Metabolism

Nucleoid with single circular chromosome, ribosome, flagellum, cytoplasm, periplasm, cytoplasmic membrane, cell wall, capsule fimbria

Nucleus, rough ER, smooth ER, ribosomes, mitochondria, golgi body, lysosome, peroxisome, centriole, cytoskeleton, cytoplasmic membrane, cilium

heterogenous structure of lipids, proteins and carbohydrates; selective barrier (separates external environment from cellular milieu), most universal and fundamental structure of cells

content of the cell except nucleus

Fraction of the cytoplasm that excludes all organelles; in prokaryotes site where almost all metabolic processes or chemical reactions take place

maintenance of the cells shape including positioning of organelles + adaptation to microenvironment; made up by three types of filaments that interact with one another, the plasma membrane and organelles

I. Intermediate Filaments: Mechanical Integrity

II. Microtubules: Transport

III. Actin Cytoskeleton/Microfilament: Plasticity

Structure => filamentous & cylindrical organelles (diameter 25nm, length variable) ; grow from “microtubule organizing centre” (MTOC); head-to-tail arrangement of alpha and beta tubulin monomers => form protofilament => 13 protofilaments assemble in a tube structure (hollow middle)

Functions => Transport of vesicles along filaments (molecular motors) + segregation of chromosomes during cell division

coat of proteins on the vesicle indicates their destination

Anterograde: to periphery of the cell, via KIF (Kinesin superfamily proteins)

Retrograde: to the cell centre, via Dynein

Transport direction is indicated as pH in the periphery differs from the one in the centre (higher pH in cell periphery)

used for ER expansion (ER “hitchhikes” on microtubules) + lysosomes anker on ER and pull it along to shape it

most abundant cytosolic protein in cells

Function => maintains characteristic structure of cell types, regulate migration, structural support and plasticity

Lysosomes travel via actin and are sometimes so fast, that they damage actin filaments

Structure => 10nm diameter, different types of IF as for varied functions for example keratin

Function => cytoplasm: vimentin and neurofilaments, mechanical integrators of cellular space (absorb mechanical stress); nucleus: lamins protect and connect different cytoskeleton components)

Energy factories (ATP-synthesizing), cell signalling, cell differentiation and cell death; roughly 2x1um oval shape; result of endosymbiosis with bacterium; mitochondria can only grow from division of already existing mitochondria

Membrane-bound organelle, organized stack of disc-like compartments = Golgi cisternae (4-8 in number); close to ER; labels and dispatches vesicles with proteins/lipids etc. to different parts of the cell

distribute vesicles around the cells

=> usually from the ER to other parts of the cell

=>distribution back to the ER also possible

small vesicles; large number of enzymes for intracellular digestion system (example pathogen degradation in immune cells, autodigestion during low nutrient/energy supply), low pH

vesicular organelles, transport molecules, formed by endocytosis (mostly), travel attached to filaments to their destination

Endosomes can also destroy receptor through low pH, if not needed anymore

micro vesicle (40-100nm), released from cell to extracellular space, for intercellular communication, can contain proteins, lipids, DNA, RNAs

created, when external product is eaten by the cell; phagocytosis => destroys foreign elements, basis of cellular immunity

in eukaryotes, archaea and some bacteria; sites of oxygen utilization, cell protection from oxidative damage, can proliferate semi-autonomously (like mitochondria)

stores nearly all DNA in eukaryotic cells; separation protects genome and separates function; cytosolic DNA is considered a warning signal for pathogen infection/cellular damage => leads to apoptosis

Surrounds nucleus

double membrane => outer layer is continuous with the ER

perforated by nuclear pores => bidirectional, selective traffic of macromolecules (3000-4000 pores in mammalian cells; transport of up to 500 molecules per second each)

dense membrane-less structure inside the nucleus

made up of proteins

RNA and DNA ribosome biosynthesis + DNA repair + cell cycle regulation + cell signalling

Membranes that extend throughout cytoplasm

largest organelle in the cell

Functions => Biosynthesis of proteins/lipids + Protein quality control + transport of eukaryotic proteins, intracellular calcium storage

rough (with ribosomes; associated with protein production) and smooth ER (no ribosomes; more engaged in synthesis/storage of lipids, glycogen, fat and sterols)

Wrong foldng of proteins triggers ER stress (in many diseases including cardiovascular diseases)

2 main chains of RNA (ribosomal RNA) + 50 different proteins

membrane less structure in all living cells

build/translate the proteins

can be bound to ER or free in the cytoplasm

string of DNA wrapped around associated proteins, during cell division in X-shape, otherwise looser structure (= chromatin), in all living organisms

Protein complex (central hollow cylinder (catalytic part, destroys proteins + ends of cylinder (regulatory part)), that destroys aberrant proteins/controls number of unneeded proteins

Proteins for destruction are marked by ubiquitin

bone marrow (primary), spleen, lymphatic vessels and lymph nodes, tonsil, adenoid, thymus (primary), appendix, Peyers patches in small intestine

Water from the muscles etc. gets pressed into the lymphatic system and gets redistributed via this system => by pumps water is getting in and out of cells

Transportation of immune cells mostly via lymphatic system

lymphatic vessels are not moved by the heart only by muscular movement

innate immunity: since birth, unspecific/limited diversity, fast, no memory, non-self-reactive, Pattern detection of PAMPs and DAMPs (e.g. Toll-like receptors, N-formyl methionyl receptors, mannose receptors, scavenger receptors)

adaptive immunity: acquired, specific, slow, antigen specific, large diversity , memory, might be self-reactive

-physical barriers like mucus and skin (keeps oils, microbes etc. out)-phagocytes => eat foreign objects (without distinguishment)

-NK cells => kill foreign cells

-Mast Cell => produce and release stimulants such as histamine and cytokines

-Dendritic Cells => activate adaptive immunity by absorbing and processing antigens and then wandering to the lymph nodes to present them to T cells + Phagocytosis

PAMPs: pathogen associated molecular pattern like chitin for fungi, flagellin + peptidoglycan and lipopolysaccharides in bacteria, RNA and DNA of viruses (single- or double-stranded)

DAMPs: damage associated molecular patterns; sharp increase in molecules that are usually in cells like ATP indicate cell damage

Immune cells can travel via following the chemotactic gradient (to find infection site/pathogens) => via cytokines (“hormones of the immune system”, proteins) and DAMPs/PAMPs (usually not proteins) and chemokines (“pheromones of the immune system)

Cells roll over the receptors till they stop by binding a presented chemokine => enter the tissue out of the vessel to go to area of damage/infection

==> cells move around the vessel and “hook” onto chemokines/ICAM-1 etc. in the area of damage => change from low affinity state to high affinity state

Neutrophils and Monocytes: migrate to sites of infection and tissue injury, cause inflammation

Naive T and B cells: migrate into secondary lymphoid organs (lymph node)

Effector and memory T cells: migrate into sites of infection and tissue injury, cell mediated immunity

multi-lobed nucleus (enables the cells to take on many forms)

Function => bacterial/fungal infection (most common first responders in microbial infection)

Neutrophils can sense, when there are too many bacteria in the area => “sacrifices” itself and releases sticky substance (NET) => bacteria are stuck in place and other neutrophils can phagocyte them (=NETosis)

bi-lobed nucleus

Function => parasitic infections and allergic reactions (inflammatory)

rare, not much known

bi/tri-lobed nucleus

Function => allergenic and antigen response (releases histamine causing vasodilation)

Deep staining, eccentric nucleus

Function => include B cells, CD4+ helper T cells and CD8+ cytotoxic T cells; operate primarily in the lymphatic system

kidney shaped nucleus

Function => phagocytosis of pathogens, presentation of antigens to T cells; eventually become tissue macrophages (remove dead cell debris and attack microorganisms)

can differentiate into phagocytes or dendritic cells => depending on which one is needed more

Activate immune cells in lymph nodes by absorbing and transporting bacteria(l substances) to lymph node

=> movement of immune cells no more passive

=> piece of bacteria is presented as code/receptor (antigen = identification of specific pathogens)

=> present it to T cells

=> T cell specific for this bacterium will clone itself

=> B-cell and T-Cell will “team up” to decide whether pathogen is harmful => B cell produces antibodies

1. Antigen recognition (via antigen presenting cell)

2. Lymphocyte activation, clonal expansion and differentiation into effector T lymphocyte and antibody producing cell

3. Antigen elimination (antibodies and effector T cells)

4. Contraction (homeostasis) = apoptosis of activated cells

5. Memory cells survive

TNF, IL-1, IFN (alpha, beta gamma), IL-6: Promote inflammation

IL-10, TGF-beta: stop inflammation

CD4+ T cells: T helper cells, help other cells like B cells to produce antibodies via cytokine production that enables cell proliferation, activated via MHC class II = antigens presented by APCs that originate from extracellular proteins (exogenous)

CD8+ T cells: cytotoxic T cells, kill and phagocyte infected cells, activated via MHC class I = endogenous antigens (from within the cell) presented by infected cells, pro-inflammatory

Regulatory T cells: anti-inflammatory, ensure that self-antigens are not causing immune responses by surpressing other lymphocytes

Differentiate into plasma cells/effector B cells, when activated

Prduce antibodies to neutralize microbe, phagocytose it and activates complement system

1. Naive T cells circulate through lymph nodes and find antigens

2. Dendritic cells carry microbes or their antigens to lymph nodes

3. Activation of naive T cells in lymph node, development of effector cells

4. Effector T cells migrate to site of infection

5. Activation of effector T cells at site of infection

6. Eradication of microbe

T cell: Thymus

B cell: Bone marrow

Antigens are presented in two pathways

=> MHC I for self-proteins (in cytosol/ER) or pathogen proteins if infected (come from within the cell)

=> MHC II for extracellular proteins/foreign/pathogenic (uptake by endocytosis)

=> through different pathways T Cells can differentiate between cells slef-molecule and absorbed molecule (which one are part of yourself, what is not) or infected cells

Process in general

1. Antigen uptake

2. Antigen processing

3. MHC biosynthesis

4. Peptide-MHC association

2 heavy chains + 2 light chains

bound to one another via disulfide bridges

Y-shape

variable region (at antigen binding sites) + constant region

= Fluorescence-activated cell sorting

Type of flow cytometry that sorts a heterogeneous mixture of cells based upon the specific light scattering and fluorescent characteristics of each cell.

1. Cells are tagged using fluorescent antibodies that bind to relevant proteins on target cells.

2. The mixture of suspended cells rapidly flows through the instrument's flow cell in a single file. Individual cells pass a laser beam, and a detector measures the fluorescence, forward-scattered light (FSC), and side-scattered light (SSC)

3. FSC and SSC are used as an indication of the cell’s size and granularity.

4. Fluorescence at several wavelengths can be detected simultaneously

5. Cells are physically sorted into different containers based on detected measurements and user entered parameters.

Cancer cells sense “attack” from T cells by recognizing IFN-y, which leas to reactive expression of PD-L1, which in turn leads to tumour escape by inactivating T cell

= no immune system at these places

• Brain

• Eyes

• Spinal cord

• Uterus (during pregnancy)

• Testicles

not specific = many cells can sense the signal

Faster/longer range (can spread to many cells across different tissues)

• Cytokines/chemical synapse

• Hemichannels

• Exosomes

very specific = only signalling to selected cells

• cell surface receptors

• gap junctions

• tunneling nanotubes

• mechnaical forces

Periodic cAMP waves drive Dictyostelium collective migration

Transmission via waves

Organisation of Migration and finding cell centre/position for later division

MinDE can generate travelling waves in mammalian cells

MinD & E are antagonist bacterial proteins; nucleotide-dependent membrane association of the MinD ATPase is antagonized by its ATPase-activating protein MinE

Autocrine: self-made molecule is transported outside of the cell and acts on the same cell

Paracrine: molecule from a neighbouring cell stimulates cell

Endocrine: molecule transported via the bloodstream stimulates cell in another part of the body

Juxtacrine: Molecule bound to receptor of a cell stimulates another cell

Positive vs. negative Feedback v. Feed forward (positive)

Target cell re-signals to the initial stimulating cell (no one way cascade); usually only forward signalling (only in target cell)

E.g. ephrins (cell surface proteins)

Cells sense each other and how many there are

More cells = more auto-inducers = increased proliferation

=> potive feedback

Electron Microscopy: not in live cells, very high resolution

Widefield: many cellular layers, low resolution

Confocal: only one layer of cells higher resolution

TIRF: cannot penetrate the cell => only outer layer visible, for structural examination of membrane/cell walls etc

Two-photon: for living tissue, many cellular layers

Contact independent: chemical signalling

Contact dependent: electrical synapse (gap junctions)

• Antigens

• microRNA

• siRNA

• cAMP

• cGAMP

• IP3

• Ca2+

Can stimulate neighbouring cells and themselves

• Ca2+

• glucose

• IP3

• PGE2

• NAD+

• ATP

• cADPR

• K+

• glutamate

Connect cells

allows exchange of molecules (mainly ions)

can also be used by viruses to infect other cells (e.g. HIV)

are made by filopodia

signal, that neighbouring cells are alive/well/unwell/infected etc.

1. MHC antigen presentation

2. Co-receptors specific for APC and T cell

3. Cytokines

4. Mechanosensing

Stimulation of cells via mechanical sensors

e.g. breast milk: cell have to make sure not to get deformed during production

e.g. Blood pressure/Stress: cell needs to be able to adapt/react in order to not deform

e.g. PIEZ01, PIEZ02: Touch proprioception

Released under migratory stimulation and stimulate other cells to also migrate in the same direction/manner (e.g. T cell migration)

1. Stimuli

2. Receptors

3. Transducers

4. Amplifiers

5. Messengers

6. Sensors and effectors

7. Cellular respone (secretion, comtraction, differentiation, prolifertion etc.)

Leads to crystal formation in the cell = cell death

ATP avoids formation of crystals/aggregations, not quite clear how, but: ATP is a hydrotope and therefore brings water/hydrogen to the aggregations/crystals and makes them soluble

Up to 10 mM of ATP in a cell, but not in all cells (concentration depends on cell type)

Provides an anchoring point and the generation of the required tension to allow the cell to exert forces over the substrate

Key proteins: vinculin, paxillin, talin, focal adhesion kinase (FAK) (and collagen)

Actin usually located at the membrane (sometimes nucleus)

Microtubules are located throughout the whole cytosol

F-actin = filamental actin (the strands)

G-actin = globular actin (building blocks of the filaments)

Centrin = protein of the centrosome (for cell division)

Centrin + soluble tubulin = microtubule building

MTOC = microtubule-organizing centre

ATOC = actin-organizing centre

Both can organize themselves on their own

In most mammalian cells the centrosome is also the MTOC

Microtubules for transportation of molecules

For cells with specific shapes like above, the vertical filaments do not come from MTOC due to the shape, but are non-central filaments from Golgi apparatus

1. Cells are put on a non-adhesive surface, under the surface lays the extracellular matrix

2. UV-illumination destroys the surface and “frees” parts of the ECM, where cells can attach (can also be accomplished by stamps, that are layered with the proteins (A))

3. The proteins of interest are then added and attach to the cellular matrix

4. Cells can adhere here and microenvironments are therefore formed, so that cells have to interact with the proteins (discover how the environment influences processes such as the orientation of the cell division axis, organelle positioning, cytoskeleton rearrangement cell differentiation and directionality of cell migration); control/influence/study  cell shaping

Micropatterns refer to precise and controlled miniature patterns created on a substrate surface, often used to regulate the spatial distribution of cell-adhesive proteins. In the realms of biotechnology and cell biology, micropatterns serve as tools to guide the behaviour and organization of cells, affecting their adhesion, morphology, proliferation, and differentiation by offering physical cues within their microenvironment

Mitochondria age, so that they “produce” less energy

=> when cells divide there must be a fair divide so that both cells get younger and older (less energy) mitochondria

=> Actin waves are moving around the cell to stir mitochondria => mitochondria get shuffled for a fair divide

Restoring/increase mitochondria through engineering lead to longer life span of worms => Rejuvenation?

Measured mitochondria potential = energy level of mitochondria

Mitochondrial activity is related to cell migration (mitochondria moves to periphery)

Steady = normal protein, non-steady = moves with the activity of mitochondria

mitochondria may divide unevenly (after fusing together) to create mitochondria with different function (e.g. when more energy is needed => one with all the cristae, one with none)

=> divided into one energy producing mitochondria and one biomolecule synthesizing mitochondria

• Ribosomes

• Nucleolus

• Proteasome

• Liquid-liquid phase separation (not mixing due to pH difference, temperature etc.)

• RNA storage (e.g. stress granules)

• Cajal bodies

sharing of lipids between organelles; tightly regulated (if cholesterol does not come, one gets sick)

1. Upatke of LDL via Clathrin-coated pit and receptor LDLR

2. Formation of endosome

3. Differentiation/Fusing to lysosome

4. Lysosome breaks fats down into cholesterol (inhibits SREBP therefore HMG-CoA Reductase => no transcription of LDLR (receptor)) and fatty acids (go into mitochondria for energy)

5. Endosome/receptor gets recycled (receptor is anew integrated into the membrane)

=> size of lipid droplets changed as they accumulated, lysosomes changed as cholesterol could not get out and accumulated

• GPCR

• Cytokine activation

• cAMP

• CO2+/iP3

• PKC/DAG

• cGAMP/STING

• ATP signalling (Signalling to neighbouring cells that you are fine by sending low concentration of ATP)

Signalling inside the cell through second messenger after stimuli binds to membrane receptor (1. Message)

+

Amplification of signals

Plethora of second messengers are needed for all the different stimuli (normally enzymes)

Enzymes/second messengers are normally coupled to receptor from inside the cell

Steroids can pass the cell membrane without a receptor (act in the cell)

Signalling to neighbouring cells that you are fine by sending low concentration of ATP

If ATP in excess = indicates cell breakage = inflammatory response

=> ATP is degraded to adenosine => acts anti-inflammatory since no ATP receipted anymore (P2X and P2Y receptor => ATP binds according to concentration)

Without inhibition of positive stimuli, activation would not subside

=> constant activated state and autoimmune response

=> Therefore, inhibitor CTLAY (slower activation/different kinetics) gets activated at the same time by the same stimulator and slowly inhibits activation

=> return to normal state after infection

1. Phospholipase C (PLC) breaks PIP2 (bound to DAG anchored in the membrane) to IP3

2. IP3 leads to opnening of Ca2+ channels = Ca2+ is released from ER into cytosol

3. Leads to PKC activation + PKC binds to the free DAG

PLC cleavage of PIP2 to IP3 and DAG initiates intracellular calcium release and PKC activation.

Cancer cells usually use methods also needed for healthy cells

=> If migration is inhibited by drugs immune cell (and other) also would not move

=> severely altered immune function (slower wound healing etc.)

=> makes treatment very difficult

= endosomal sorting complexes required for transport

Part of a pathway inside cells that helps sort and move other proteins

One of their main jobs is to form structures called multivesicular bodies (MVBs) which help sending of certain proteins

+

repair of nuclear envelope ruptures/lysosomal membrane/plasma membrane (severs damaged membrane patch from membrane)

=> No calcium = no shedding of damaged membrane patch

=> Ring around the damaged region of the membrane and contracts to sever the damaged parts and therefore repair the membrane

Without Ca2+: cell necrosis/cell death

Overdose of Ca2+: Cell death => necrosis in sudden increase and apoptosis in long lasting increase

After stimulating via Ca2+, Ca2+ is transported outside the cell (Ca2+ pumps (SERCA/PMCA)) or stored in organelles to stop activation => organelles can only hold it for a certain amount of time => exchange Ca2+ between organelles until Ca2+ pump has pumped enough outside

E.g. for Ca2+ signalling/activation: using your muscles or neurons too little leads to forgetting/less muscle, too much activation leads to damage as well => activated via Ca2+

Calcium oscillations increase the efficiency and specificity of gene expression

NFAT (nuclear factor of activated T-cells)

ER is never completely devoid of Ca2+ => not good for cell => limited amount (uptake via SERCA, release via InsP3R)

Binding of STIM1 to Orai1 and activates them to let Ca2+ in

Transport in the ER is generally not free => no free diffusion of Ca2+ in the ER

Via contraction and expansion of the tubular network of the ER molecules are moved in the ER (“pumping” it through the ER)

measures electricity in microcapillary via direct contact with the cells

Hypothesis: all organelles have different action potentials => Needs to be tested without patchclamp as measurement is not independent of the cell membrane; Result => Lysosomes (90 mV) etc. have a different and independent action potential from each other

pH and voltage: difference in pH = difference in H+ = difference in voltage => measuring voltage by pH in theory, problem: difference in pH did not change voltage in the same way (other ions like Ca2+ etc. also available for voltage)

Voltage/pH studies useful for lysosomal diseases (Niemann-Pick Type C (cholesterol accumulation) Type A and B (Sphingomyelin accumulation), Gaucher disease, Mucopolysaccharidosis)

Via TRPML1

measures direct interaction between two proteins

Peripheral fission

=> for mitochondria with different signalling

=> ER/Lysosomes break mitochondria to achieve the signalling type that is needed

Midzone fission

=> division of mitochondria in the middle

Single: singular cell is polarized (front-rear-polarization) and migrates

Collective: single cells all move due to same signal in the same manner, singular cells are polarized (single cell polarity)

Supracell: polarity within the whole complex (not in each cell

Front-rear polarisation is needed for movement direction

High dependence on adhesion, slow speed, cells modify the matrix

Steps of mesenchymal cell migration:

1. Establishment of front-rear-polarity

2. Leading edge extension (Lamellipodium formation)

3. Formation of new adhesions4. Cell body contraction

5. Rear retraction

low dependence on adhesion, fast speed (around 6x faster than mesenchymal), cells squeeze through the matrix (cell is modified itself; matrix is only minorly modified)

asymmetric distribution of myosin is important for movement at the rear => pressing the cell together at the back to push forward

used by most immune cells

monolayer of cells in a petri dish is scratched => evaluation of the time and way the gap is closed again (e.g. studying wound healing)

Mitochondria depolarize during migration depending on energy needed

=> very active in front and back of the cell to push nucleus forward

If mitochondria are not activatable through knock-out cells move much slower , but use other metabolic energy sources

ER stress (usually wrongly folded proteins) reduces mesenchymal migration

ER is almost everywhere as it controls the Ca2+ signalling + protein folding

Three pathways for unfolded/incorrectly folded proteins:

1. ATF6

2. IRE-1

3. PERK

activated via Tunicamycin (TN), Azetidine etc.

PERK is responsible for the speed of cells => adding PERK to cells with ER stress (TN) lead to normal migration speed (similar to control)

Membrane/cell can only move, if it has focal adhesion; during ER stress focal adhesion is impaired

Mitochondria and ER help together to establish focal adhesion

ER is important for phosphor tyrosine activation for membrane protrusion (= Ausstülpung)

Studying mesenchymal migration via micropatterning of adhesive lanes

Micropatterning for collective cell migration can also be used

=> if pattern is circular cells migrate until they form a circle and start to rotate, how do cells react to adhesive lanes with sharp turns etc.

Cells, which normally don’t move (like HeLa cells), are triggered to move during confinement

=> to escape and avoid damage at the nucleus

High substrate adhesin allows focal adhesion formation, which in conditions of low contractility promotes stable cell adhesion

CCR7 is a receptor for chemokines and CCL19 its ligand, induces uptake by the cells to create a gradient for the following cells

=> if there was no gradient the cells would just move around the centre of the chemokine

Cells, which took up CCR7 create a self-generated gradient

=> chemotaxis is stopped as no chemokine is there anymore

=> area in which cells react gets smaller

=> limits cell number to only those that are needed = activation according to damage

CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals

Actin is transported retrograde to move the cell forward

Cells can be fast in one unchanging direction as changing the direction requires new polarisation and actin flow

=> cells try to persist in the same direction as long as possible

Sustained actin flow contributes to cell speed

Organelles are pushed back by actin flow => nucleus gets deformed

=> How do cells avoid damage? Unclear

Types of bias for choosing the correct path: extreme confinement, Extracellular matrix obstacles, hydrostatic pressure, chemokine, adhesion (always chooses good adhesion), stiffness, electrical field etc.

When no chemotactic gradient (other indicators) is present, but paths are different sizes, cells choose the one that fits the nucleus, so it does not break => tries every path and measures, then decides

In absence of bias, how do cells decide? Unclear

Cancer cells take faster decisions in path choice than healthy cell as they have a lot of actin at the front = move very fast

=> repolarization and change in flow is much more difficult at that speed

=> sometimes take “wrong” turns

Usually, cells don’t migrate through too tight spaces as to not damage the nucleus

=> cancer cells are not preoccupied with avoiding nucleus damage

Healthy cells in confinement: build blebs to move and try to escape confinement, but only if the nucleus is confined

=> senescence after too many times due to DNA damage

Cancer cells do not go into senescence during confinement, but it leads to migration and invasion of the cells into different tissue, DNA damage is not relevant

Ca2+ dependent branch retraction

Myosin-II for contraction of cell

Calpain for adhesion of cell

-mutations/oncogenes

-failure in apoptosis

-proliferation without growth signals

-environmental damage (UV rays)

-immunosuppression

-viral/bacterial infections

-genetic predisposition/gene therapy

-DNA repair failure

-Epigenetics

-Migration

Neuroblastoma: no apoptosis, but neurons don’t divide often = small growth, but skull is narrow and surgery would always damage the brain

Epithelial cancer: no apoptosis + cells proliferate excessively

Melanoma (rarely just one tumour, often more) and Leukaemia: aggressive cancers, no apoptosis + high proliferation + metastatic (migration)

Most aggressive types of cancer: no apoptosis + high proliferation + metastatic + immune evasion

Pankreatic cancer: often reaches the aorta = death; often the whole pancreas would have to be removed => not possible; very intense stomach pain; no cure

Endometriosis: tissue growth near or in the nerve => therefore very painful

Cancer cells have a disrupted cell-cell adhesion and therefore loss of contact inhibition => normally, when cells are in a petri dish cells proliferate and adhere to one another until the dish is covered, then they stop => cancer cells don’t stop proliferating and stack on top of each other

Singular detached cancer cells are migrating (metastasis) via the bloodstream and attach at another part of the body, where they form a secondary tumour

EMT = Epithelial to mesenchymal transition

=> lower E-cad

=> higher N-cad and Integrins

Invasion

=> higher MMPs (destroy matrix)

=> higher LOX

Activates during cell extension and leads to the cell’s contraction

Used during collective cell migration

Normal cells have a negative feedback loop for ERK, by inhibiting Ras, which is part of the signal cascade, via ERK

Cancer cells with a Ras mutant do not respond to inhibition, which leads to higher cell proliferation (Ras cannot be inactivated) => also potential point to interfere with cancer cells

healthy cells break of small pieces of themselves during cell migration

=> pieces can move and survive for as long as they have energy => harmless

In cancer cells cytoplasts are broken off as well

=> can get into the bloodstream and attach themselves to sites in the body

=> prepare the site by inflaming the epithelium (gets sticky) for the actual cells

=> secondary tumour is made

Cancer associated fibroblasts (CAF) and tumour associated macrophages (TAM) help cancer cells to grow at faster speed

=> cancer cells make fibroblasts create a matrix (ECM), which enhances proliferation

UPR (from ER stress) decreases migration of healthy cells, but not in cancer cells as they ”do not care” about ER stress

Cancer cells can express soluble molecules to put other cells around them into ER stress

=> slow movement of other cells including immune cells like DCs, macrophages etc.

=> immune evasion

Cancer cells use UPR for resistance

Immune system evasion of cancer cells may also happen by invasion of other cells

=> “hiding” inside other cells to avoid MHC contact

Collagen around dormant cancer cells are without structure

Collagen around active cancer cells are structured

=> traps immune cells by a kind of pull

M1: normal, bactericidal activity, inflammation, immunostimulation

=> anti-tumoral activity

M2: TAM, tissue repair, matrix remoddelling, angiogenesis, immunosuppression

=> pro-tumoral activity

Cancer cells are faster, when they adhere to neurons (higher adhesion and migration)

Bioelectricity impacts cancer cells