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POM > Cellular basis of Malignancy > Flashcards

Cellular basis of Malignancy Flashcards

1
Q

What is the difference between a Malignant or Benign tumour?

A

Invasion
(not metastasise)
invade and hence destroy local tissues

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2
Q

Epithelial Tissue

A

Consumates communal cells
-not individualists/exist by themselves like fibroblasts
-instead form structured sheets/ducts/glands
Held together by Adherins Junctions

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3
Q

Change in Epithelial cells upon invasion

A

Invasion, requires a break/change in immaculately ordered epithelial cell structure
–> become motile and destructive

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4
Q

Adherens Junctions

A
  1. Hold together epithelial cells
    composed of integral membrane protein E cadherins
    -goes through membranes of both partner cells
    -forms calcium dependant connection in the inter cellular space
  2. E chadherin inside the cell is connected to Actin cytoskeleton
    (Intercellular links connected to cytoskeleton giving cells their structure)
    -via 2x intermediate proteins
    a) B-catenin
    b)A-catenin
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5
Q

1st mechanism of epithelial cell invasion

A

Irreversible mechanism EMT = Epithelial –> Mesenchymal Transition
-genetic or epigenetic
a) Loss of E cadherin expression (due to genetic mutation or epigenetic silencing)
b) Loss of alpha A Catenin
=
-Loss of junctions b/w cells
-Loss of cellular polarity
Lose epithelial form to form Diffuse Spreaded single cell relatively Structureless tumours
=Diffuse Gastric Carcinomas
= Diffuse Breast Carcinomas (when hereditary syndrome assoc.)

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6
Q

2nd mechanism of epithelial cell invasion

A

Reversible mechanism
-Microenvironmental mechanism
EMT = Epithelial –> Mesenchymal Transition
Primary tumour maintains differentiated feature
-Big pleomorphic nuclei
-Primary tumour/cancer
–>
a) often Metastasize and invade
-seed distance cancers which share same epithelial glandular cellular polarised structure
-can see focal dissociation of carcinoma cells (regions where structure breaks down to produce motile cells which are able to
1) first invade
Focal dissociation tends to occur at margins of tumours where inflammatory cells are
-macrophages/fibroblasts, which secretes growth factors, such as Hepatocyte Growth factor HGF
-binds to their specific receptor (HGFR is a tyrosin kinase)
-induces a signalling response, which results in phosphorylational and transcriptional events which induces motile mesenchymal phenotype
2) later Potentially form distant metastases
-forms well differentiated primary tumour structure,
-due to reverse process occurring MET Mesnechymal –> Epithelial transition (back to original state)
a) phosphorylation events (HGFR phosphorylate E cadherin and b catenin, inducing reversible breakdown of adherins junctions, enabling invasion
b) induce snail protein (migration)
-transcriptional repressor which turns off epithelial structure/gene encoding E cadherin
-signalling pathways induced by HGF and other EMT inducers, causeing reversible loss of epithelial structure, resulting in invasion and metastases

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7
Q

EMT re wound healing

A

Same thing

  • similar to re-epithelialisation and wound healing
  • wound healing it is beautifully coordinated and controlled
  • cancer is regulated but obherently so
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8
Q

How are Hepatocyte Growth Factor HGF and Receptor Deregulated when cancer develops?

A
  1. Deregulated (abnormal) expression of HGFR (in aggressive tumours) –> increased signalling –> increased EMT
  2. CRC, Metastatic Tumours, Amplification of HGFR gene (increased copy number, protooncogen –> oncogene)
  3. Papillary Renal Cell Carcinoma –> Point mutations of HGFR gene (turn on tyrosine kinase activity, increasing molecular response)
  4. Autocrine activation of Receptor. Single tumour cell can both produce the growth factor and express the receptor –> hence drive its own mesenchymal phenotypic conversion
    - Identifies important of HGF signalling as a key inducer of EMT
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9
Q

Mechanism of invasion

A
  1. Motility
  2. Production of Hydrolytic Enzymes
    - break down and destroy tissues
    - provide route for cancer invasion
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10
Q

Defining criterium of cancer

A

Ability to invade into normal tissues
Proteases and Heparonases are released by cancer cells
-break down/solubilise adjacent tissues

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11
Q

What are Growth Factors

A

Fibroblasts
Macrophages (e.g. HGF)
-bind to receptors and stimulate signalling

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12
Q

What happens after signalling is stimulated by HGFR and HGF binding?

A

1) induce formation of Invadopodia/Podosome on mesenchymal/invading cells
- structures that allow cells to contact ECM
- involved in contact and invasion
2) express receptor for protease called uPA urokinase-type Plasminogen Activator
- uPA activates substrate of plasmin

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13
Q

Plasmin

A

important protease
a) Thrombolytic- important for maintaining blood flow after ischaemic event/thrombis
b) Remodels Tissues: wound repair
always circulating in body as plasminogen waiting for appropriate trigger to activate
(inactive plasminogen cleaved to plasmin active protease)-must be carefully controlled
-Activated by uPA
-plasmin is able to activate class of enzymes called pro-mmP (matrix metalloproteinases) (mmP upon cleavage)

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14
Q

mmP

A

Matrix MetalloProteinases
-atleast 20 known
-v important in inflammatory responses and tissue remodelling
“metallo proteinases” as contain ZINC in active centre
-produced by variety of cells including Inflammatory cells (macrophages, neutrophils), Fibroblasts, Tumour cells

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15
Q

What can break down ECM Extra Cellular Matrix Proteins?

A

Invadopodela structure: series of 3x levels of proteases
uPA
Plasmin
mmPs
(break down fibronectins, collagens, elastins)
-the essential packing proteins that holds tissues in normal size and shape
-allows tumour cells to invade

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16
Q

Other Pro Tumour functions due to Proteolytic Activation

A
  1. Many Growth factors bound within ECM. These growth factors are released tumours move forward due to Invadopodea and ECM breaking down. Provides Feed Forward Stimulation for tumour behaviour (encourages and aids)
  2. ECM protein Laminen. When cleaves releases chemotactic fragments
    - tumours can stimulate own invasion by cleaving Laminen, results in peptide fragments that will further stimulate tumour invasion
  3. If proteases feed back and nibble on Intracellular junctions (e.g. E cadherin) will break it down Proteolytically, contributing towards tumour invasion
  4. Plasmin can feed back. uPA originates from progenitor pro. uPA.
    - Plasmin can feedback and activate its own activator (pro. uPA) resulting sustained environment, in direction that tumour cells are progressing, maintaining tissue destruction
  5. Invadopodea Receptors = Integrins
    - link tumour cell to substrate
    - helps to form directionality
    - can signal into cell, promoting invasive behaviour
    a) e.g. result in more expression of pro-uPA
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17
Q

Invadopodea

A
  1. uPA
  2. Plasmin
  3. mmP
  4. Receptors = Integrins
    - link tumour cell to substrate
    - helps to form directionality
    - can signal into cell, promoting invasive behaviour
    a) e.g. result in more expression of pro-uPA
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18
Q

Overview of Mechanism of Invason

A

complex of enzymes and receptors on front surface of cells contacting ECM
-enable tumour cell invasion

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19
Q

Tumour Hypoxia

A 
tumours grow because induce blood supply
tend to outgrow blood supply
-often poorly vascularised
-therefore part of tumours becomes hypoxic and necrotic
-200 microns from BV cells will se
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20
Q

Normoxic or Oxic

A

200microns from BV
cells will see enough Oxygen to be normoxic/be metabolically active
-about 10 Diameters
-enough oxygen to grow normally (badly as tumour cels)

21
Q

Hypoxic

A

zone present in many tumours

  • too far from functional blood vessel
    1) Viable
  • hypoxic cells undegoing glycolysis
    2) Nonviable
  • uale to maintain viabilitiy
  • die via oncosis/necrosis
  • reason for having centres of necrosis/ulceration in tumours
22
Q

What limits cancer treatments?

A

Shell of small proportion of vaible hypoxic cells
Between Oxic and Non viable cells
Small proportion of cells has disproportionate effect on tumour growth
-hypoxia in cancer is associated with poor prognosis and metastasis

23
Q

What is the relationship between Cancer and Hypoxia re Therapy?

A

Hypoxia in cancer is associated with poor prognosis and metastasis

  • Are Therapy resistance
    1) TxR
  • Radiotherapy
  • Radiation needs Oxygen to fix initial radiation damage
  • when hit a cell with radiation there is initial DNA damage needed to kill cancer cells. but in order to be long term/and result in DNA breaking and Death of cancer cell requires oxygen
    2) Chemotherapy
  • chemo drugs target dividing cells
  • many viable hypoxic cells leave cell cycle, therefore less sensitive to targetted agents
24
Q

Radiotherapy

A

Efficient and killing oxic cells as are oxygenated
but wont efficiently kills viable hypoxic cells
Few days after radiation: Oxic cells would have fallen away. vaible hypoxic cells + loss of intervening oxic cells + become oxygenated –> Regrow

25
Q

What is the relationship between Cancer and Hypoxia re Blood vessels?

A

Viable Hypoxic Cells are able to induce new Blood vessel development

  • Angiogenesis
  • hypoxic cells occur as oxic cells have outgrown blood supply
  • but overcome by maintaining/stimulating ongoing development of blood supply, supporting tumour growth
26
Q

What is the relationship between Cancer and Hypoxia re Tumour Aggressiveness?

A

Viable Hypoxic cells are able to select for tumour aggressiveness

  • Hypoxic cells die via Apoptosis (p53 mediated effect (p53 wild type +/+))
  • p53 wild type tumours cells in a hypoxic environment eliminate themselves via apoptosis
  • but p53 mutants are resistant to apoptosis, so will hang around in a hypoxic environment (have a selective advantage)/darwinian preferential survival
  • more aggressive (lose control of cell cycle/ apoptosis/ dont repair DNA as well) and hence preferentially populate the tumour == more aggressive tumour
27
Q

What is the relationship between Cancer and Hypoxia re promotion of phenoytpe?

A

p53 promotes a more invasive phenotype

  • hypoxia induces expression of snails/other transcriptional repressors
  • induce EMT
  • -> Hypoxia increases invasiveness
28
Q

What is the main mediated response to hypoxia?

A

HIF1-a Hypoxia Inducible Factor 1 alpha

29
Q

HIF1a in oxic conditions

A

Hypoxia Inducible Factor 1 alpha
protein in cells
1) oxic conditions:
-hydroxylated, ubiquinated and degraded (by protein VHL)
-so in our cells there is very little HIF1a

30
Q

What happens after a Stroke/ Heart attack in regards to HIF1a

A

(after heart attack/stroke/ischaemia, HIF1a will be induced and promote glucose transport protein production. –> cell can live on glucose since not enough oxygen around for mitochondria)

31
Q

HIF1a in oxic conditions

A

2) hypoxic conditions:
- HIF1a protein isnt degraded
- protein builds up in concentration
- binds to DNA response element, acting as a transcription factor, turns on number of genes which are involved in promoting cell survival of hypoxia
a) -produces VEGF (hypoxic cells induce BV) (Vascular Endothelial Growth Factor) –> causes angiogenesis –> enables tumour cells to grow
b) targets HGFR
- drive EMT (independently of snail)

32
Q

Hypoxic Use

A

People trying to use hypoxia as Tumour specific Lever to target anticancer drugs

  • create Prodrugs, activated into –> cytotoxic drugs on in oxygen deficient (hypoxic) regions of tumours
  • drugs which are armed only when there are microenvironmental hypoxia
  • that drug would hopefully only kill tumour cells,and not normal cells (which in most cases are well oxygenated)
33
Q

High vascular Density

A

a marker of poor prognosis

-tumours which are able to cause high blood vessel development are more aggressive tumours that cause more harm

34
Q

Angiogenesis causes

A
  • normally caused by
    1. Metabolic stress
  • hypoxia, acidosis, low glucose levels
    2. Inflammation
  • wound repair/damage, develops granulation tissue which is defined by ingrowth of BV (Granulation tissue is spotty as contains rich microvascular density)
    3. Acitvation of Oncogenes (RAS) or Inactivation of Tumour Surpressor Genes (p53)
35
Q

Granulation tissue

A

Inflammation
Wound repair/damage, develops granulation tissue
Granulation tissue is defined by ingrowth of BV
Granulation tissue is spotty as contains rich microvascular density
-Inflammation –> induces angiogenesis

36
Q

What makes it difficult to manipulate the process of angiogenesis for therapeutic benefit?

A

there are multiple pathways/mechanisms

-the options for supressing angiogenesis very difficult

37
Q

Angiogenic Sprouting

A
  1. Tumour cell with hypoxic centre
  2. Multiple mechanisms turn on production of Angiogenic VEGF
  3. VEGF picked up by adjacent peripheral endothelial cells lining BV
    - endothelial cells have receptors for VEGF
    4) upon VEGF signal. break down BM surrounding venule, endothelial cells enter tissue
    5) Migrate towards VEGF (VEGF is chemotactic for endothelial cells) (stimulates endothelial cells so they migrate away from original BV towards VEGF source)
    - Tick pathfinder cells at front
    - behind are proliferating cells producing more endothelial cells
    6) then differentiate and form junctions between cells –> tubes –> merge to form loops
    7) New microvascular network
38
Q

Angiogenic Sprouting in Breast Cancer Evolution

A

Duct of mammary epithelial cells with few surrounding BV
1.formation of hyperplastic ducts (Cell overproduction)
-sign of loss of growth control
2. Dysplastic Duct
-big irregular nuclei
-cells showing evidence of lost maturation
=Ductal Encarco In situ
3. Switch
-Colosal Proliferation of BV around duct
-distinct step in development of mammary encarcinomas
4. Next step is Early invasive ductal carcinomas

39
Q

Angiogenic Co-optation

A

Variation of sprouting
-Describing with asocytomas in breast
1) Existing BV network
2) original early tumours growing along existing network
(tumours co-opts an existing blood vessel network)
3) eventually cell tissue production places too much of a demand on the existing vasculature
-to many cells using oxygen
-whole system becomes hypoxic
-massive necrosis
-system crashes
4) at this stage enough survinvg tumour cells, to turn on angiogenic switch, and induce sprouting
“co-option stage of early usage of existing BV to get tumour off the ground, and then when that crashes sprouting follows”

40
Q

Four manners of which Tumour cells acquire BV supply

A
  1. Sprouting
  2. Co-operation
  3. Intussuspception
  4. Mimicry
  5. Vascuologenesis
41
Q

Angiogenesis Intussusception

A

Intussusception = “splitting”
1. Ragard front of growing tumour cells pressing against the BV
2. BV gets flattened
3. Eventually BV splits into numerous little BV as tumour cells grow against it
“Intussusception is when tumour cells grow against an existing BV supply and causing it to deform and split under the pressure of cell growth”
-Passive process

42
Q

Angiogenesis Treatment

A
  1. Treat Sprouting Tumour angiogenesis by targetting endothelial cells
  2. Intussusception (endothelial cells responding passively to tumour growth)
43
Q

Angiogenesis Vascular Mimicry

A
  1. Bv lined by endothelial cells
  2. Cancer cells transdifferentiate into endothelial-looking cells
    -illustrate tumour cell plasticity
    -tumour cells can contribute to their own BV
    In CRC Colorectal Carcinoma 15% of BV are mosaic –> therefore 4% of BV SA Surface Area is composed of tumour cells
    Implication:
    Grotty Tumour cells lining BV
    =can easily get sloughed off into circulation
    =10^6 cells per gram per day are washed into BV.
    able to potentially gain access to different site in body ==> contributing to metastises –> kills 90% of cancer patients
44
Q

Tumour cell Plasticity

A

Plasticity in differentiation state

  1. Into Endothelial looking cells in Angiogenesis vascular Mimicry (become endothelial cells to line BV)
  2. Mesenchymal cells to invade
45
Q

Vasculogenesis

A

Angiogenesis= sprouting from original vessels
Vasculogenesis
=forming new BV from scratch by importing progenitors
-contibute de novo/from scratch
1) Bone marrow releasing progenitor cells (angioblasts, hemeangioblasts) that are circulating
2. Recruited into tumours
a) under VEGF influence
-become endothelial cells
b) under PDGF (Platelet erived Growth Factor)
-become pericytes/Smooth muscle cells

46
Q

Natural Inhibitors of Angiogenesis/Targetting Vasculature for Cancer Treatments

A

1) Angiostatin
2) Endostatin
- natural peptides
- anti-angiogenic. contribute towards normal supression and balance of new BV development (great in mouse, not yet in humans)
3) Avastin
- Monoclonal antibodies against VEGF
- does have some activity against some tumours (e.g. Renal Cell Carcinomas)
- not huge
4) Sorafimin
- Low Molecular Weight inhibitors
- Target multiple Tyrosine Kinases
- incl. VEGFR
- some cancers, moderate degree of activity
- targets vasculature rather than tumour cell (so normal cells don’t develop resistant variants, like cancer cells)

47
Q

When are you undergoing angiogenesis naturally

A

Dont undergo angiogenesis unless

  1. undergoing Female Reproductive Cycle
  2. arent wounded
48
Q

tyrosine kinase example

A

VEGFR

Vascular Endothelial Growth Factor Receptor

POM (33 decks)

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