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Samenvatting Algemene en Experimentele Oncologie (16/20)
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Dit is een samenvatting van de slides en lesnotities van het vak Algemene en Experimentele Oncologie.
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ALGEMENE EN EXPERIMENTELEONCOLOGIE
INHOUD
1.1 Celdeling als motor van ontwikkeling, groei en weefselhomeostase ........................................................ 8
1.2 Neoplatische groei ..................................................................................................................................... 8
1.3 Invasief en metastatisch gedrag ................................................................................................................ 9
1.3.1 Invasie .................................................................................................................................................. 10
1.3.2 Metastasering ...................................................................................................................................... 10
1.4 Selectie van tumorcellen .......................................................................................................................... 10
1.5 Hallmarks of cancer.................................................................................................................................. 11
1.5.1 Zelfvoorzienend in groeifactoren ........................................................................................................ 11
1.5.2 Ongevoelig voor groeiremmende signalen ......................................................................................... 12
1.5.3 Vermijden van celdood ........................................................................................................................ 12
1.5.4 Onbeperkte celdeling .......................................................................................................................... 12
1.5.5 Inductie van angiogenese .................................................................................................................... 13
1.5.6 Activatie van invasie en metastasering ............................................................................................... 14
1.6 Bijkomende hallmarks of cancer (2011) .................................................................................................. 14
1.6.1 Genomische instabiliteit en mutaties .................................................................................................. 14
1.6.2 Tumor-bevorderende inflammatie ...................................................................................................... 14
1.6.3 Herprogrammeren van energiemetabolisme ...................................................................................... 15
1.6.4 Ontwijken van het immuunsysteem .................................................................................................... 15
1.7 Bijkomende hallmarks of cancer (2022) .................................................................................................. 15
1.7.1 Fenotypische plasticiteit ontsluiten ..................................................................................................... 15
1.7.2 Epigenetische herprogrammering ....................................................................................................... 16
1.7.3 Belang van het microbioom ................................................................................................................. 16
1.7.4 Senescente cellen ................................................................................................................................ 16
1.8 Hoe manifesteert kanker zich in een patiënt? ......................................................................................... 17
1.9 Tumorclassificatie .................................................................................................................................... 18
2.1 Oncogenen ............................................................................................................................................... 20
2.1.1 Mechanismen van virale oncogenese ................................................................................................. 20
2.1.1.1 Retrovirale cyclus ........................................................................................................................ 21
2.1.1.2 Acuut transformerende retrovirussen ........................................................................................ 21
2.1.1.3 Virale oncogenen en hun cellulaire homologen ......................................................................... 21
2.1.2 Genetische mechanismen die leiden tot constitutieve activatie van oncogenen bij de mens ........... 21
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, 2.1.2.1 Mutaties in oncogenen ............................................................................................................... 22
2.1.2.2 Transcriptionele deregulatie t.g.v translocatie ........................................................................... 23
2.1.2.3 Amplificatie van oncogenen ....................................................................................................... 23
2.1.2.4 Vorming van fusiegenen en fusieproteïnen ................................................................................ 24
2.2 Tumorsuppressorgenen ........................................................................................................................... 25
2.2.1 “Two-hit” hypothese van Knudson ...................................................................................................... 25
2.2.1.1 Retinoblastoom........................................................................................................................... 25
2.2.1.2 RB als tumorsuppressorgen ........................................................................................................ 25
2.2.2 Genetische mechanismen van verlies van 2e wildtype allel (gaat vaak gepaard met LOH) ................ 26
2.3 Kanker als ziekte van de celcyclus ............................................................................................................ 27
3.1 Inleiding: epidemiologisch onderzoek van kanker ................................................................................... 28
3.2 Frequentie: incidentie en prevalentie van kanker ................................................................................... 28
3.3 Epidemiologische gegevens van België, Nederland en de wereld ........................................................... 28
3.3.1 Voorkomen .......................................................................................................................................... 28
3.3.2 Kanker op de lijst van doodsoorzaken ................................................................................................. 29
3.3.3 Evolutie van de kankermortaliteit 1930-2000 ..................................................................................... 29
3.3.4 Kankerincidentie in België en Nederland (2006) ................................................................................. 29
3.3.5 Evolutie van de kankerincidentie in de tijd ......................................................................................... 30
3.4 Preventie en screening ............................................................................................................................ 31
3.4.1 Primaire preventie ............................................................................................................................... 31
3.4.2 Secundaire preventie ........................................................................................................................... 32
3.5 Etiologie: oorzaken van kankerontwikkeling ........................................................................................... 32
3.5.1 Genotoxische, niet-genotoxische en epigenetische carcinogenen en tumorpromotors .................... 33
3.5.1.1 Chemisce agentia ........................................................................................................................ 33
3.5.1.2 Fysische agentia .......................................................................................................................... 34
3.5.1.3 Biologische agentia ..................................................................................................................... 34
3.5.1.4 Erfelijkheid .................................................................................................................................. 34
4.1 Introductie ............................................................................................................................................... 35
4.1.1 Wat is radiotherapie? .......................................................................................................................... 35
4.1.2 Hoe werkt radiotherapie? ................................................................................................................... 36
4.1.3 Radioresistentie ................................................................................................................................... 36
4.2 Radiotherapie in de praktijk ..................................................................................................................... 38
4.2.1 Hoe lang bestaat radiotherapie? ......................................................................................................... 38
4.2.2 Brachytherapie .................................................................................................................................... 38
4.2.3 Teletherapie......................................................................................................................................... 38
4.2.4 Wat heb je nodig voor moderne radiotherapie? ................................................................................. 38
4.2.4.1 Machinerie .................................................................................................................................. 38
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, 4.2.4.2 Mensen ....................................................................................................................................... 39
4.2.5 CT/MRI dosimetrie............................................................................................................................... 39
4.2.6 Externe radiotherapie: lineaire versneller ........................................................................................... 40
4.2.7 Casus .................................................................................................................................................... 40
4.3 Bijwerkingen radiotherapie ..................................................................................................................... 41
4.3.1 Acute bijwerkingen .............................................................................................................................. 41
4.3.2 late bijwerkingen ................................................................................................................................. 41
4.4 Moderne radiotherapie ........................................................................................................................... 42
4.4.1 Ontwikkeling in de radiotherapie ........................................................................................................ 42
4.4.2 Klassieke radiotherapie ....................................................................................................................... 42
4.5 Nieuwe ontwikkelingen ........................................................................................................................... 43
4.5.1 Recente ontwikkelingen ...................................................................................................................... 43
4.5.2 De trend voor de komende jaren ........................................................................................................ 44
4.5.2.1 Hypofractionering en stereotactische RT ................................................................................... 44
4.5.2.2 Nieuwe ontwikkelingen .............................................................................................................. 44
4.5.3 Besluit .................................................................................................................................................. 44
5.1 Apoptose in carcinogenese en kankerbehandeling ................................................................................. 45
5.1.1 Apoptose vs necrose............................................................................................................................ 45
5.1.2 Morfologische kenmerken van apoptose ............................................................................................ 46
5.1.3 Apoptose verloopt in 3 fasen .............................................................................................................. 47
5.1.3.1 Fase 1: Stimulus- of initiatiefase ................................................................................................. 47
5.1.3.2 Fase 2: Regulatiefase .................................................................................................................. 47
5.1.3.3 Fase 3: Executiefase .................................................................................................................... 47
5.1.4 De executiefase van apoptose ............................................................................................................. 48
5.1.5 De intrinsieke of mitochondriële pathway .......................................................................................... 48
5.1.5.1 BCL2-familie ................................................................................................................................ 48
5.1.6 De extrinsieke of ‘death receptor’ pathway ........................................................................................ 50
5.1.7 De apoptose-cascade als doelwit voor antikankertherapie ................................................................ 50
5.2 p53: bewaker van het genoom ................................................................................................................ 51
5.2.1 Historiek van p53 ................................................................................................................................. 51
5.2.2 Structuur van wild type en gemuteerd p53 ......................................................................................... 52
5.2.2.1 P53: typsiche bouw van transcriptiefactor ................................................................................. 52
5.2.2.2 Kenmerken van p53 mutaties in tumoren .................................................................................. 52
5.2.2 Regeling van p53-concentratie en -activiteit in basale omstandigheden............................................ 52
5.2.3 Regeling van p53-concentratie en -activiteit in abnormale omstandigheden .................................... 53
5.2.4 Cellulaire effecten van verhoogde p53-activiteit ................................................................................ 53
5.2.4.1 Autoregulatie van p53-respons .................................................................................................. 54
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, 5.2.4.2 Inhibitie van de celcyclusprogressie ........................................................................................... 54
5.2.4.3 Genetische stabiliteit .................................................................................................................. 54
5.2.4.4 Apoptose ..................................................................................................................................... 54
5.2.4.5 Inhibitie van angiogenese ........................................................................................................... 54
5.2.5 P53 als aangrijpingspunt voor moleculaire antikankertherapie .......................................................... 55
6.1 Inleiding: definitie van hypoxie ................................................................................................................ 57
6.2 Pathogenese van tumorhypoxie .............................................................................................................. 57
6.2.1 Acute hypoxie: perfusie gelimiteerd ................................................................................................... 57
6.2.2 Chronische hypoxie: diffusie gelimiteerd ............................................................................................ 57
6.3 Het ontstaan van hypoxietolerantie ........................................................................................................ 58
6.3.1 Algemeen ............................................................................................................................................. 58
6.3.2 Hypoxie-induceerbare factor 1 (HIF-1) ................................................................................................ 58
6.3.3 Invloed van hypoxie op biologische processen ................................................................................... 59
6.3.3.1 Celproliferatie en progressie doorheen de cyclus ...................................................................... 59
6.3.3.2 Apoptose ..................................................................................................................................... 60
6.3.3.3 Energieproductie en -verbruik .................................................................................................... 60
6.3.3.4 Angiogenese................................................................................................................................ 61
6.4 Belang van hypoxie binnen het kankeronderzoek ................................................................................... 61
6.4.1 Hypoxie en resistentie tegen radiotherapie ........................................................................................ 61
6.4.2 Hypoxie en resistentie tegen chemotherapie ..................................................................................... 62
6.5 Experimenteel luik: modellen voor kankeronderzoek ............................................................................. 63
6.5.1 In Vitro hypoxiemodellen .................................................................................................................... 63
6.5.2 In vivo hypoxiemodellen ...................................................................................................................... 63
6.5.2.1 Tumorgroei induceren bij muizen ............................................................................................... 64
6.5.2.2 Clamp hypoxia............................................................................................................................. 64
6.5.2.3 Inhaleren van lage zuurstofconcentraties .................................................................................. 64
7.1 Introductie ............................................................................................................................................... 65
7.2 Preclinical cancer models ......................................................................................................................... 65
7.2.1 Syngeneïsche (allograft model) ........................................................................................................... 65
7.2.2 Xenograft models ................................................................................................................................ 65
7.2.3 Van patiënten afgeleide xenograften (PDX-modellen) ........................................................................ 66
7.2.4 Genetisch gemanipuleerd muismodel ................................................................................................. 66
7.3 Plaats van inoculatie/implantatie ............................................................................................................ 67
7.4 Moleculaire beeldvorming ....................................................................................................................... 67
7.4.1 PET/CT ................................................................................................................................................. 67
7.4.2 Positron emission tomography ............................................................................................................ 67
7.4.3 Single Photon Emission Computed tomography (SPECT) .................................................................... 68
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