Edmead lecture 5 - metastasis Flashcards
Once cancer becomes metastatic therapy must become ______ which opens up the possibility of ___ _____.
Systemic
Side effects
Only some cells within the tumour mass can ______. These are possibly the earlier, less ____, stem cell like cells of the tumour that can adapt to different ______/_____ and grow elsewhere. Whereas more _______, _____ cells probably can’t grow elsewhere as they are more restricted.
Metastesis
Differentiated
Environments/niches
Differentiated, progenitor cells
Metastasis is the ability of cancer cells to break away from site of _____, travel to and ______ a distant site. This is one of the differences between ____ and ______ growths. ____ stay encapsulated in one localisation and are _____ to remove in surgery. _____ are invasive, difficult to tell the boundaries of growth and spread into other tissues.
Origin Colonise Benign and malignant Benign Easier Malignant
About ___% of solid tumours have metastasised at the time of ______. Often this is the time when patients present with_____. Checking the body regularly and being familiar with the body can help diagnose quicker. This is important as once cancer has metastasised, this is a poorer _____ for the patient.
50%
Diagnosis
Symptoms
Prognosis
Issues with metastases:
Spread of cells throughout body results in:
1) physical ____
2) competition with normal cells for ____ and __
3) Invasion and interference with ____ function
Obstruction
Nutrients and O2
Organ
Metastasis requires a ___ ____ in cell-cell ____ and degradation of the _____ ____. So tumour masses involve cells that are attached together in a ball/mound/layer due to cell-cell ____. This needs to break and the cells need to break through the ________ matrix and then be carried through the body usually in the ____ _____. The cells then need to break out of the _____ ____ into tissues back through the ______ matrix so they can regrow and colonise.
Break down Adhesion basal lamina Adhesion Extracellular Blood vessels Blood vessels Extracellular
Mutations in _-____ cause them to relax and breaks cell-cell ____. This is essential as cells must break free from constraints that link adjacent cells. _-____ acts as a _____ _____ as it normally functions to secure cell cell _____ and suppress metastasis of tumour cells to distant sites. Transfection of _-____ gene into metastatic epithelial cells can render them non-invasive. Mutations in the extracellular domain and _____ in the promoter region of the _-_____ gene has been identified in prostate carcinomas. Hence metastasis can occur.
E-cadherins Adhesion E-cadherins Tumour suppressor Adhesion E-cadherin
Integrin receptors mediate cell-_ _ _ interactions and intracellular signal transduction. Altered integrin receptor expression in tumour cells enable mobility and invasion of metastasising cells by modifying membrane distribution and allowing adherence to different _ _ _.
ECM (extracellular membrane)
ECMs
MMPs degrade components of the _ _ _. This allows cells to move through it and recolonise other areas. The protein that produces MMPs is often __ regulated in tumour cell membranes. This allows more degradation to occur so more cells can metastasise.
ECM
Up regulated
Intravasation of tumour cells occurs once the ____ _____ has been ______. This leads to entry of tumour cells into ____/lymphatic vessels. These cells home towards the nearest blood cells through the endothelium and back into other tissues.
Basal lamina
Degraded
Blood
Targeting metastasis can be challenging as extravasation is a process that is used by ___s - interfering with _____ molecules may also prevent ___s coming out of tissue to fight infection. As well as cancerous cells. Targeting MMPs, integrins and selectins is not _____ enough for tumour cells - may lead to ___ ____ or lack of ____.
WBCs Adhesion WBCs Specific Side effects Efficacy
There are two theories that attempt to explain why tumour cells move to certain sites to metastasise.
1) 1st pass organ - explain
2) Pre metastatic niches - explain
1) 1st pass organ - Tumour cells are carried through the blood stream, the blood slows at the next major organ in the body and the tumour cells then move from the blood into the tissue of the organ and recolonise it. So you can look at the 1ry tumour and then the next organ that the blood flows to to try and predict the next site of metastasis - not seen in all cases
2) Pre metastatic niches - Similar principle to stem cells and nurse cells. Tumour cells can recolonise in tissue that has similar growth factors to the site of the 1ry tumour. So the tumour cells move to a niche that provides the growth factors that it requires to grow. OR the secondary site may be prepared to receive the tumour cells so the required nurse cells/growth factors are sent to that site in advance. It was found that factors secreted from 1ry tumours acted on downstream 2ry sites. If the 1ry tumour was removed then recolonisation didn’t occur so recolonisation depends on factors released from the 1ry tumour e.g. cytokines or growth factors. BUT also cases where remove 1ry tumour then 2ry tumours grew so may be tumour suppressing!
Metastatic colonisation can’t occur without formation of new blood vessels (______) as the tumours need _____ and ___ to grow
Angiogenesis
Nutrients and oxygen
Often tumours have a ____ core as the outside of the tumour has a good ___ supply meaning it receives the ____ and ____ it needs to grow. These cannot get to the middle of the tumour due to poor ____ supply. This results in some tumour cells responding differently to drugs. E.g. the cells on the ____ are killed off but the ones in the inside with less ___ supply feeding them don’t receive the drug as don’t die. If just one cell is left than this one cell can _____.
Necrotic Blood Nutrients and oxygen Blood Outside Blood Recolonise
Cancer tumour cells want a good blood supply so they can grow and we want cancer cells to have a good blood supply so we can deliver ___ to them.
Drugs
Name 3 times that angiogenesis normally occurs.
So these processes don’t often occur in mature humans. This represents a different that tumour cells shave so this could be a good ____. If you cut off tumours blood supply then you starve the tumour of ____ and ____ so it dies.
1) Embryogenesis
2) Menstruation
3) Wound healing - repair damaged blood vessels
Target
Nutrients and oxygen
Angiogenesis is controlled by endogenous angiogenic growth factors and inhibitors. Growth factors cause blood vessel growth and ___. E.g. ___, ____ (platelet derived growth factor) and ____ (vascular endothelial growth factor)
Angiogenic inhibitors: _____ and _____ normally there is an _____ of these to keep the process dampened down and if need to repair blood vessels then reactivate angiogenic growth factors then dampen down again once done.
Repair
FGF, PDGF, VEGF
Angiostatin and endostatin
Excess
Angiogenic process:
1) Surrounding cells e.g. stromal/______ cells or tumour cells in tumour release ______ factors
2) These bind specific GF receptors on nearby _____ cells causing them to become activated.
3) ______ cells then produce enzymes through _____ _____
4) Enzymes digest _____ _____ to make a hole in the blood vessel
5) Once a hole is made the _____ cells proliferate and divide and migrate out of the hole
6) _____ molecules and ____ aid formation of growing blood vessel. The _____ digest the ECM to make room for the growing vessel
7) The new vessels are stabilised by _____ ____ cells and pericytes.
1) endothelial - angiogenic growth
2) endothelial
3) endothelial - gene transcription
4) basement membrane
5) endothelial
6) Adhesion - MMPs - MMPs
7) smooth muscle
In angiogenesis: blood vessels grow and sprout towards the source of the ______ ____ that induced it. e.g. towards a tumour that secretes ____. The ____ binds receptors on endothelial cells causing them to grow towards the tumour so it receives its own blood supply.
Angiogenic factors
VEGF
VEGF
Tumour cells can switch on ____ production. It must be transcribed and translated. Oncogenes and hypoxic factors e.g ___ switch on ____ production.
VEGF
HIF
VEGF
Designing an anti-angiogenic agent is hard because not all tumours utilise the same angiogenic growth factors. E.g. not all tumours use ____. So if design an agent against ____ and the tumour doesn’t use it then it won’t be efficacious. Alternatively, if the tumour does use ____ and this agent prevents it’s activity then the tumour may utilise an alternative angiogenic growth factor!
VEGF
VEGF
There are _ forms of VEGF. VEGF_ is the ____ in cancer. Its expression is switched on by oncogenes and hypoxia mediated stabilisation of ___ _____ that drive VEGF expression.
5
VEGFA is the ligand in cancer
Transcription factors
How to target VEGF:
1) can try to _______ levels of _____ _____ e.g by using an ______ RNAI approach to knock down levels of angiogenic factors e.g bFGF or PDGF
2) Can try to mop up xs ____ ____ by using soluble _____ or with ______ _____. E.g ______ that mops up excess ____ targets the ligand not the receptor and it prevents it binding the receptor. ______ __ = _____ which is used in _______ _____ _____. It inhibits blood vessel growth and prolongs survival. Can give this in combination with cytotoxic drugs e.g. _-__ or other kinase inhibitors e.g. the ____ inhibitor Erlotinib.
3) Enzyme inhibitors can also be used. Enzymes with an intrinsic _____ ____ can be targeted. Can block the _____ domain with small molecule _____ ____ inhibitors. This blocks the receptor signalling as it blocks __________ e.g Sorafenib or Sunitinib.
4) Activation of tumour suppressors - e.g. ___.
___ can up regulate anti angiogenic factors e.g. thrombospondin, endostatin or angiostatin or down regulate bFGF. But if lose activation of ___ then alter the balance and imbalance of proangiogenic factors and no apoptosis so allow tumours to induce blood vessel supply and grow more. SO reinstating ___ can help up regulate anti angiogenic factors.
1) Downregulate
Growth factors
antisense
2) growth factor receptors monoclonal antibodies Antibody VEGF Monoclonal antibody = Avastin Renal cancer patients 5-FU EGFR
3) Kinase domain
Kinase
Small molecule tyrosine kinase
Autophosphorylation
4) P53
P53
P53
Issues: majority ineffective against established tumours due to the fact that they have established ____ vessels. These agents only prevent the formation of new ____ vessels. Long term treatment may also impair _____ ______.
Good points:
Might be useful to prevent _____ if caught early enough. Can use in combination therapy with lower dose ____ drugs or other angiogenics acting at different stages.
Blood
New
Wound healing
Metatasis
Cytotoxic
