Edmead Lec 4 - Stem Cells Flashcards
Want to maintain a balance between a_____, p_____ and d______. Aberrations in any of these pathways can alter the balance resulting in accumulation of non functional cells.
Apoptosis
Proliferation
Differentiation
Many cancer cells look immature (____ ____), their morphology has changed and this leads to ____ of function. As cells differentiate and become more _____, generally proliferation _____ SO there is a theory that cancerous growth can be reduced by making cells more differentiated. However, the issue is that cancer is a disease of ______ cells.
Blast like Loss Specialised Reduces Proliferating
If a cell is not dividing it is ___ likely to acquire mutations as it is not passing genetic information onto ______ cells.
Less
Daughter
Tumours are often a ________ mass in terms of cellular differentiation (not all cells look the same). Cells on the outside of a tumour are exposed to ________ fluid and have a different _______ to those in the centre of the tumour. This differing ______ of cells is the reason why tumour masses response differently to drugs - some of the mass is more susceptible to the drugs and those that are resistant are left, often in the ____ of the tumour. These resistant cells can then regrow.
Heterogenous Extracellular Morphology Morphology Core
Cancers are ____ (arise from single cells) but not all of theses cells look the same.
Clonal
Most cells have a _____ lifetime and do not live long enough to acquire 3 or more mutations. Every mutation that occurs should be picked up by ____ _____ enzymes and killed off by _____. So these cells need to evade ____ and live long enough to maintain mutations to pass on to daughter cells. Hence why cancer is a disease of the _____ - need time to accumulate mutations.
Finite DNA repair enzymes Apoptosis Apoptosis Elderly
Embryonic stem cells are _____ and can differentiate into many different cell types. Mature cells that are differentiated are no longer ______ and cannot __-differentiate.
Pluripotent
Pluripotent
De-differentiate
As _____ embryonic cells change into differentiated cells they go through various stages - _____ phases make them become more _____.
Pluripotent
Progenitor
Specialised
Generally differentiation is ____ and these cells cannot acquire properties of ____ _____ and __-______.
Terminal
Self Renewal
De-differentiation
Stem cell division is _____. When they divide they produce one identical copy and one more _____ copy.
4 stages - what are they?
Asymmetric
1) Totipotent stem cell
2) Multipotent stem cell - restricted potential stem cell
3) Unipotent stem cell - progenitor cell
4) Terminally differentiated cell
A small number of residual stem cells have been identified in adult tissues - 1st seen in ____ ____. Stem cells are required here as ___ and ___ have a high turnover so _____ stem cells divide to produce these cells.
Bone marrow
RBC and WBC
Progenitor
In other tissues with reduced turnover, stem cell function is used in healing. So if tissues are damaged then stem cells proliferate to produce new cells e.g. in ____ or ____ cells.
Liver
Muscle
Adult stem cells are present in ___ numbers. Proliferation is normally _____ as it is only required when repair is needed. If repair is needed, ______ is released and _____ occurs and when enough cells are produced they are _____ again.
Small Suppressed Suppression Proliferation Suppressed
If you take _____ stem cells or early stage _____ cells and implant them into tissues (in animal models) they grow into ____. (With variety of tissues as they _____ into different tissues)
Embryonic
Progenitor
Tumours
Differentiate
____ may occur in tissue stem cells e.g. proto-oncogene to oncogene or loss of ____ ____ genes or changes to chromosomal structure. As stem cells reside for a long time, when they are reactivated they grow quickly and can pass ____ onto ______ cells which then acquire more ______.
Mutations Tumour suppressor Mutations Daughter Mutations
Stem cells - occur in ____ with their growth normally suppressed in adults. They are surrounded by other cells ‘____ cells’ which control the function of the stem cell. They usually secrete ____ ____ - _____ cytokines and factors which keep the stem cell subdued. When new cells are required, ______ is removed and stem cell can divide into daughter cells. A surge of proliferation occurs but as you move through to more differentiated cells the proliferation rate ______.
Niches Nurse Antigrowth - suppressor cytokines and factors Suppression Decreases
Stem cells are ___ lived - they are the same cells left from the embryo and they self-____. This gives more of an opportunity for _____ to _____ as they are around for a long time compared to say RBC which have a short lifespan of around 3 months.
Long
Renew
Mutations
Accumulate
______ division of stem cells may account for _______ of tumour masses. This may also explain the different responses of tumour cells to growth and _____. Some tumour cells grow quickly and contribute to the tumour ____ and others slow down and become more specialised making them more/less susceptible to _____.
Asymmetric Heterogeneity Drugs Mass Drugs
Chemotherapeutic drugs target rapidly proliferating cells so often target ones contributing to the tumour mass. Hence why you see a _____ in tumour mass when treating with these agents. But they may not affect those that are slightly more _____ as they proliferate less. These may reside at the ____ of the tumour and remain after treatment to _____ at a slightly slower rate.
Reduction
Specialised
Core
Recolonise
Many of the signalling pathways involved in self renewal processes within stem cells are similar to pathways that are mutated in ____ cells. E.g those with protooncogene to oncogene and tumour suppressor gene mutations.
Cancer
Cancer stem cell hypothesis has 4 models: What are they?
1) Expansion of normal stem cell niche permits the expansion of caner stem cells that arose from normal stem cells - more niches that support growth of more stem cells = more proliferation
2) Stem cells may acquire mutations that allow them to switch niches - idea of metastasis and why colonise some tissues and not others - stem cells that acquire mutations or break off and travel through body look for another nice that provides it with right growth signals
3) Cancer stem cells that arose from normal cells become niche independent and self renewal is autonomous - learn to ignore suppressor signal from rich or provide themselves with right growth signals e.g EGF to drive growth pathways
4) Shift in programmed decline in replication potential so cancer stem cells arise from progenitor cells - progenitor cells fail to lose ability to proliferate so keep growing which drives cancer
Self renewal of cancer cells prods an extended window of time for ______. Stem cells are long lived targets for chance _____ compared to _______ cells that die within few days/months.
Mutations
Mutations
Differentiated
Wnt is a _____ _____ ___ that is mutated in around 90% of ____ cancers. Dysregulation of the Wnt pathway occurs due to ____ __ ____ of the tumour suppressor gene ___. Losing ___ results in over activation of the pathways which drives ___ ____. Various stages of this pathway can be mutated which ultimately leads to increased _ _____ activity.
Proto oncogene Colon Loss of function APC APC Cell growth B Catenin activity
Wnt is an intracellular signalling molecule that acts as a ____ to trigger a signal transduction pathway. Wnt binds to ____ which disrupts an _______ _____ which usually_____ cell proliferation. The ______ _____ usually sequesters _ ______ (transcription factor) which is required to drive the cell cycle as it is responsible for the transcription of cyclin _ (drives cell cycle from G1 to _ phase). This complex consists of Axin, CKI, GSK3 and ___
If _ ____ is active then cyclin _ is produced and the cell cycle and proliferation occurs.
Ligand Frizzled Inhibitory complex Suppresses Inhibitory complex B catenin Cyclin D S APC B catenin Cyclin D
In the absence of Wnt in the Wnt signalling pathway. ___ phosphorylates B catenin and it is _______ and _____ so cell cycle and proliferation does not occur.
GSK3
Ubiquitinated
Degraded
Mutations that ______ activate the Wnt pathway have been identified in ___% colorectal cancers. Most mutations inactivate ___ function or activate _ ____. Those with inherited cancer predisposition syndrome (___) carry a germline mutation in ___ and develop an increased number of ____ in the colon which increase the risk of colorectal cancer. This ___ gene is a tumour suppressor gene. If both copies of this gene are inactivated then ___ cannot form the ______ ____ so _ _____ will remain free to act as a _____ _____ and drive cell growth and proliferation.
Constitutively 90% APC B catenin FAP APC Polyps APC APC Inhibitory complex B catenin Transcription factor
Intestinal tissue is regenerative. Stem cells and epithelial ______ give rise to more differentiated cells that move up the ____. When they reach the top of the ____ the differentiated cells undergo ____ and the intestinal epithelium is ____ in a few days. Normally ____ signalling is required to maintain stem cells and progenitors of the crypt. Constitutively active ___ signalling e.g a mutation (____) of the ___ gene leads to carcinoma. This is seen in stem cells of the ____ intestine.
Progenitors Villi Villi Apoptosis Renewed Wnt Wnt Deletion APC Small
Hh pathway!
Hh binds to ____ receptor (tumour suppressor gene) and when this Hh ligand binds it releases ____ of _____. ____ can then release ___ transcription factor to drive _____. Over expression of Hh or ___ or loss of function of ____ can cause cancer.
Patched Inhibition Smoothened Smoothened Gli Proliferation Gli Patched
Telomerases are ____. Telomeres are tandem repeats found on the ends of ______. They aid chromosomal replication. When DNA is copied the _____ enzymes move along the chromosome and copies the chromosomes before cells divide during ____. The two chromosome copies go into the _____ cells. As the DNA polymerase is a big enzyme, when it reaches the end of the chromosome it falls off and can’t copy the last few ____ of the chromosome. So during each round of cell replication, the chromosomes get _____. This is the theory of ageing - as chromosomes get ____ they eventually get too ____ and parts of previously functional genes are lost causing cells to ___.
Enzymes Chromosomes Polymerase Mitosis Daughter Bases Shorter Shorter Short Die
Telomers on the ends of chromosomes aid replication but are non ____ so can afford to lose them off the end of chromosomes when they are replicated. When telomeres get too short they are recognised as damaged DNA and ___ is activated to induce senescence or ____ - as long as ___ is active. Telomerases are _____ ____ enzymes containing an ___ template so they can add short repeats onto the ends of chromosomes. So when DNA is copied the chromosomes still shorten but then the telomerase add repeats onto the ends so DNA ____ can still copy the chromosomes. Cells therefore avoid _____ and senescence as the chromosomes do not shorten and critical parts of the chromosomes are copied. Telomerases are found in rapidly dividing and ____ line cells but most fully ___ ____ (differentiated cells) lack telomerase.
Coding P53 Apoptosis P53 Reverse transcriptase RNA Polymerase Apoptosis Germ Mature, somatic
Stem cells have telomerase and so do ____ cells. _____ cells express telomerases and can repair chromosomes to extend the life of ____ cells. This allows _____ to accumulate. In these cells telomerase enzymes are reactivated. If you could switch off temoerases the chromosomes would get _____ and ____ cells would eventually die as long as ___ is there to activate the ______ pathway. Presence of telomerase correlates with proliferative ability of tumour and is an indicator of ____ prognosis. These are a potential target for anti cancer therapy - block telomerase specific to tumour cells e.g telomerase ______.
Cancer cells Cancer cells Cancer cells Mutations Shorter Cancer P53 Apoptotic Poor Antisense
Put these in order of most telomere ends... Cancer cells Somatic cells Embryonic/stem cells Senescent cell
Cancer cells - persistent growth
Embryonic/stem cells - indefinite replication
Somatic cells - breakage - limited replication
Senescent cells - chromosome instability - cell death
