from a primary tumour mass. Among
the earliest characteristics of transformed cells are genetic and phenotypic instability. Cancer
cells are more prone to mutation and phenotypic drift than their normal counterparts. Genetic
instability, coupled with a Darwinian type of selection—survival of the fittest—results in
populations resistant to normal homoeostatic growth controls, immune attack, and
environmental restraints.6 The rate of progression varies and, within any neoplastic mass,
subpopulations can be isolated with different malignant potential.
Thus, not all tumours are metastatic, nor are all cells within so-called metastatic tumours
capable of metastasising. Even cells isolated from large metastases show substantial
heterogeneity when assessed experimentally, raising questions as to whether cells might
transiently acquire metastatic potential.
Recent evidence suggests that tumour cells might begin conditioning distant tissues for
colonisation by establishing a so-called pre-metastatic niche. As yet unknown factors mobilise
haematopoietic stem cells to tissues, remodel the matrix, and modify stromal cells and the
growth factor milieu such that tumour cells are attracted to or have increased predilection for
growth at these sites. In a transgenic mouse colon carcinoma model, CD34+ immature
myeloid cells expressing the chemokine receptor CCR1 were recruited from the bone marrow
to the edges of local primary lesions and stimulated local invasion by tumour cells expressing
the ligand CCL9.
Importantly, genetic instability, generation of variants, and establishment of pre-metastatic
niches represent intrinsic tumour cell and microenvironmental changes that take place before
cancer cell dissemination.
Lancet 2007; 369
Epithelial-mesenchymal transition
Neoplastic cells might acquire the ability to metastasise by dedifferentiation to a more motile mesenchymal cell
phenotype, a process called epithelial-mesenchymal transition (EMT). Once established in a new environment,
metastatic cells might then revert back to a non-metastatic phenotype, via a mesenchymal-epithelial transition.
Epithelial-mesenchymal transition can be induced by different stimuli, with transforming growth factor (TGF)
signalling having a key role. Other important mediators include oncogenic signalling pathways (notably
phosphoinositide 3 [PI3] kinase), mitogen-activated protein (MAP) kinases, loss of E-cadherin (or a switch to Ncadherin), and activation of transcription regulators such as Twist and Snail (SNA1). Interestingly, Wnt, Notch,
and Hedgehog signalling pathways (also implicated in stem cell maintenance) are linked to epithelialmesenchymal transition.
Cells induced to undergo epithelial-mesenchymal transition not only exhibit enhanced motility but also are resistant to
apoptosis: key requirements for successful metastasis. However, other cancer cells might use a collective
migration that is independent of an epithelial-mesenchymal transition. The fact that Wnt signalling can also
induce collective migration in addition to epithelial-mesenchymal transition emphasises the complex interrelations
and plasticity in all of these processes.
Although a role for epithelial-mesenchymal transition during development is well accepted and can be demonstrated
and manipulated in many experimental tumour models, some question whether it occurs in human cancers, and it
is important to state explicitly that epithelial-mesenchymal transition is not synonymous with invasion or
metastasis.
Lancet 2007; 369
Resistance to apoptosis and anoikis
Dissemination requires that tumour cells detach from the matrix or cell–cell anchor(s) that control tissue architecture. Under normal
circumstances, epithelial cells undergo apoptosis (programmed cell death) when adhesion to the correct substrate is disrupted.
Indeed, a specialised form of apoptosis—anoikis—results when normal cells are maintained in suspension; this process is
clearly a mechanism designed to protect multicellular organisms from rogue cells establishing themselves outside their correct
anatomical location. Metastatic cells therefore must be resistant to anoikis and apoptosis to survive during dissemination and
colonisation of ectopic sites. Many studies show that crucial apoptotic modulators are deregulated in metastases. This
deregulation is accomplished by various means: activation of survival pathways (eg, PI3 kinase-AKT), upregulation of matrix
metalloproteinases (which downregulate death receptors, release growth factors, and condition the extracellular matrix for
invasion); overexpression of anti-apoptotic proteins (BCL-2, BCL-XL) or focal adhesion kinase (FAK), and inactivation of
p53, among others.
The importance of anoikis resistance in metastasis was elegantly shown in experimental studies where a functional screen for
suppressors of anoikis identified the neurotrophic receptor TRKB as a key mediator. Rat intestinal epithelial cells are very
sensitive to detachment-induced anoikis and are non-tumourigenic, but when transfected with TRKB, they become highly
tumourigenic and metastatic via both the lymphatic and haematogenous routes, even destroying bone. TRKB is often
overexpressed in human malignancies and is mutated in colon cancer. Its activation also induces vascular endothelial growth
factor (VEGF) expression via hypoxia inducible factor (HIF), potentially assisting with establishment and angiogenesis of
tumours at secondary sites.
Lancet 2007; 369
Angiogenesis and lymphangiogenesis
That tumour growth and progression is limited before vascularisation of the neoplastic mass is generally accepted.Vascularisation is achieved via
neoangiogenesis, co-option of existing blood vessels, vasculogenic mimicry (in which poorly differentiated, highly malignant tumour cells can form a
primitive vascular system), or a combination of these processes. Newly formed leaky capillaries can also serve as conduits for disseminating cells.
Hypoxia and activated oncogenes, including RAS, EGFR, and HER2/NEU, upregulate angiogenic cytokines (eg, VEGF and interleukin 8) and proteolytic
enzymes (eg, matrix metalloproteinases, urokinase plasminogen activator [uPA]) and downregulate inhibitors such as thrombospondin (TSP1) via PI3
kinase and MAP kinase signalling pathways, thus potentiating angiogenesis, tumour growth, and spread. Hypoxia could also directly affect tumour cell
motility, invasion, and metastasis, with a key component recently identified as HIF1-regulated lysyl oxidase (LOX). LOX is linked to poor prognosis in
several tumour types, including breast and oral cancers. It is thought to regulate FAK activity, cell-matrix adhesion, and motility, potentially creating a
niche permissive for metastatic growth at secondary sites. CXCR4, a chemokine implicated in site-selective metastasis, is also upregulated by hypoxia as
well as oncogenes such as HER2, MET, and EGFR. Hypoxia regulates many other genes linked to tumour progression, recruits macrophages and other
inflammatory cells, and can also contribute to increased genetic instability and resistance to apoptosis.
A parallel process—lymphangiogenesis—has been invoked as a potential facilitator of lymphatic metastasis, although functional lymphatic vessels within
human tumours are rare and co-option of existing lymphatic vessels could also occur. The major lymphangiogenic cytokines (VEGF-C and VEGF-D) and
lymphangiogenesis have been linked to poor prognosis in some cancers, and more specifically with lymph node metastasis. Experimental manipulation of
these cytokines modulates lymphatic metastasis in some experimental models. VEGF-A and other signalling systems—eg, angiopoietin:Tie, ephrin:Eph,
and PDGF-BB:PDGFR—could also be involved. Recently, so-called zip codes have been identified on the lymphatic endothelium in tumour xenografts
which, when blocked, inhibited lymphatic metastasis.
Two questions are of particular interest: can the propensity for lymphatic metastasis be predicted from gene expression signatures, as has been claimed for other
sites of metastasis? And does lymphatic dissemination predispose to distant metastasis? The role of lymphatic dissemination has recently been reviewed,
and that nodal metastases could serve as a bridgehead for further dissemination in certain cancers is clear; however, direct haematogenous dissemination
occurs in others. Clearly, more careful kinetic and molecular dissection of cancer spread is required to delineate the importance of tumour cells detected
not only in nodes, but also in the blood and bone marrow.
Lancet 2007; 369
Dissemination and colonisation of secondary sites
Several million cells per gram of tumour can be shed daily into the lymphatic system or bloodstream. The fate of
bloodborne tumour cells is somewhat controversial and experimental evidence contradictory. In some models, most
circulating cells die, whereas in others, most survive and extravasate. Insufficient data exist to quantify the fraction of
shed tumour cells that successfully seed secondary tissues, especially in human cancers. Nevertheless, all studies show
that most cells entering the vasculature fail to form macroscopic foci at distant sites.
What, then, is required of a cell to successfully colonise another tissue? These abilities must co-exist within a single
cell since metastases are mainly clonal. To accomplish this process, tumour cells use a variety of motility mechanisms,
chemokine gradients, and proteinases (eg, matrix metalloproteinases, cathepsins, uPA, etc) to enter and exit the
circulation. Many of the processes are also activated by endothelial cells during angiogenesis. Interestingly, Friedl and
colleagues recently showed that the migration of tumour cells through collagen matrices still occurs in the presence of
broad-spectrum proteinase inhibitor cocktails. Additionally, the intuitive assumption that these enzymes are derived
from tumour cells has been challenged by the finding that most are produced by stromal cells.
Ultimately, metastatic cells must lodge at secondary sites and re-establish adhesive connections. During
haematogenous dissemination, the transit time is only seconds, thus cells are unlikely to shut down transcriptional
expression of adhesion molecules as they depart the primary tumour and re-express them when they arrive at
secondary sites. Cells could use alternative adhesion molecules or might selectively alter adhesion by post-translational
modification of already expressed proteins, glycoproteins, lectins, or other molecules.
Metastatic cancer cells must also evade immune effectors or co-opt immune/inflammatory cells to assist them in
completing subsequent steps of the metastatic cascade, and they must resist hydrostatic sheer forces (ie, turbulence
within vessels). Susceptibility to such stresses can vary widely and could contribute stochastically to metastatic
inefficiency. Nonetheless, a successful metastatic cell must overcome whatever challenges to its survival are mounted.
TUMOREN
- Definities
- Ontstaan & evolutie
Oorzaken
Precancereuze condities
Metastasering
- Verdediging
- Morfologische diagnose (labotechnieken)
VERDEDIGING
Het lichaam kan zichzelf tegen tumoren
verdedigen op 3 manieren :
1) door tumor-suppressor genen
2) het immuunsysteem
3) door inflammatie