Week 4 - Cancer and signalling Flashcards
Neoplasm
tumour
apoptosis
cell programmed death
necrosis
when cells die but not by apoptosis
hyperplasia
an increase in the size of an organ as a result of cell proliferation
hypertrophy
an increase in the size of an organ due to an increase in size of consituent cells
criteria used to classify tumours
in terms of biological behaviour - benign or malignant
in terms of origin - differentiation or histogenesis
benign
will never metastasise but may grow
malignant
can spread and invade
compare benign and malignant nuclei
benign - small, regular, uniform, grow slow
malignant - larger, increased DNA content, faster growth
metaplasia
a change from one type of differentiated tissue to another - often resulting tissue is better adapted to environment
categories of cells or tissues that tumours are classed under
epithelial
connective
haematopoietic/lymphoid
neural
routes by which tumour cells metastasise
local invasion
lymphatic spread - travel to draining lymph nodes
blood spread via vessels
Transcoelomic spread
Describe G0 phase
phase when cells are not actively dividing
not always permanent
red blood cells always here
interphase
G1, s, G2
G1 phase
Growing in size
Monitoring environment
RNA and protein synthesis in preparation for S phase
Growth-factor dependent
S phase
synthesis of DNA
G2 phase
further growth
cell organelle replication
prepare for mitosis
M phase
mitosis and cytokinesis
order of mitosis phases
prophase, (prometaphase), metaphase, anaphase, telophase
prophase
chromatin condenses into chromosomes
nucleolus disappears
centrioles move to poles
pro-metaphase
nuclear membrane dissolves
chromosomes attach to microtubules and begin moving
metaphase
spindle fibres align chromosomes along metaphase plate
anaphase
paired chromosomes separate and move to opposite sides of the cell by microtubule generated pulling forces
telophase
chromatids arrive at opposite poles of cell
new membranes form around daughter nuclei
chromosomes decondense
spindle fibres disperse
cytokinesis
cleavage of cell to produce daughter cells
role of CDKs and cyclins
regulate progression through cell cycle
role of cyclin D in cell cycle
activates CDK4/6 to regulate the restriction point
role of cyclin dependent kinase inhibitors
small proteins that inactivate the CDK either by binding directly to form an active complex or by acting as a competitive ligand
three families that offer an extra level of controlling CDK activity
P21 CIP
P27 KIP
P16 INK
progression from G2 to M is dependent on…
CDK1/cyclin B also known as maturation promoting factor (MPF)
CDK1 needs to phosphorylate lamins so lamins can destroy nuclear lamina
chromosome condensation is required
activation of CDK1
cyclin B synthesis starts in G2
once there is sufficient amount, it becomes associated with CDK1 - loss of phosphorylation makes it an active kinase
4 checkpoints of cell cycle
restriction point (G1) DNA damage checkpoints (late G1 and G2) metaphase checkpoint
define checkpoint
Point in the cell cycle where progress through the cycle can be halted until conditions are suitable for the cell to proceed
restriction point is dependent on…
presence of growth factors
accumulation of cyclin D
if growth factor is detected in restriction checkpoint…
cell makes cyclin D, activating CDK4/6 which phosphorylates RB protein - RB protein is then free from the inhibiting factor E2F - RB can now transcribe genes needed for S phase
tumour suppressor genes
encode normal cell proteins that inhibit cell proliferation and growth of cell
cause cell-cycle arrest in abnormally dividing cells and repair DNA damage
explain DNA damage checkpoints
p53 detects DNA damage - results in production of CKI p21 – this binds to CDK2/cyclin E or A at the G1/S transition halting progression to S
At G2/M, progression is halted by p21 binding to CDK1/cyclin A or B
metaphase checkpoint
delays anaphase until all chromosomes are correctly attached to mitotic spindle
Once all attached – inhibition removed and the anaphase promoting complex is activated which allows for the separation of sister chromatids
six characteristics of cancer cells
uncontrolled self proliferation inactivation of tsg that normally inhibit growth evasion of apoptosis limitless replication potential sustained angiogenesis tissue invasion/metastasis
oncogene
mutated forms of proto-oncogene - involved in inducing cancer
proto-oncogene
a normal cellular gene that encodes for a protein normally involve in regulation of cell growth and proliferation
tumour suppressor gene
a gene whose encoded protein directly or indirectly inhibits progression through cell cycle
compare normal cells and cancer cells
cancer cells have large variably shaped nuclei, many dividing cells, variation in size and shape, loss of normal differentiated features (anaplasia), nucleus becomes bigger, accumulation of mRNAs and rRNAs in cytoplasm will make it more basophilic (appear bluer)
tumourigenesis
Initiation step usually result of environmental carcinogen such as chemicals and radiation or viruses
Then the accumulation of many more mutations, some activating oncogenes and others losing tumour suppressor gene activity enhance proliferation potential
Further mutations within population of cells results in a cell that has acquired further mutations with capabilities to become malignant
key controlling mechanisms in cell cycle
presence of a growth factor,
an activating signal and the RB protein
examples of proto-oncogenes in normal cells
Platelet-derived growth factor (PDGF)- function: matrix formation and involved in production of proteases
RAS genes - when RAS proteins are switched on it switches on other genes which switches on genes involved in cell proliferation
examples of tsg
RB - blocks entry to cell cycle in restriction point
p53 - detects DNA damage
BRCA1 - DNA repair
mutations of proto-oncogenes forming oncogenes
deletion/point mutation
regulatory mutation
gene amplification
chromosome rearrangement
result of a point/deletion mutation to proto-oncogene
hyperactive protein made in normal amounts
regulatory mutation or a gene amplification to proto-oncogene
normal protein is greatly over produced
result of chromosome rearrangement to proto-oncogene
nearby regulatory DNA sequence causes normal protein to be overproduced
or
fusion to actively transcribed gene produces hyperactive fusion protein
example of chromosome rearrangement resulting in cancer
The BCR gene on chromosome 22 is brought together with abl gene on chromosome 9
Results in the Philadelphia translocation – results in the BCR-ABL hybrid which is found in Chronic Myeloid Leukaemia
do TSGs or proto-oncogene mutations have the dominant effect
proto-oncogenes bc only one copy of the gene needed to be affected
how do cancer cells invade
produce proteases - need to degrade the surrounding storm and ECM so they can move through it - can travel through blood
how epithelial cells metastasise
e-cadherin is part of adherens junctions - loss of e-cadherin allows adjoining cells to break apart and metastasise
why signalling is important in medicine
to coordinate development and to maintain normal physiological functions
diseases from abnormal signalling
Diabetes type 1 – don’t produce enough insulin
Type 2 diabetes – all target tissues for insulin have lost ability to respond properly to insulin released in body
Cancer – mutated K-Ras is too active and causes cells to grow/divide/survive in the absence of growth factor signals
3 types of signal
physical - sets off a chemical or electrical
electrical
(bio)chemical
stages of cell signalling
signal binds to receptor in or on target cell
transduction - transmission of signal from receptor to part of cell that produces response
response
signalling responses
altered gene transcription in nucleus
altered target protein activity
altered target protein binding
altered protein localisation
signals for intracellular receptors are…
hydrophobic eg. steroid hormones - oestrogen and testosterone or gases
what happens when signal binds to cell surface receptor
it causes a change in conformation of the receptor – alters the activity of intracellular part of receptor – change in shape/activity sets in motion the cellular response to the signal
3 main types of cell surface receptor
enzyme-linked receptor
g-protein-coupled receptor
ion-channel receptor
integration of signal response
multiple signals working together to produce an overall cellular response
3 outcomes of multiple signals working at the same time
conflict - cell ignores one and responds to other
signals can work independently - multiple responses
integration - one overall cellular response
classification of chemical signals
classified based on their chemical structure and by the distance over which they act
four classifications of signals by distance over which they act
endocrine - long distance
paracrine = nearby cells
juxtacrine - neighbouring cell (direct contact)
autocrine - same cell that releases signal
signalling pathway of enzyme-linked receptors
signal binds to receptor activating an enzyme in cytoplasmic side of membrane - enzyme may be beside receptor or an integral part of cytoplasmic domain of the receptor - if signal is dimeric then binding causes dimerisation - the two parts of the receptor come together and this is what activates the enzyme activity
examples of enzyme-linked receptors
receptor tyrosine kinases (RTK) - enzyme is tyrosine kinase - kinase activity is intrinsic to receptor
many growth factors work via this pathway
signalling pathway of of G-protein-coupled receptors
G-protein-coupled receptor is bound to a G protein - Activated g-protein activates enzyme that passes on signal into a cell
examples of of G-protein-coupled receptors
adrenaline and serotonin
example of ion-channel receptor
glutamate neurotransmitter
how do ion-channel receptors work
Signal binds to ion-channel receptor – ion channel opens and ions can flow through that channel across the membrane, by diffusion along a concentration gradient - Ion flow into cell changes electrical properties of cell
receptor tyrosine kinase pathway
ligand binding - receptor dimerisation and activation - autophosphorylation (two subunits both have kinase activity so phosphorylate each other) - relay proteins recruited to docking sites and these are what transmits the signal further into the cell (phosphorylation allows relay proteins to bind)
example of a signalling pathway activating multiple responses
EGF binding to EGFR promotes cell survival, cell proliferation and cell migration
2 main ways that a signal can be transmitted
kinase cascades or production of second messenger
explain the enzyme cascade method of transmitting signal
Each step in a cascade is catalytic (catalysed by an enzyme)
Final enzyme in the cascade alters the function of an effector molecule which produces the cells response to the signal
Cascade system means that in addition to passing on the signal, there is amplification of the signal
MAPK cascade (mitogen-activated protein kinase)
A MAP kinase kinase kinase (MAPKKK) phosphorylates and activates a MAPKK which phosphorylates and activates MAPK – MAPK phosphorylates the cascades effector proteins - this can be deactivated by dephosphorylation at the same site carried out by phosphatase
second messenger method of transmitting a signal
Small molecules are produced in large quantities inside the cell after receptor activation to coordinate the cell’s response
Other second messengers work by activating other protein kinases eg. DAG activates protein kinase C
common second messengers
cyclic AMP (cAMP) produced by enzyme adenylyl cyclase Inositol triphosphate (IP3) and diacylglycerol (DAG) – produced by the enzyme phospholipase C Calcium ions – released from intracellular stores by IP3 or flow into cell upon ion channel activation
how can a disfunction in the pathway of GF signalling via receptor tyrosine kinases lead to cancer
if the GF/RTK pathways are too activated - Can happen if the receptor is overexpressed or if specific mutations occur (Raf and Ras)
explain how lipophilic steroid hormones elicit their effect
These hydrophobic hormones bind to intracellular receptor proteins in cytoplasm
Hormone-receptor complex then acts as a transcription factor, moving into the nucleus, binding to DNA and altering the transcription of specific genes
Target cell changes the genes/proteins it expresses in response
3 main stages of life before birth and their time frames
week 1 - preimplantation stage
weeks 2-8 - embryonic stage (organogenesis occurs)
weeks 9-38 - fetal stage (growth and development)
cleavage
As zygote starts to develop, the maternal and paternal genes start to mix and that triggers division of the zygote from one cell to two, two cells to four… this process of cell division is called cleavage
define zona pellucida
tough glycoprotein coat around the outside of embryonic cells - stops embryo getting bigger and also stops it sticking to uterine wall (premature implantation)
define morula
embryo forms a cluster of cells - tight junctions between cells for communication - after morula stage, embryo moves into uterus and the formation of a blastocyst stage embryo starts
blastocyst formation
inner cell mass forms embryo and extra embryonic tissues
trophoblasts contibute to placenta
embryo enters uterine cavity, fluid enters via zona pellucida into spaces of inner cell mass
fluid filled blastocyst cavity forms
what happens at about 5-6 days when embryo starts to run out of nutrients?
blastocyst hatches out of zona pellucida
fluid inside blastocyst starts to build up until blastocyst cavity expands and causes holes to form in zona pellucida
eventually bursts - sticky trophoblast cells make contact with uterine lining and attach and implant
2 layers of bilaminar disk
epiblast and hypoblast
during implantation the cells closest to inside of embryo differentiate to…
a single layer of cells called cytotrophoblast
syncytiotrophoblast
outer layer that forms during implantation - more extensive and is the invasive layer
implantation of embryo process
blastocyst makes contact with the endometrium of uterus and decidualisation occurs in the stromal cells of the uterus - triggers production of several molecules and promotes trophoblast cells to become invasive - implanting sysncytiotrophoblast cells communicate with maternal side of placenta and establishes a connection to enable diffusion of oxygen, waste and nutrients via blood supply
trophoblast layer differentiates to form…
two placental layers - cytotrophoblast and the invasive syncytiotrophoblast
ectopic implantation
implantation occurs at an abnormal site - can be due to slow transit in uterine tube or premature hatching of a blastocyst
name the four extra embryonic membranes/fetal membranes
amnion, chorion, yolk sac and allantois
describe an amnion membrane
- continuous with the epiblast
- lines a structure called the amniotic cavity which is filled with fluid and acts to protect the developing embryo
- present up until birth
describe a chorion membrane
double layered
formed by trophoblast and the extra embryonic membranes
lines a structure called the chorionic cavity (seen in early pregnancy but disappears due to expansion of the amniotic cavity
forms the fetal component of placenta
describe a yolk sac
continuous with hypoblast
important in nutrient transfer in weeks 2-3 but disappears completely by week 20
important in blood cell formation and formation of the gut
describe an allantois membrane
forms as an outgrowth of the yolk sac
contributes to the umbilical arteries and connects to the fetal bladder
gastrulation
process in cell division and migration resulting in the formation of three germ layers
formation of epiblast into trilaminar embryo
three germ layers
ectoderm
mesoderm
endoderm
describe the invagination process
Primitive streak appears and it encourages migration of the cells of the epiblast
Cells migrate towards primitive streak and move down through embryo to create a new layer called mesoderm
More cells push even further down, pushing past hypoblast cells, displacing them to create a new bottom layer called endoderm
Cells left on the top (where epiblast was) become ectoderm
which tissues and organs do cells in the ectoderm give rise to
epidermis of skin epithelial lining of mouth and anus cornea and lens of eye nervous system sensory receptors in epidermis adrenal medulla tooth enamel epithelium of pineal and pituitary glands
which tissues and organs do cells in the mesoderm give rise to
notochord skeletal system muscular system muscular layer of stomach and intestine excretory system circulatory and lymphatic systems reproductive system dermis of skin lining of body cavity adrenal cortex
which tissues and organs do cells in the endoderm give rise to
epithelial lining of digestive tract epithelial lining of respiratory system lining of urethra, ulinary bladder and reproductive system liver pancreas thymus thyroid and parathyroid glands
teratoma
tumour with tissue or organ components resembling derivatives of the germ layers
germ cell teratomas are usually found in the gonads
