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
possible mediators in metastasis of evasion of host defenses when in body vessels
- reduced MHC class 1
- shedding of ICAM-1 blocks the TCR
possible mediators in metastasis of adherence to the vessel endothelium
binding of CD44 to an endothelial ligand
possible mediators in metastasis of extravasation
integrins and laminin receptor
how do invasive cells move through 3D tissues
making space by- destruction of tissue, widening of spaces by oedema
what 3 things does invasion require
change and or loss in cell-cell and cell-matrix adhesion.
- focal proteolysis of the matrix
- movement to occupy the space
role of cadherins in carcinogenesis
they are central to cell-cell adhesion, establishing cell polarity and differentiation.
- invasion can be inhibited by E-cadherin expression in animal models
- carcnioma cadherins and the downstream signalling components are extensively mutated.
- mouse models of colon cancer show a cusal role for Ecadherin in the transition from adenoma to carcinoma.
what do integrins do
regulate cell-matrix adhesion and participate in intracellular signalling pathways which regulte cell survival and proliferation.
difference between integrins in stationary and motile cells?
stationary = clustered receptors to the assembled matrix motile = dispersed and unstable receptors in the cell membrane and adhesion to a secreted matrix. tumour cells lose the apoptotic response to changes in the matrix signals
how is the matrx degraded in carcinogenesis
1 - tumour cells secrete callagenases, hyaluronidases and metalloproteinases.
- the non-neoplastic stroma also secretes these enzymes, notably the metalloproteinases but these are normally in quilibrium with tissue inhibitors of metalloproteinases (TIMPs).
- this is a tissue remodelling process so there is a constant cross-tlak between the tumour cells and the surrounding non-neoplastic stroma. as in wound healing.
how far can diffusion occur in solid tumours
nly 150microm from capillaries, henc the need for neovascularisation.
whats the angiogenic switch.
the range of mechanisms controlling tumour angiogenesis
promotion of angiogenesis in a tumour
angiogenic factors from - cancer cells, infiltrating macrophages, the release of sequestered factors from the breakdown of matrix (FGF). there are often extrememly high levels of angiogenic factors in tumours.
pattern of growth of neovascularisation in tumour cells
the very high levels of angiogenic factors, paradoxically, lead to the formation of vessels that are dilated and relatively inefficient at gas exchange. hence, some tumours show angiogenesis and a centre of hypoxic necrosis. this has a profound effect on treatment
common routes of metastasis
usually via blood and lymph.
- can also be via tissue spaces such as peritoneal and pleural cavities. common stomach cancer is transcoelomic spread to the ovary.
do all cell shed metastasise
no. cells are contsantly shed from primary tumours but only a small sub-population are metastatically competent.
metastatic spread is random or not?
not.
- anatomy - lymphatic or vascular drainage.
- organ specificity - adhesion is important and some cancer cells express adhesion molecules specific to certain capillary beds.
- chemokines and their receptors are often important and are differentially expressed.
- common sites = liver, lung, bone, brain.
- no genetic changes have been found yet that are specific to invading and metastasising cells.they can be found in pre-invasive lesions.
what are cancer stem cells
- there is evidence that both leukaemias and solid tumours contain small subpopulationso f cells that:
- self renew
- proliferate indefinitely
- can reproduce the cancer through serial transplantation in mice
- they were first isolated in AML
- since identified and isolated from breast,colon and gliomas
how may cancer stem cells arise
through mutations in the tissue stem cell population or through mutations in a transit amplifying cell.
conventional therapies for cancer
1 - surgery. remove or debulk
2 - radiotherapy. local and regional
3 - chemotherapy. systemic treatment for metastatic disease. combinations of drugs used.
how does chemo cause cancer cell death
it seems by inducing apoptosis. it is important to try and tailor the therapy used ot the molecular changes in a specific patient or the treatment could enhance progression.
how does radiation kill cancer cells
largely through expression of wild type p53. as do topoisomerase inhibtitors (camptothecin, etoposide) and possible spindle toxins (taxol)
what is mdr
a membrane channel secretion protein that is overexpressed in cancers resistant to some drugs
targets of targeted treatments
1 - growth factors 2 - growth factor receptors 3 - signalling molecules 4 - cell cycle proteins 5 - pro-angiogenic molecules 6 - pro-apoptotic molecules
what are angiostatics of such interest
as they kill normal cells (vasculature) not cancers cell directly. hence there is less risk of acquired resistance to the drugs.
- these are very effective in mouse models.
- clinical trials have varied effects.
what is glivec
Imatinib
a small molecule inhibitor of bcr/abl fusion protien in CML. 90% of patients enter remission. but the gene is still detectable in the bone marrow.
herceptin
mab to the HER-2/ERB-B2/ neu receptor (EGFreceptor family)
only effective in HER-2 overexpressing breast cancers.
what is avastin
a mab to VEGF, first line treatment for colorectal cancer
what is panitumumab
a mab to a EGFR in colorectal cancer but only effective in cancers without K-ras mutations
why is cancer resistance such an inevitability
becuase of their intrinsic mutability they contain a range of drug resistant sub-clones even before treatment and these are then selected for.
the ras pathway
GRB-2 and SOS couple EGFR activation to Ras activation.
Ras activates 2 pathways
1 - proliferative - RAF-MEK-ERK
2 - survival - PI3K/PTEN-AKT
how may have metastases evaded the immune system
1 - downregulation of MHC 1
2 - induction of non-responsiveness to tumour antigen
3 - release of immunosuppressive factors such as TGF-beta
whats the issue with BRCA1/2 defects
defefctive DNA strand repair (homologous repair).
what is olaparib
a PARP inhibitor which kills BRCA1/2 cancers by blocking another major DNA repair pathway
what is synthetic lethallity
Synthetic lethality arises when a combination of mutations in two or more genes leads to cell death, whereas a mutation in only one of these genes does not, and by itself is said to be viable
what does PARP inhibition block
base-excision repair. a major DNA repair method
how do cancers develop resistance
- over expression of mdr
- drug exporter proteins
- mutation or amplification of target proteins
- mutations in cell death pathway
hanahan and weinberg 2000, 6 hallmarks
1 - self sufficiency in growth signalling (cell cycle control)
2 - evading apoptosis
3 - sustained angiogenesis
4 - limitless replicative potential (immortalisation)
5 - tissue invasion and metastasis (adhesion, proteolysis and movement)
6 - insensitivity to anti-growth signals (signalling pathways)
2 hallmarks added in 2011
- deregulation of cellular energetics
- avoiding immune destruction
what characteristics are enabling of oncogenesis
- genomic instability and mutation
- tumour promoting inflammation
