cancer progression, invasion, metastasis and therapy Flashcards
how do colon cancers arise
clinical and histopathological evidence suggests 80-90% arise from adenomas.
mutations in colon cancer
frequently mutated genes - APC, MSH2/MLH1, K-ras, SMAD4, p53.
- together with a variety of other gene mutations
- APC and MSH2/MLH1 can be inherited or acquired. acquired MLH1 defect is usually through promoter methylation.
loss of APC causes
loss of orderly cell replication, loss of adhesion and cell migration
inactivation of APC causes a change in crypt architecture
- replicating cells heap up in the mucosa
- secondary hit or mutations are made more likely
-APC regulates beta catenin levels
-
what is nuclear beta catenin
a transcriptional master switch in intestinal crypts controlling proliferation versus differentiation.
what are the possible pathways to colorectal cancer
1 - adenoma-carcinoma = commonest
2 - ulcerative colitis - small fraction
3 - HNPCC/lynch 2-5%
4 - FAP 1%
mutation of tumour suppressor genes vs oncogenes
tuour suppressor genes require mutation of both alleles.
no of changes for malignant colon cancer
at least 6 different genes but less in the adenoma
what are gliomas
tumours of the astrocytes
- they show a spectrum of abnormality and are graded 1-4 on histopathology
- grade 4 = glioblastoma multiforme and is the most abnormal with a poor prognosis.
molecular analysis SHOWS THAT INCREASING GRADE IS ASSOCIATED WITH INCREASING GENETIC CHANGES
mutations in grade 2/3 glioma
3-4 mutations. most often in IDH1/2 and p53 loss
mutations in grade 4 gliomas
6-8 mutations:
- IDH1/2
- loss of G1-S checkpoint control
- loss of p53
- telomerase activation
- amplification of EGF-R
- loss of PTEN
- 1p19q codeletion
compare and contrast glioma and colorectal carcinoma mutations
different specific mutations except both p53.
- same general scheme of a loss of tumour suppressor and activation of oncogenes.
what is calssification of leukaemias based on
clinical course and cell maturation (acute or chronic)
-cell lineage (myeloid or lymphoid)
difference between leukaemias and other cancers
- gross aneuploidy and rearragements seen in carcinomas are not seen here.
- there are specific clonal chromosome abnormalities. usually translocations, deletions or inversions.
- usually only a few abnormalities 1-3
- in many leukaemias no chromosome changes can be identified and the DNA has to be sequenced to identify the mutations.
what is a fusion protein
the result of chaemeric mRNA that is the result of translocation of exons of 2 separate genes so that they are transcribed together.
what is the philadelpia chromosome
a translocation of 9 and 22. the signature of chronic myeloid leukaemia. (CML)
- this causes bcr/abl fusion and is almost certainly the initiating mutation in the development of CML.
pathogenesis of CML
bcr/abl fusion - 3-4years latency - p53 deletion or mutation - Ras activation - duplicaiton of the Ph+ this causes the transformation to acute myeloid leukaemia. another example of multi-step carcinogenesis.
what clonal abnormalities of Acute Leukaemia are clinically important
reciprocal translocation of 15 and 17 in acute promelocytic leukaemia (PML). this joins the retinoic acid receptor (RAR) to the PML gene. this causes expression of RAR making the leukaemic cells sensitive to retinoids. treatment with retinoic acid can then be effective.
what does PML stand for
acute promelocytic leukaemia
what does AML stand for
acute myeloid leukaemia
what does CML stand for
chronic myeloid leukaemia.
what are the hallmarks of cancer
invasion and metastasis. invasion is central as metastasis cant proceed without it.
what are the sequence of events of metastasis
1 - detachment and invasion of surronding tissues
2 - penetration of body cavities and vessels (lymph and blood)
3 - release of tumour cells for transport to other sites in vessels
4 - evasion of host defenses and immune destruction
5 - adherence and reinvasion or extravasation at the site of arrest.
6 - manipulation of the new environment to promote survival, vascularisation and growth.
possible mediators in metastasis of detachment
loss of adhesion molecules ie cadherins
possible mediators in metastasis of invasion
metalloproteinases
- upreg of integrins
- downreg of tissue inhibitors of metalloproteinases
possible mediators in metastasis of intravasation
metalloproteinases and downreg of their inhibitors