CANCER; Lecture 4, 5 and 6 - Biological basis of cancer therapy, External factors controlling division and behavior of normal and cancerous cells, Invasion - regulation of cell migration Flashcards
(130 cards)
1
Q
What are the most common cancers?
A
Lung, breast, bowel, prostate and stomach
2
Q
What are the 4 main anti-cancer modalities?
A
Surgery, radiotherapy, chemotherapy and immunotherapy
3
Q
Which types of genetic mutations can cause cancer?
A
Chromosome translocation Gene amplification (copy number variation) Point mutations within promoter or enhancer regions of genes Deletions or insertions Epigenetic alterations to gene expression Can be inherited
4
Q
What are the 2 types of systemic therapy for cancer?
A
Cytotoxic chemotherapy and targeted therapies
5
Q
What are the types of cytotoxic chemotherapies?
A
1) Alkylating agents 2) Antimetabolites 3) Anthracyclines 4) Vinca alkaloids and taxanes 5) Topoisomerase inhibitors
6
Q
What are the types of targeted therapies for cancer?
A
Small molecule inhibitors and monoclonal antibodies
7
Q
How does cytotoxic chemotherapy work?
A
Given IV (occasionally orally); works systemically, non-targeted: affects all rapidly dividing cells in the body
8
Q
When can you use cytotoxic chemotherapy?
A
Post-op = adjuvant; pre-op = neoadjuvant; monotherapy/combnation and with curative/palliative intent
9
Q
What are alkylating agents?
A
Add alkyl groups to guanine residues in DNA and then it cross-links DNA strands and prevents DAN from uncoiling at replication -> then triggers apoptosis; encourages mispairing
10
Q
What are psuedo-alkylating agents?
A
Add platinum to guanine residues in DNA, triggering the same mechanism of death as alkylating agents
11
Q
Name some alkylating agents.
A
Chlorambucil Cyclophosphamide Dacarbazine Temozolomide
12
Q
Name some psuedo-alkylating agents.
A
Carboplatin, cisplatin and oxaliplatin
13
Q
What are the side effects of pseudo/alkylating agents?
A
Hair loss (not carboplatin) Nephrotoxicity Neurotoxicity Ototoxicity (platins) Nausea Vomiting Diarrhoea Immunosuppression Tiredness
14
Q
How do anti-metabolites work?
A
Masquerade as purine/pyrimidine residues, leading to inhibition of DNA synthesis, breaking of ds-DNA and apoptosis -> block DNA transcription/replication. Can be purine/pyrimidine analogues, also folate antagonists (inhibit dihydrofolate reductase, required to make folic acid)
15
Q
Give examples of anti-metabolites
A
Methotraxate** 6-mercaptopurine Fludarabine (purine) 5-fluorouracil Capecitabine Gemcitabine (pyrimidine)
16
Q
What are the side effects of anti-metabolites?
A
Hair loss (alopecia) - not 5-fluorouracil or capecitabine Bone marrow suppression causing anaemia, neutropenia and thrombocytopenia Increased risk of neutropenic sepsis (and death) or bleeding Nausea and vomiting (leading to dehydration) Mucositis and diarrhoea Palmar-plantar erythrodysesthesia (PPE) Fatigue
17
Q
How do anthracylcines work?
A
Inhibit transcription and replication by intercalating nucleotides within DNA/RNA strand; block DNA repair and create DNA-damaging and cell membrane damaging oxygen free radicals
18
Q
Give examples of anthracyclines.
A
Doxorubicin and epirubicin
19
Q
What are the side effects of anthracyclines?
A
Cardiac toxicity (arrhythmias, heart failure) - probably due to damage induced by free radicals Alopecia Neutropenia Nausea Vomiting Fatigue Skin changes Red urine (doxorubicin = ‘the red devil’)
20
Q
What are vinca alkaloids and taxanes?
A
Derived from natural sources; inhibit assembly (VA) or disassembly (T) of mitotic microtubules causing dividing cells to undergo mitotic arrest
21
Q
What are the side effects of taxanes and vinca alkaloids?
A
Nerve damage: peripheral neuropathy, autonomic neuropathy Hair loss Nausea Vomiting Bone marrow suppression (neutropenia, anaemia etc.) Arthralgia (severe pain in a joint without swelling or other signs of arthritis) Allergy
22
Q
What are topoisomerase inhibitors?
A
Topoisomerases are responsible for uncoiling DNA; preventing torsional strain on DNA during replication and transcription -> induce temporary single strand (topo1) or double strand (topo2) breaks in the phosphodiester backbone of DNA -> protect free ends of DNA from aberrant recombination. TII alter binding of complex to DNA and allow permanent DNA breaks
23
Q
Give examples of Topoisomerase inhibitors?
A
Topotecan (topo1), irinotecan (topo1), etoposide (topo2)
24
Q
What are the side effects of topoisomerase inhibitors?
A
Irinotecan = acute cholinergic type syndrome (diarrhoea, abdominal cramps, diaphoresis (sweating) - they are therefore given atropine) Hair loss Nausea Vomiting Fatigue Bone marrow suppression
25
What are the routes to apoptosis?
26
Summarise the side effects and treatment methods of anti-metabolites vs. anthracycline vs alkylating agent
27
What are the resistance mechanisms that form in cells to survive the chemotherapy?
28
What are the targeted therapies for cancer?
* Non-cytotoxic and seek to manipulate what we know about cancer cells -\>
* mainly involved monoclonal antibodies and small molecule inhibitors -\>
* in monogenic cancers the signalling can be cut
* for others, parallel pathways and feedback cascades are activated -\> so dual kinase inhibitors are created
29
What are the 6 (+ 4 new ones) hallmarks of cancer (SPINAP DIE U)?
* Self-sufficient
* Pro-invasive/metastatic
* Insensitive to anti-growth signals
* Non-senescent
* Anti-apoptotic
* Pro-angiogenic
* Dysregulated metabolism
* Inflammation
* Evades immune system
* Unstable DNA
30
How are cancer cells insensitive to anti-growth signals?
Tyrosine kinase linked receptors are associated with 50% of human malignancies -\> Over-expression of receptors/ligand or constitutive receptor activation
31
Which receptors are over expressed in cancers?
HER2 -\> amplified and O-E in 25% breast cancers; EGFR - O-E in breast and colorectal and PDGFR - in gliomas (brain); all lead to upregulation of kinase cascade and signal amplification
32
Which ligands are over expressed in cancers?
VEGF -\> prostate, kidney and breast; also leads to upregulation of kinase cascade and signal amplification
33
Which receptors undergo constitutive receptor activation in cancer (ligand independent)?
EGFR - lung; FGFR - head and neck cancers, myeloma
34
What are the different suffixes for monoclonal antibodies and what do they mean (with examples)?
35
What is the difference between humanised and chimeric antibodies?
36
What is the function of monoclonal antibodies?
Neutralise the ligand , prevent receptor dimerisation and cause internalisation of receptor -\> activate Fcgamma receptor-dependent phagocytosis or cytolysis induced complement-dependent cellular cytotoxicity (CDC) or Ab-dependent cellular cytotoxicity (ADCC)
37
Give examples of monoclonal antibodies in oncology
Bevacizumab (binds and neutralises VEGF) and Cetuximab (targets EGFR)
38
What do small molecule inhibitors do?
Bind to kinase domain within the cytoplasm and block auto-phosphorylation and downstream signalling
39
What is Bcr-abl?
* Translocation in CML patients which creates its own fusion protein Bcr-abl -\>
* enzyme that drives over-production of white cells
40
How do small molecule inhibitors work - especially with CML patients?
* Glivec (SMI) targets ATP binding region with kinase domain on c-ABL
* which inhibits the kinase activity of ABL1.
* By acting on receptors either externally/internally, targeted therapies block cancer hallmarks without toxicity observed with cytotoxics
41
Give examples of small molecule inhibitors that inhibit receptors.
Erlotinib (EGFR) Gefitinib (EGFR) Lapatinib (EGFR/HER2) Sorafenib (VEGFR)
42
Give examples of small molecule inhibitors that inhibit intracellular kinases.
Sorafenib (Raf kinase) Dasatinib (Src kinase) Torcinibs (mTOR inhibitors)
43
What are the dis/advantages of monoclonal antibodies and small molecule inhibitors?
44
What are the resistance mechanisms to targeted therapies?
Mutations in ATP-binding domain (e.g. BCR-Abl fusion gene and ALK gene, targeted by Glivec and crizotinib respectively) Intrinsic resistance (herceptin is effective in 85% of HER2+ breast cancers, suggesting other driving pathways) Intragenic mutations Upregulation of downstream of parallel pathways (that lead to cell proliferation)
45
What are anti-sense oligonucleotides?
* Single stranded, chemically modified DNA-like molecule 17-22 molecules in length -\>
* causes complementary nucleic acid hybridisation to target gene hindering translation of specific mRNA -\>
* recruits RNase H to cleave target mRNA -\>
* good for undruggable targets
46
What is RNA interference?
Single stranded complementary RNA -\> lagged behind anti-sense technology in cancer therapy mainly -\> compounds have to be packaged to prevent degradation
47
What is the major obstacle to target approach for cancer?
Tumour heterogeneity
48
How was b-RAF targeted in cancer treatment?
49
How did immune modulation help in cancer treatment?
Via programmed cell death 1 -\>
50
What is nivolumab?
Anti-PD1 antibody -\> In treatment-refractory melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC) Saw overall response rates of 31% in melanoma (cf the usual 5-15%) Median survival of 16 months (phase I trial)
51
Why would you sequence tumours genetically before starting therapy?
Depends on reliable methods – currently not being done (risk of false negative results) Used to provide treatment as well as prognostic information Concentrate on particular pathways for certain cancers? Circulating biomarkers, tumour cells or DNA
52
What are the new therapeutic avenues that are present in cancer?
Nanotherapies – delivering cytotoxics more effectively Virtual screening technologies to identify “undruggable” targets Immunotherapies using antigen presenting cells to present “artificial antigens” Targeting cancer metabolism
53
What is cell behaviour?
Describes the way cells interact with their external environment and their reactions to this, particularly proliferative and motile responses of cells
54
What external influences are detected by cells?
Chemical (hormones, growth factors, ion concs, ECM, molecules on other cells, nutrients and dissolved gas (O2/CO2) concs) and physical (mechanical stresses, temperature, the topography or “layout” of the ECM and other cells)
55
Which external factors can influence cell division?
All external factors may influence cell proliferation but in cancer cell behaviour = Growth factors, cell-cell adhesion cell-ECM adhesion
56
What is the basic behaviour of cells in culture?
Cells settling on culture surface, spreading and acquiring motility; obtain polarity, with front usually as motile part = not a passive process; energy is required to modulate cell adhesion and cytoskeleton during spreading
57
What is required for cell-ECM adhesion?
* Cell requires to be bound to ECM to be fully competent for responding to soluble growth factors -
* suspended in agar = few cells entered S phase;
* if able to stick to small patch which didn't allow them to spread fully, then only a small proportion of cells proliferated and
* if the patch was larger then almost all cells started proliferating
58
What is the importance of cell spreading?
Most cells will stick to fibronectin -\> if a small spot of fibronectin and cell cannot spread it dies by apoptosis; if same amount of fibronectin but spread out then cell can spread and it will survive and grow. Not just adhesion is required for cells to proliferate, also need to be able to spread to enable the cells to respond to GF and proliferate
59
What are the main 3 factors needed for cell-ECM adhesion?
In suspension, cells do NOT significantly synth proteins/DNA; cells require attachment to ECM and degree of spreading to begin protein synth and proliferation; attachment to ECM may be req for survival = ANCHORAGE DEPENDENCE
60
What molecules are required for cell-ECM adhesion?
Cells have receptors present on cell surface which binds specifically to ECM, means there is mechanical continuity between ECM and cell interior -\> integrins are key
61
What are integrins?
* Most important matrix receptor -\>
* about 10 alpha and 8 beta subunits forming more than 20 known combo which specifically binds short, specific peptide sequence (often found in more than one ECM molecule)
62
How are the integrins linked intracellularly?
* Via actin-binding proteins to the actin cytoskeletons -\>
* APART from a6, b4 complex found in epithelial hemidesmosomes which are linked to the cytokeratin cytoskeleton -\>
* complexes cluster to form local adhesions (most) or hemidesmosomes (a4-b6).
* Some integrins bind to more than one ECM molecule
63
What is the function of the integrin clusters?
Involved in signal transduction -\> not just adhesive patch for cells; also platform for signalling. Dual function allows cell to interpret matrix composition of envirionment
64
What are some adaptations of integrins?
Designed to bind to specific adhesion molecules on other cells -\>a5b3 binds to PECAM-1 and a2bB2 binds to ICAM-1 on endothelial cells in inflammation
65
What is the function of ECM receptors?
Act to tranduce signals in both directions -\> outside-in signal or inside-out
66
How do integrins act as tranducers of signals and how do inside-out signals work?
Signal generated inside cell can act on integrin complex to alter the affinity of the integrin = inside-out integrin signalling. Could cause integrins to be folded over, so have low affinity for matrix molecules. Signals generated within the cell could also make them unfold and go into a high affinity conformation and become sticky (platelets work like this)
67
What is outside-in signalling?
Cell can receive information about its surroundings from its adhesion to ECM -\> e.g. composition of ECM will determine which integrin complexes bind and which signal it receives, altering phenotype of cells
68
What is the role of focal adhesions and how do they work?
Sense the mechanical properties of their surroundings -\> amount of force generated at a focal adhesion depends on both the force generated by the cytoskeleton and the stiffness of the ECM
69
How are integrins activated into high affinity state?
* Low affinity can be switched on by inside out signal -\> once they bind to matrix, you get other changes taking place;
* ligand binding also causes change in conformation, legs separate and cytoplasmic signalling molecules can then bind which allows signalling to take place (outside-in).
70
What is another role of integrins?
Recruit cytoplasmic proteins which promote both signalling and actin assembly
71
What is the effect of ECM on phenotype of cells?
* Eg: Mammary epithelium was grown in a gel matrix -\>
* one set containing type 1 collagen and the other containing basal membrane proteins (laminins).
* The ones in type 1 collagen, formed balls of cells that were clumpy and loosely associated with each other;
* the ones in laminins organised themselves into organoids with polarised epithelium, and produced milk proteins -\>
* ECM has a profound effect on phenotype of cells
72
What is density-dependence of cell division?
Most cells when grown in culture they require a surface to stick to and as they become densely packed, rate of prolif starts to slow down; and when space is full, division stops or becomes very minimal -\> caused by lack of growth factors not contact with neighbouring cells -\> density of cells was too high and there wasn't enough growth factor available for cell growth
73
Which signals control cell proliferation?
GF trigger ERK cascade and cause cell division -\> cross-talk between ECM and GF signalling, with both types of signalling interacting to produce prolif (anchorage and density dependence) and both activate the MAPK pathways. Individual activation is weak/transient, but together it is strong and sustained = act synergistically
74
What are the short term contact interactions between cells?
Transient interactions between cells that do not form stable cell-cell junctions
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What are the long term contact interactions between cells?
Stable interactions resulting in the formation of stable cell-cell junctions
76
What is the cell-cell contact between non-epithelial cells?
Most non-epithelial cells when they collide don't form stable cell-cell contacts -\> actually repel each other by paralysing motility at the contact site -\> promotes formation of motile front at other site of cell so cell moves away -\> CONTACT INHIBITION OF LOCOMOTION. Responsible for preventing multi-layeriing of cells in culture/vivo
77
What are the different long term cell-cell contacts?
Some cell types strongly adhere and form specific cell-cell, true for eppithelial/endothelial cells and neurones forming synapses and myocardial tissue-\> adherens junctions, desmosomes, tight junctions, gap junctions
78
What are the different types of cell-cell junctions in epithelia?
Junctions arranged as continuous belts (zonula) or as discrete spots (macula)
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What is contact-induced spreading of epithelial cells?
* Stable junctions formed between cells -\>
* allows epithelial cells to be able to promote the type of behaviour that will enable them to form a coherent epithelium
80
How does cell adhesion affect proliferation?
* When Ca is removed (many cell-cell junctions are Ca dependent) and cells are still at high density, although they touch each other the junctions aren't forming -\>
* this led to increased MAPK activation, decreased level of p27KIP1 (inhib of prolif in cell cycle) and HIGH prolif.
* When Ca reintroduced, junctions reformed and MAPK inactivated, increased p27KIP1 and LOW prolif.
* Also tried it with adhesion blocking Ab which had the same effect
81
How are adherens junctions organised?
* Master junctions of cells -\>
* control formation of other junctions -\>
* consists of cadherin which binds to similar molecules on adjacent cells -\>
* IC binds to b catenin which is associated with a-catenin,
* which links to actin cytoskeleton
82
What is the function of beta-catenin in the cell?
* Adenomatous polyposis coli gene product is a protein involved in degradation of b-catenin -\>
* rapidly degraded in cytoplasm by APC, but if any accumulates in cytoplasm,
* associates with LEF-1 to form complex that acts as a transcription factor,
* which enters the nucleus and influences gene expression and prolif.
* In APC, the mutation reduces efficiency of degradation of b-catenin leading to accumulation of beta-catenin in cytoplasm,
* so more association with LEF-1 so more prolif
83
What is the mechanism for contact inhibition of proliferation?
When bound to cadherin at membrane, b-catenin is not available for LEF-1 binding and nuclear effects, but if b-catenin levels in cytoplasm rise as a result of inhibition of degradation/loss of cadherin-mediated adhesion, bc/LEF1 complex enters nucleus and influences gene expression. Clustering of cadherins after cell-cell contact is known to alter activation of small GTPases which can influence prolif; some GFR are associated with cell-cell junctions, reducing their capacity to promote prolif
84
What happens when cells lose their behavioural restraints?
Proliferate uncontrollably (lose density dependence of proliferation) Are less adherent and will multilayer (lose contact inhibition of locomotion and lose anchorage dependence) Epithelia break down cell-cell contacts Not hayflick limited - they express telomerase and become immortal
85
What is the difference in layering of normal vs cancer cells?
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Other than promoting the formation of solid tumours, what is an important consequence of loss of contact inhibition of locomotion for the progression of cancer?
It allows invasion of surrounding tissue In order to spread, the cancer must be able to pass through regions of other tissues
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What is loss of growth factor dependence?
If a protein in signalling pathway is mutated so the protein is constitutively active, pathways are permanently turned on; short-circuiting leading to uncontrolled prolif as a result of loss of growth factor dependence
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What are oncogenes?
Mutant gene which promotes uncontrolled cell prolif
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What are protooncogenes?
Normal cell gene which corresponds to the oncogene -\> receptors, signalling intermediates and signalling targets
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What are examples of proto/oncogenes?
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What is the incidence of Ras mutation in certain cancers?
30% of all cancers
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How do cancers undergo uncontrolled proliferation?
Loss of density dependency and anchorage dependence -\> doesn't need these signals as one of the signals downstream is permanently turned on
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What is the difference between benign and malignant cells?
Benign - too much prolif but contained in one place.
Malignant - poorly differentiated cell and invade surrounding tissues
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How is local invasion and metastasis important?
in addition to deregulated proliferation, a major feature of cancerous tumours is their ability to spread Most human cancers are carcinomas (i.e. of epithelial origin) in order to spread to other sites (metastasis), cells must break away from the primary tumour, travel to a blood or lymph vessel, enter the vessel, lodge at a distant site, leave the vessel, and ultimately establish a secondary tumour
95
How does a primary carcinoma cell metastasise?
* Cell-cell adhesion must be down regulated, cells must be motile;
* degradation of ECM must take place (MMP levels increased) in order to migrate through basal lamina and interstitial ECM -\>
* carcinoma cell-cell adhesion is an indicator of how differentiated the primary tumour is and indicates invasiveness and prognosis
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What is the metastatic process?
x
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What are the molecular mechanisms that regulate motility?
Microfilaments, regulation of actin dynamics, cytoskeletal proteins, signalling proteins
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What are the steps of tumour progression?
* Use MMP's to break down the basement membranes;
* when benign tumours reach this point they become malignant
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How does metastasis occur?
* Break basement membrane,
* migrate through stroma,
* reach lymphatic/blood vessels,
* get out from the vessels,
* invade and become metastatic
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What are the different types of tumour cell migration?
* Stratified classification -\>
* ameboid = autonomous cell breaks off and metastasises elsewhere.
* Mesenchymal = single/multi cells migration one after the other.
* Cluster = lots of cells migrating together (with coordination).
* Multi-cellular strand/sheets = many cells move together.
* This process is actually a normal process during embryo stage where they move from one side to another, when differentiating
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What do tumour cells mimic in metastasis?
* Morphogenic events -\> Vascular sprouting: one cell pulling the others, which opens up the blood cell;
* very rapid,
* don't respect neighbours
* very disorganised movement
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Which genes are upregulated in invasive cells?
Cytoskeleton regulation and motility machinery; e.g. EGFR gene
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Which stimuli cause movement?
Organogenesis and morphogenesis wounding growth factors/chemoattractants dedifferentiation (tumours)
104
How does the cell know which way to move, when to stop and how to move?
Polarisation of migration -\> golgi faces towards direction. Directionality tells the cell where to go, contact-inhibition motility tells the cell when to stop and specialised structures tells the cell how to move (focal adhesion, lamellae, filopodium)
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How do cells attach to the substratum (ECM proteins)?
Focal adhesions (cells attach and grab strongly - act as anchors for the filaments; important for cells to generate force when moving), filamentous actin; integrins act as the IC anchors for the cytoskeleton (hook, stay put and drive force)
106
What are filopodia?
Structures used for motility -\> finger-like protrusions - sensing where cells should touch and move, rich in actin filaments
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What are lamellipodia?
Structures used for motility -\> sheet-like protrusions - sheet of memebrane moves towards hooked site to increase the number of possible anchors, rich in actin filaments
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When and why do you need cell movement?
Cell movement = changing cell shape. Within cell to coordinate what is happening in different parts; regulate adhesion/release of cell-ECM receptors; from outside to respond to external influences (sensors and directionality); motility can be hapoptatic (no particular direction, just moving) vs chemotatic
109
What is the process of cell movement?
* Fillopodia move towards new anchor,
* then lamellipodia bring more bits of the cell,
* to form tight contact (new adhesion),
* and move upwards,
* deattach and move to the next anchor
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How are g and f actin involved in cell movement?
* Actin cytoskeleton is framework of cells, which supports body and tells it how to change -\>
* can be polymerised.
* When signal is detected in other direction, then actin filaments are broken down and built up on the other side instead of turning cell the whole way round -\>
* actin is polarised which differentiates which proteins attach to each side
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How are filaments organised and structured in the cell?
Lamellopodium has criss-crossed fibres
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How are actin filaments remodelled?
If nucleation isn't wanted then sequestration can occur
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How does nucleation occur?
* Arp2-3 complex mimic the actin to build up the filament;
* monomers are difficult to join, so the complex picks up monomers and stabilises them, so they can then continue to increase
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How does elongation of actin occur?
* Profilin comes in an adds onto the +ve end of the filament forming actin-profilin complex which lets elongation occur.
* Thymosin sequesters the monomer and keeps it there, preventing elongation of the monomer
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How do capping and severing of actin occur?
* Capping -\> prevents addition of monomers, with capping protein, so then chain depolymerises from the back (some bind to +ve and some to -ve end).
* Severing - clips all filaments into shorter bits, forming minifilaments, which also need to be capped as otherwise they will continue to grow
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How do actin functions cooperate to generate filaments?
* Filament -\>
* monomer binds to GTP and becomes active, which can be elongated then severed -\>
* leads to annealing, capping or grows again
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How do actin cross-link and bundle together?
Certain proteins bundle in different ways -\> filamin makes particular angles
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How do actin functions cooperate to organise filaments?
Some allow motor proteins to come in and stabilise the proteins
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How does branching of actin occur?
Always at 70" angles -\> Arp2/3c initiates filament growth which occurs at 70"
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How does the gel-sol transition occur?
By actin filament severing -\> rigid structure of cross-linked proteins and a severing protein comes and forms a looser structure
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At which parts of the cell movement cycle does actin participate?
122
What is lamellae protrusion?
Highly energetic process
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What are filopodia involved in in the cell movement cycle?
Filaments make a force that can force the membrane up -\> bundling proteins increase it; with retraction operating at the bottom to prevent over growth
124
What are the different cell shapes and how is the actin cytoskeleton organised?
Villi are not filopodia but look similar; stereocilia are similar also.
125
What signalling mechanisms regulate the actin cytoskeleton?
126
What molecules control the actin cytoskeleton?
Can be upregulated in different tumours
127
What are the 3 different members of the Rho family of small GTPases?
* Cdc42 = filopodia formation;
* Rac = pancake due to protrusion of lamellipodia;
* Rho = activate extreme contraction and thick filaments (stress fibres)
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How does signalling from small GTPases regulate actin cytoskeleton and motility?
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What is the role of small GTPases on cell migration?
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How do glial cells migrate in scratch wounds?
They move uniformly as a mass, one behind the other stretching until reaching the opposite side cells where contact inhibition occurs
