Molecular Oncology
C1/27; Surgical oncology - CRC
Als colorectaal chirurg opereer je CRC, maar ook Crohn's Disease and protocology en
Pelvic Floor surgery. Acute buiken kunnen obstructies van de darm zijn, wat kan leiden tot
een gebarsten darm, wat kan leiden tot buikvliesontsteking. Kankerbehandeling leidt tot
twee wensen, je wilt beter worden waarbij kwaliteit van leven wordt behouden. Ablative
therapy is het weghalen van de tumor.
- Huid, long, borst, prostaat en dikkedarm kanker zijn de big 5.
Preventie zoals roken verbieden is een vorm van kanker bestrijding, bij darm kanker heb je
dit niet. Als je familiar belast bent kan je worden gescreend middels coloscopie. Eerst een
FIT test, meet Hb in ontlasting; positief dan coloscopie. Je prognose bij CRC hangt vaak af
van de stagering van je kanker bij ontdekking. Kanker care is multidisciplinair. Middels
imagining kan je onderzoeken of de kanker lokaal of uitgezaaid is. Er zijn verschillende
stadia. Stage 0; polyp, stage 2; lokaal groeien, stage 3; doorgegroeid door de darm wand,
stage 3; Groei door lymfeklieren, Stage 4; uitzaaiing in lever. ← cTNM.
- Stage 3 overleeft 60% na 5 jaar, 4 is 15-20%.
Voor stage 1 t/m 3 is chirurgie de nummer 1 methode, chemotherapy alleen is niet
genezend. Oncologisch bewezen beter is een 3 incisie operatie tov hele buik open snijden.
Bij CRC surgery haal je de kanker en de lymfeklieren weg, je haalt een centraal segment
van de darm met de bloedbvaten weg. AMI, links zijdige colon, AME rechts zijdige colon. Via
cavale systeem gaat het bloed weer naar het hart, alles wat via de darm wordt gepompt
gaat via portale systeem; reden voor eerste plaats hematogene metastase. De
endeldarm kan uitzaaien via het cavale systeem, uitzaaiing in longen. Het onderste deel sluit
namelijk hierop aan. Je moet weten middels imaging welke klieren metastases hebben om
ze mee te kunnen nemen.
Evolutie in de operatie leidt tot minder invasiviteit. Chirugie kwalitiet verbetering leidt er toe
dat chiruurgie de grootste factor is in overleving. Rechtszijdige, linkszijdige tumoren en
endeldarm tumoren hebben allemaal andere operaties nodig.
- ALs je alle lymfeklieren laat zitten zal je minder overleving hebben.
Endeldarmkanker ligt in de kleine bekken. Bij endeldarmkankerbehandeling wordt de
rectum verwijderd en is er beschadiging van de zenuwen die hier liggen die zorgen voor
seks, plassen en poepen. In endeldarm kanker, meer dan darmkanker, heb je meer
morbiditeit; zenuw schade, infectie, bloedingen.
Darmkanker; endoscopie en CT scan. Endeldarm kanker ook nog MRI nodig voor
lokale staging. Ook het emsorectum wordt verwijderd. Voor alle astadia verschillende
behandeling, vroege stadia is alleen lokale verwijdering wat leidt tot functie behoudt. Grotere
dan moet alles weg en als de tumor echt te groot en buiten de randen groeit eerst chemo
dan operatie.
- T1/T2 (stadium 1) is lokaal weghalen; hiervan kan je genezen met behoudt van
functie. Als er in de histologie risicofactoren zijn moet je na verwijdering bestralen.
radicale therapy for RC, low anterior resection and - (dia 110).
~Voor stadium 4 heb je metastase die verspreiden op 3 manieren, via bloedbaan (lever en
long), lymfebanen (gek genoeg minder erg) en je hebt buikvliesuitzaaing, gek want heeft
geen bloedbaan nodig. Operative morbidity; comes healthy with cancer, leaves sick without
cancer. 10% na darm operatie dood doordat nietjes in de darm springen → Acuut buik. 4
, C2/28; Introduction CRC
It takes a lot for a cell to become cancer. There are different stages of CRC, 4 is metastatic,
0 is not officially cancer; a lot of cell division hyperplasia, for cancer you it to be invasive
and different types of changes. Cancer is a multi-hit model (4-5), which is why it takes a
long time to get cancer; it could take 20-50 years from first hit to cancer. It is tried to be
defined how long it takes from first hit to cancer, around 20-40 years for all types of cancer.
When cells lose to ability to proliferate they become senescent. By introducing
mutations/viruses that influence cell-cycle control, virus SV40 produces LT which can
inhibit p53 and Rb. Rb controls cell cycle progression and p53 plays a role in cell cycle
apoptosis choices. This is still not enough to be cancerous due to telomareses. Telomeres
are repetetive sequences which are trimmed shorter and shorter every cell cycle round and
when no telomeres = Senescence. SC express hTERT, which maintains telomere length. No
telomeres aren't a declining clock but a timer which gets reset.
- Inhibiting p53, RB and introducing hTERT you get immortal cells.
To get cancerous growth kRAS is introduced which induces a continuous proliferative
signalling. Now the cell is malignant. In CRC you need 4 hits. But the reality is more
complex; in reality in solid cancers, like CRC there can be 1500-1.5 million
mutations in CRC; Once cancer is occurring the system is really uncontrolled
leading to more mutations.
Not all of these mutations are in the coding part of genes.
Hallmarks of cancer are the thinfs a cell needs to be cancerous; limitless
replicative potential, tissue invasion and metastasis, sustained angiogenesis,
evade apoptosis,, self-sufficiency in growth signals and insensitivity to antigrowth
signals.
Fearon and Vogelstein did validation of different steps in CRC stages. Colonoscopy can
be used to make it easier to study cancers in humans, but can also be used to remove them.
They took all different stages, would dissect them and analyze them for mutations. They
looked at early, intermediate and late adenoma and carcinoma to define what is happening;
kRAS were introduced only not in early adenomas. They also found that chromosome 17p
was lost, which is p53, and is introduced in late adenoma or carcinoma; a later event.
Familial Adenomatous Polyposis (FAP) is a form of CRC, incidence of cancer formation in
these patients is 100%, like CRC, duodenum cancer etc. In this cancer we see the early
adenomas. In Salt Lake City, many people with FAP syndrome and have a lot of inbreeding.
They looked for chromosomal composition for the locus of induction of FAP. In humans
chromosome 5 far end they identified the gene responsible for FAP, APC adenomatous
polyposis coli; Normal epithelium → hyperplastic epithelium. Juvenile Polyposis is
syndrome with early onset of polyp formation and –. BMP induces differentiation of tissue in
the intestine and stops proliferation due to binding to receptor and phosphorylation of TF and
driving transcription. No proliferation is protective against cancer but when lost cancer
formation between kRAS and P53.
- APC = self sufficiency in growth, kRAS = self sufficiency in growth signals, smad4 =
insensitivity to anti-growth signals, p53 = evading apoptosis.
Using Crips and organoids you can do in-vitro colon cancer. First induce APC, then p53 and
kRAS and then SMAD4 and had all the different combinations; single or double mutation is
no tumor growth. Triple showed some effect and quadruple mutant shows cancerous
growth.
, C3/28; Wnt
Harold Varmus discovered the cellular origin of retroviral oncogenes. MMTV induces breast
cancer in mice by integrating in DNA on a particular site that drives cancer formation.
Insertion in different site does not have to lead to cancer formation. Together with Roel
Nusse they identified the sites of insertion leading to cancer; INT1 is a place that they
looked specifically to. This site lays in the promoter gene. Induced very strong promoter in
DNA for virus but also affects the sites adjacent to its insert which can be oncogenic.
Christiane Nüsslein-Volhard. Pattern in flies is orchestrated by a defined set of
developmental genes. She identified Wg when mutated they lose their wings, Wg lose
segmentation. Mutation in Tcf would also lead to loss of segmentation and no wings. Wg
and INT were the same leading to the name of Wnt. 80% of spontaneous CRC patients
have APC mutation leading to hyperproliferation of cells. When inserting virus in front of Wnt
you get the same effect as APC. Lynch syndrome (HNPCC) have a mutation in B-catenin;
linkage between B-catenin and APC was not there, meaning these mutations were
exclusive; they are active in the same pathway and thus both mutations both being present
doesnt bring a selective advantage. Hans Clevers looked at this pathway. Hans identified
TCF-1 a TF expressed in T-cells. When introducing TCF1-1 to luciferase nothing happened
but when also introducing B-cat there was luciferase activity. B-cat is a binding partner of
TCF and APC and b-cat are in the same pathway. It was seen that B-catenin pathway is
highly active in CRC, when reintroducing wildtype APC in CRC with APC mutation, the
luciferase went off. So APC inhibits B-catenin which leads to TCF activation and
proliferation, when mutating APC you get uncontrolled B-catenin and thus TCF activation.
Lynch syndorme have b-catenin mutations, these mutations almost always occur in
N-terminal positions 33, 35 and 45; mutations always in serine or threonine. B-catenin is
phosphorylated by GSK3b and CK1 APC binds in the heart of the protein adn TCF binding
site is at the C-end. Somehow phosphorylation regulates the protein. Ubiquitin-ligase system
drives b-catenin to be broken down. Phosphorylation leads to binding of ubiquitin-ligase
systems and thus degrades. No phosphorylation sites is no break down of b-catenin and
thus driving binding to TCF.
TCF and Wg have a similar phenotype, loss of segmentation suggesting that they are part of
the same pathway; WNT is secreted and is regulated, its get out of the cell and signals to
other by binding to WNT recetpors. Under normal conditions you have APC in complex with
other proteins that allows B-catenin to be phosphorylated and degraded. When WNT binds,
the complex dissociates, no binding to APC to b-catenin, no phosphorylation, no degradation
and now it can enter the nucleus and bind to DNA. So WNT inhibits APC which inhibits
b-catenin and TCF which do transcription.
When looking at gene expression profiles of WNT and no WNT you see the downstream
effect of the b-catenin and thus WNT. When shutting down TCF signalling; down regulates
350 genes and upregulate 250 genes.
Loss of APC is uncontrolled WNT pathway activation. You can hit on B-catenin, INT1 and
WNT. WNT is a ligand which serves as an oncogene.
C1/27; Surgical oncology - CRC
Als colorectaal chirurg opereer je CRC, maar ook Crohn's Disease and protocology en
Pelvic Floor surgery. Acute buiken kunnen obstructies van de darm zijn, wat kan leiden tot
een gebarsten darm, wat kan leiden tot buikvliesontsteking. Kankerbehandeling leidt tot
twee wensen, je wilt beter worden waarbij kwaliteit van leven wordt behouden. Ablative
therapy is het weghalen van de tumor.
- Huid, long, borst, prostaat en dikkedarm kanker zijn de big 5.
Preventie zoals roken verbieden is een vorm van kanker bestrijding, bij darm kanker heb je
dit niet. Als je familiar belast bent kan je worden gescreend middels coloscopie. Eerst een
FIT test, meet Hb in ontlasting; positief dan coloscopie. Je prognose bij CRC hangt vaak af
van de stagering van je kanker bij ontdekking. Kanker care is multidisciplinair. Middels
imagining kan je onderzoeken of de kanker lokaal of uitgezaaid is. Er zijn verschillende
stadia. Stage 0; polyp, stage 2; lokaal groeien, stage 3; doorgegroeid door de darm wand,
stage 3; Groei door lymfeklieren, Stage 4; uitzaaiing in lever. ← cTNM.
- Stage 3 overleeft 60% na 5 jaar, 4 is 15-20%.
Voor stage 1 t/m 3 is chirurgie de nummer 1 methode, chemotherapy alleen is niet
genezend. Oncologisch bewezen beter is een 3 incisie operatie tov hele buik open snijden.
Bij CRC surgery haal je de kanker en de lymfeklieren weg, je haalt een centraal segment
van de darm met de bloedbvaten weg. AMI, links zijdige colon, AME rechts zijdige colon. Via
cavale systeem gaat het bloed weer naar het hart, alles wat via de darm wordt gepompt
gaat via portale systeem; reden voor eerste plaats hematogene metastase. De
endeldarm kan uitzaaien via het cavale systeem, uitzaaiing in longen. Het onderste deel sluit
namelijk hierop aan. Je moet weten middels imaging welke klieren metastases hebben om
ze mee te kunnen nemen.
Evolutie in de operatie leidt tot minder invasiviteit. Chirugie kwalitiet verbetering leidt er toe
dat chiruurgie de grootste factor is in overleving. Rechtszijdige, linkszijdige tumoren en
endeldarm tumoren hebben allemaal andere operaties nodig.
- ALs je alle lymfeklieren laat zitten zal je minder overleving hebben.
Endeldarmkanker ligt in de kleine bekken. Bij endeldarmkankerbehandeling wordt de
rectum verwijderd en is er beschadiging van de zenuwen die hier liggen die zorgen voor
seks, plassen en poepen. In endeldarm kanker, meer dan darmkanker, heb je meer
morbiditeit; zenuw schade, infectie, bloedingen.
Darmkanker; endoscopie en CT scan. Endeldarm kanker ook nog MRI nodig voor
lokale staging. Ook het emsorectum wordt verwijderd. Voor alle astadia verschillende
behandeling, vroege stadia is alleen lokale verwijdering wat leidt tot functie behoudt. Grotere
dan moet alles weg en als de tumor echt te groot en buiten de randen groeit eerst chemo
dan operatie.
- T1/T2 (stadium 1) is lokaal weghalen; hiervan kan je genezen met behoudt van
functie. Als er in de histologie risicofactoren zijn moet je na verwijdering bestralen.
radicale therapy for RC, low anterior resection and - (dia 110).
~Voor stadium 4 heb je metastase die verspreiden op 3 manieren, via bloedbaan (lever en
long), lymfebanen (gek genoeg minder erg) en je hebt buikvliesuitzaaing, gek want heeft
geen bloedbaan nodig. Operative morbidity; comes healthy with cancer, leaves sick without
cancer. 10% na darm operatie dood doordat nietjes in de darm springen → Acuut buik. 4
, C2/28; Introduction CRC
It takes a lot for a cell to become cancer. There are different stages of CRC, 4 is metastatic,
0 is not officially cancer; a lot of cell division hyperplasia, for cancer you it to be invasive
and different types of changes. Cancer is a multi-hit model (4-5), which is why it takes a
long time to get cancer; it could take 20-50 years from first hit to cancer. It is tried to be
defined how long it takes from first hit to cancer, around 20-40 years for all types of cancer.
When cells lose to ability to proliferate they become senescent. By introducing
mutations/viruses that influence cell-cycle control, virus SV40 produces LT which can
inhibit p53 and Rb. Rb controls cell cycle progression and p53 plays a role in cell cycle
apoptosis choices. This is still not enough to be cancerous due to telomareses. Telomeres
are repetetive sequences which are trimmed shorter and shorter every cell cycle round and
when no telomeres = Senescence. SC express hTERT, which maintains telomere length. No
telomeres aren't a declining clock but a timer which gets reset.
- Inhibiting p53, RB and introducing hTERT you get immortal cells.
To get cancerous growth kRAS is introduced which induces a continuous proliferative
signalling. Now the cell is malignant. In CRC you need 4 hits. But the reality is more
complex; in reality in solid cancers, like CRC there can be 1500-1.5 million
mutations in CRC; Once cancer is occurring the system is really uncontrolled
leading to more mutations.
Not all of these mutations are in the coding part of genes.
Hallmarks of cancer are the thinfs a cell needs to be cancerous; limitless
replicative potential, tissue invasion and metastasis, sustained angiogenesis,
evade apoptosis,, self-sufficiency in growth signals and insensitivity to antigrowth
signals.
Fearon and Vogelstein did validation of different steps in CRC stages. Colonoscopy can
be used to make it easier to study cancers in humans, but can also be used to remove them.
They took all different stages, would dissect them and analyze them for mutations. They
looked at early, intermediate and late adenoma and carcinoma to define what is happening;
kRAS were introduced only not in early adenomas. They also found that chromosome 17p
was lost, which is p53, and is introduced in late adenoma or carcinoma; a later event.
Familial Adenomatous Polyposis (FAP) is a form of CRC, incidence of cancer formation in
these patients is 100%, like CRC, duodenum cancer etc. In this cancer we see the early
adenomas. In Salt Lake City, many people with FAP syndrome and have a lot of inbreeding.
They looked for chromosomal composition for the locus of induction of FAP. In humans
chromosome 5 far end they identified the gene responsible for FAP, APC adenomatous
polyposis coli; Normal epithelium → hyperplastic epithelium. Juvenile Polyposis is
syndrome with early onset of polyp formation and –. BMP induces differentiation of tissue in
the intestine and stops proliferation due to binding to receptor and phosphorylation of TF and
driving transcription. No proliferation is protective against cancer but when lost cancer
formation between kRAS and P53.
- APC = self sufficiency in growth, kRAS = self sufficiency in growth signals, smad4 =
insensitivity to anti-growth signals, p53 = evading apoptosis.
Using Crips and organoids you can do in-vitro colon cancer. First induce APC, then p53 and
kRAS and then SMAD4 and had all the different combinations; single or double mutation is
no tumor growth. Triple showed some effect and quadruple mutant shows cancerous
growth.
, C3/28; Wnt
Harold Varmus discovered the cellular origin of retroviral oncogenes. MMTV induces breast
cancer in mice by integrating in DNA on a particular site that drives cancer formation.
Insertion in different site does not have to lead to cancer formation. Together with Roel
Nusse they identified the sites of insertion leading to cancer; INT1 is a place that they
looked specifically to. This site lays in the promoter gene. Induced very strong promoter in
DNA for virus but also affects the sites adjacent to its insert which can be oncogenic.
Christiane Nüsslein-Volhard. Pattern in flies is orchestrated by a defined set of
developmental genes. She identified Wg when mutated they lose their wings, Wg lose
segmentation. Mutation in Tcf would also lead to loss of segmentation and no wings. Wg
and INT were the same leading to the name of Wnt. 80% of spontaneous CRC patients
have APC mutation leading to hyperproliferation of cells. When inserting virus in front of Wnt
you get the same effect as APC. Lynch syndrome (HNPCC) have a mutation in B-catenin;
linkage between B-catenin and APC was not there, meaning these mutations were
exclusive; they are active in the same pathway and thus both mutations both being present
doesnt bring a selective advantage. Hans Clevers looked at this pathway. Hans identified
TCF-1 a TF expressed in T-cells. When introducing TCF1-1 to luciferase nothing happened
but when also introducing B-cat there was luciferase activity. B-cat is a binding partner of
TCF and APC and b-cat are in the same pathway. It was seen that B-catenin pathway is
highly active in CRC, when reintroducing wildtype APC in CRC with APC mutation, the
luciferase went off. So APC inhibits B-catenin which leads to TCF activation and
proliferation, when mutating APC you get uncontrolled B-catenin and thus TCF activation.
Lynch syndorme have b-catenin mutations, these mutations almost always occur in
N-terminal positions 33, 35 and 45; mutations always in serine or threonine. B-catenin is
phosphorylated by GSK3b and CK1 APC binds in the heart of the protein adn TCF binding
site is at the C-end. Somehow phosphorylation regulates the protein. Ubiquitin-ligase system
drives b-catenin to be broken down. Phosphorylation leads to binding of ubiquitin-ligase
systems and thus degrades. No phosphorylation sites is no break down of b-catenin and
thus driving binding to TCF.
TCF and Wg have a similar phenotype, loss of segmentation suggesting that they are part of
the same pathway; WNT is secreted and is regulated, its get out of the cell and signals to
other by binding to WNT recetpors. Under normal conditions you have APC in complex with
other proteins that allows B-catenin to be phosphorylated and degraded. When WNT binds,
the complex dissociates, no binding to APC to b-catenin, no phosphorylation, no degradation
and now it can enter the nucleus and bind to DNA. So WNT inhibits APC which inhibits
b-catenin and TCF which do transcription.
When looking at gene expression profiles of WNT and no WNT you see the downstream
effect of the b-catenin and thus WNT. When shutting down TCF signalling; down regulates
350 genes and upregulate 250 genes.
Loss of APC is uncontrolled WNT pathway activation. You can hit on B-catenin, INT1 and
WNT. WNT is a ligand which serves as an oncogene.
