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Cancer Biology and Medicine 4 > L5: Invasion and metastasis > Flashcards

L5: Invasion and metastasis Flashcards

1
Q

What are the metastatic cascade events?

A
  • Invasion (changes in cell adhesion; enhanced cancer cell migration; ECM degradation); intravasation (basement membrane invasion); circulation (anchorage independent survival); extravasation (basement membrane invasion); colonization (cell adhesion and proliferation)
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2
Q

What is metastatic tropism?

A
  • Cancers metastasis is not random
  • The tendency of cancers to metastasise to specific organs
  • Different cancers prefer different organs
  • Depends highly on pre-metastatic niche
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3
Q

How does premetastatic niche facilitate tumour spread?

A

The premetastatic niche facilitates tumour spread
- Cancers can precondition distant environments to enable metastasis
- Includes inducing vascular leakage, immune suppression, ECM remodelling at the site of extravasation
- Can have premetastatic niche development at the site of colonization: growth factor liberation, ECM remodelling, exosome delivery

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4
Q

What are the epithelial and mesenhymal features?

A

Epithelial features:
- Organized in regular columnar morphology
- High degree of cell adhesion
- Cell-cell junctions
- Specialized apical membrane
- Underlying basement membrane
- Cells relatively static

Mesenchymal features:
- Irregular rounded or elongate morphology
- Loss of apico-basal polarity
- Front-back polarity
- Dynamic adhesions
- Lamellipodia and filopodia
- Cells highly motile

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5
Q

What are the molecular regulators of EMT?

A
  • EMT is regulated in many complex ways, there are cotranscriptory regulators: Snail, Slug, Twist, Zeb
  • We have microRNAs that co-regulate these transcriptors
  • Transcription factors are difficult to target therapeutically
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6
Q

What is a key enzymatic driver of EMT?

A

Src: a key enzymatic driver of EMT
- Src is a non-receptor tyrosine kinase with both catalytic and scaffolding functions (in addition to transferring phosphate groups on target proteins, it can also bind proteins and help form complexes)
- Disrupts normal epithelial structure and promotes an invasive and mesenchymal phenotype
- Therefore, stimulates cell migration
- Inhibition of Src reduces tumour cell invasion, delaying dissemination and progression of disease
- Recently secured a novel Src inhibitor: eCF506. Very potently reduces breast cancer metastasis in mice
- inhibits both kinase activity and scaffolding properties – which is really effective

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7
Q

What are the adhesion molecules that form cell-to-cell and cell-to-matrix complexes?

A
  • Two superfamilies of cytoskeleton-linked transmembrane adhesion molecules
  • Cadherins mainly mediate cell-cell attachment (dynamically disassembled during EMT) disrupts cells contact – allows them to move
  • Integrins mainly mediate cell-matrix adhesion (dynamically assembled during EMT)
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8
Q

What forms adherens junctions?

A

cadherins

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9
Q

What are the types of cadherins? Where are they expressed?

A
  • Cadherins form a diverse family of adhesion proteins
  • Tissue specific expression:
    o E-cadherins (epithelium)
    o N-cadherin (neuron)
    o VE-cadherin (vascular endothelium)
    o R-cadherin (retina)
  • This allows cells to form specific cell-cell interactions with the cells that are most relevant for them
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10
Q

How can cancer cells disassemble adherens junctions?

A
  • Cancer cells can disassemble adherens junctions by:
    o Phosphorylating cadherins (eg Src)
    o Acquiring mutations (eg in E-cadherin’s gene)
    o Mutating or removing cadherin-associated factors (beta-catenin)
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11
Q

How can EGFR activation affect regulation of adherens junctions?

A
  • Abberant EGFR activation (very common in cancer) can stimulate beta-catenin and p120-catenin phosphorylation and promote junction disassembly
  • Phospho-beta-catenin may antagonize association between alpha-catenin and E-cadherin
  • Mediated by excess growth factor production: eg EGF, PDGF, often overexpressed by cancer cells or highly expressed by tumour microenvironment
  • potential drug target
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12
Q

How can Src activation affect regulation of adherens junctions?

A
  • Oncogenes such as Src, Yes, Lyn can directly phosphorylate β-catenin and p120-catenin.
  • Src can additionally phosphorylate E-cadherin to target it for proteolysis.
  • Src is upregulated in several human cancers and correlates with invasion and metastasis.
  • Src potential drug target
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13
Q

Describe ECM, its structure, function

A

Cells reside in an extracellular matrix (ECM)
- ECM is reinforced matrix of structural proteins (collagen, laminin, fibronectin) that are organised as fibrillar structures embedded within a gel containing proteoglycans, glycoproteins, water, growth factors and other metabolites secreted by the cells
- Provides structural support and biochemical signals for multicellular tissue and organ systems.
- Contributes to cell identity and spatial organisation in tissues.

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14
Q

What are integrins?

A
  • Heterodimeric α/β receptor pairs which bind ECM to transmit signals over cell membrane.
  • Diversity of ECM proteins requires integrin diversity: at least 18 α-subunits, 8 β-subunits.
  • Cells express specific integrins according to their extracellular surroundings.
  • Integrins connect ECM to actin cytoskeleton
  • Signal bidirectionally: both intracellular and extracellular cues influence integrin state and affinity for ECM proteins / intracellular adaptors
  • integrins also coordinate cell migration and movement
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15
Q

What are focal adhesions?

A
  • Focal adhesions are specialized multi-protein complexes that form at the interface between a cell and its extracellular matrix (ECM). These structures physically link the ECM to the intracellular cytoskeleton and serve as hubs for biochemical signaling.
  • Concentrated locales of integrin-binding adhesion proteins
  • Very diverse family – hundreds of proteins localise at focal adhesions
  • Permits functional diversity - integrin adhesion can co-ordinate many cellular processes (primarily migration), because you can recruit many functional proteins to adhesions
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16
Q

What functions does altered integrin expression in can lead to?

A

o Promote invasion
o Promote metastasis
o Suppress apoptosis
o Drive cell signalling (via downstream adaptors eg focal adhesion kinase)

17
Q

What is the function of focal adhesions kinases?

A

FAK is a core adhesion-linked signalling hub:
- Activated by binding active integrins
- Activates Src
- Co-ordinates mitogenic signalling with ECM binding
Very frequently over-expressed in cancer

18
Q

What happens when focal adhesion kinases are targeted therapeutically?

A

Therapeutic targeting:
- Inhibits adhesion disassembly
- Inhibits cell migration
- Reduces invasion and metastasis
- Inhibits cancer-mediated immune suppresion

19
Q

What is the unexpected role for adhesion signalling in non-adherent cells?

A
  • Adhesion signalling complexes (integrins, FAK, etc.) can be internalised through endocytosis.
  • Active adhesion signalling prevents anoikis: an adhesion-dependent pathway of apoptosis.
  • Rab21-mediated traffic of active adhesion complexes (EEA1-positive)
20
Q

What is the FAK activation pathway?

A

Upon integrin activation FAK is recruited to the integrins, FAK autophosphoralates on this Y397 site, which then acts a site for things like Src to come and bind along.

21
Q

What is actin? How does it form? What is its function?

A

Actin is a filamentous structure that drives cell movement
- Filamentous (f)-actin forms from actin monomers
- Assembles into fibres which control cell shape and movement

22
Q

Where from does actin assemble?

A
  • Focal adhesions are sites of Rho GTPase regulation
  • Small, monomeric GTPases which regulate factors that control actin polymerisation and cell movement
23
Q

What are Rho faimily proteins? What is their function?

A
  • Different actin structures are polymerised by different Rho family members
  • RhoA (or RhoB/C): form stress fibres: provide elasticity, contractility during migration
  • Rac1: forms lamellipodium: broad protrusion at the front of migrating cells.
  • Cdc42: forms filopodia: fine, actin-rich processes which protrude intro the microenvironment.
  • Co-ordinated action of Rho GTPases controls cell motility.
24
Q

What are the types of cancer invasion?

A
  • mesenchymal and amoeboid
  • Gradient of states from mesenchymal to amoeboid according to:
    o Rho status
    o Integrin engagement (or lack thereof)
    o Surrounding ECM context
    o ECM-degrading activity of cancer cells
25
Q

What are the main groups of ECM degrading enzymes?

A

o Matrix metalloproteinases (MMPs) require bound calcium or zinc as co factors for activity
o Serine proteases have conserved serine residue in the active site
o Note that a wide family of proteins can regulate ECM-degrading enzyme activity

26
Q

Whay do cancer cells use to invade the tissue?

A
  • Invadopodia are dynamic, actin-rich membrane protrusions that degrade ECM.
  • MMPs and other proteolytic enzymes enrich at invadopodia
    o Hence, MMPs are concentrated at sites that cancer cells use for invasion
  • Formed in cancer by aberrant adhesion and Rho activity
27
Q

Why have MMP directed therapies have failed?

A
  • MMP inhibition seems smart to reduce invasion.
  • However, amoeboid-type migration is largely MMP-independent.
  • MMP inhibition selects for amoeboid invasion! Another form of plasticity in invasion
28
Q

Describe 2D cell assays of invasion and metastasis

A
  • Cells migrate passively over chemotactic gradient
  • Easy to set up and image but not representative of in vivo tumour
  • You can do this by making a wound model
  • Nice, cheap but not representative
29
Q

Describe 3D cell assays of invasion and metastasis

A
  • Seed cells onto a Matrigel plaque: an ECM substitute made of laminin and collagen (mostly).
  • Allow to invade over several days then image with confocal microscope.
  • Alternatively (as discussed earlier), embed cells into Matrigel and record invasion.
30
Q

What are the challenges with invasion and metastasis models?

A
  • Challenges with selection of matrix and physiological integrin engagement / protease activation.
  • Time-course differences: timescale of metastasis in the lab drastically different to in clinical setting.
  • Appropriate model for invasion and metastasis? How might we induce it in an animal model? Injection directly into circulation? Wait for primary tumour to metastasis “naturally”?
  • Most metastasis models use exceptionally aggressive cancer cells: does this model the entire cascade?
31
Q

Why are there currently no approved therapies specifically targeting metastasis?

A
  • Adaptive switching of cancer cells between migration modes complicates use of therapeutics
  • Overlap between metastatic processes and tissue homeostasis. After operation – might interrupt healing
  • Difficulty in selecting for clinical trials: metastases often present at diagnosis and new micro-metastases very difficult to detect in the clinic.
  • Studies are often very long - up to years before a metastasis can be detected in some cancers.

Cancer Biology and Medicine 4 (19 decks)

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