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PATH3309 > 10 - Invasion and Metastasis > Flashcards

10 - Invasion and Metastasis Flashcards

1
Q

Neoplasia

A

Clonal proliferation of cells which grows in an excessive and uncoordinated way, in
comparison to normal tissue, and persists in the absence of the stimulus that first evoked the change

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2
Q

Benign

A

Neoplasm lacking ability to invade and metastasize

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2
Q

Benign macroscopic features

A

Generally rounded, well circumscribed, encapsulated tumours

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3
Q

Benign microscopic features

A

Banal features (uniform cells, well differentiated, low mitotic rate)

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4
Q

Malignant

A
  • Neoplasm with capacity for local invasion and metastasis
  • Very inefficient and therefore few circulating tumor cells initiate successful metastatic colonies
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5
Q

Malignant macroscopic features

A

Generally infiltrative (crab like), not encapsulated, hard, fibrous

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6
Q

Malignant microscopic features

A
  • Pleomorphism (different appearance between cells)
  • Anaplasia (look nothing like cells they’re derived from)
  • Hyperchromasia
  • Mitoses (numerous and abnormal forms)
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7
Q

Invasion

A

Process whereby tumour cells disobey organ boundaries and cross into foreign tissue

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8
Q

Metastasis

A

Secondary tumour established at site distant from primary tumour

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9
Q

Steps of invasion

A
  • Altered cell-cell interactions
  • Matrix dissolution
  • Altered cell-ECM interactions
  • Migration/locomotion
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10
Q

Steps of metastasis

A
  • Intravasation
  • Vascular dissemination
  • Extravasation
  • Colonisation
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11
Q

Cell-cell interactions in normal tissue

A
  • Tight intercellular adhesions (e.g. E-cadherin homodimers)
  • Tight adhesions lead to transduction of signals (maintain terminal differentiation, regulate growth, prevent cytoskeletal remodelling)
  • “Contact inhibition”
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12
Q

Altered cell-cell interactions in cancer

A
  • Tumour cells down regulate adhesion molecules and dissociate from one-another
  • Loss of “contact inhibition”
  • De-differentiation
  • Up-regulated growth
  • Increased cytoskeletal
    remodelling
  • E-cadherin is a frequently disrupted molecule in some
    carcinomas
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13
Q

Matrix dissolution in normal tissue

A
  • Tissue compartments are separated by the “extracellular
    matrix unit (ECM)”
  • ECM consists of basement membrane (BM) and interstitial matrix
  • BM is a dense matrix of collagens, glycoproteins (e.g. laminins) and proteoglycans
  • Interstitial matrix is loose matrix of fibrous structural proteins (e.g. collagens, elastins), adhesive glycoproteins and proteoglycans and water
  • These structural elements must be degraded for invasion to occur
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14
Q

Matrix dissolution in cancer

A
  • Tumour cells either secrete or induce ECM cells (e.g. fibroblasts/inflammatory cells) to secrete proteases
  • MMPs breakdown ECM components for physical passage of tumour cells
  • Elaborates growth factors from ECM
  • Strong correlation between MMP expression and invasive and metastatic potential
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15
Q

Proteases secreted by tumour cells/ECM cells

A
  • Matrix metalloproteinases (MMPs)
  • Heparanases
  • Serine proteases
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16
Q

MMPs

A
  • Family of zinc-dependent protease molecules capable of
    degrading all ECM components
  • .21 structurally related MMPs
  • Divided based on substrate specificity (e.g. collageneases, gelatinases)
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17
Q

Physiological function of MMPs

A
  • Embryogenesis and growth
  • Uterine cycling and postpartum involution
  • Tissue repair
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18
Q

Regulation of MMPs activity

A
  • Regulated by tissue inhibitors (TIMPs)
  • 4 structurally related proteins (TIMP1-4)
  • Block MMP activity by binding to their conserved zinc binding site
  • Synthesised and secreted by ECM cells as a host response to limit tumour invasion
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19
Q

Overexpression of TIMPs

A
  • Correlated with reduced invasive capacity
  • Complex interplay between MMPs and TIMPs determines the degree of ECM degradation
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20
Q

Normal cell matrix interactions

A
  • Cells have receptors (e.g. integrins) for ECM constituents (e.g. laminin) along their basal surface
  • Adhesions lead to transduction of inhibitory signals (contact inhibition) that maintains terminal differentiation, regulates growth and prevents cytoskeletal remodelling
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21
Q

Physical effects of altered cell matrix interactions

A

Regulate the shape, orientation and movement of cells

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22
Q

Integrins

A
  • Large family of transmembrane glycoprotein heterodimers with an alpha and beta subunit attached to the intracellular cytoskeleton
  • The binding target and the intracellular signal upon
    binding is determined by the particular combination of
    the α and β chains
23
Q

Altered cell-matrix interactions in cancer

A
  • Some integrins e.g. αVβ3, almost universally promotes tumour invasion and metastasis
  • Others e.g. α2β1 are growth promotory in some cancers
    (melanoma, gastric, prostate) but inhibitory in others (breast)
24
Q

MIgration/Locomotion

A
  • Final step of invasion
  • Complex process involving many families of receptors and signalling proteins which have ultimate effect of altering the cytoskeleton
  • Leading edge attaches to ECM constituents, detaches at the trailing edge and contract the cytoskeleton to propel forwards
  • Movements potentiated and directed by the mileu of
    promigratory factors at the leading edge
25
Q

Mesenchymal migration

A

Tumours invading as single cells

26
Q

Collective migration

A

Tumours invading as groups of cells

27
Q

Promigatory factors

A
  • Secreted by tumour cells, ECM cells, inflammatory cells and liberated from ECM itself
  • E.g. cytokines, ECM cleavage products and GFs
28
Q

Advantage of collective migration

A
  • A multi-cellular contractile body capable of more efficient movement
  • Protection of inner cells from immune attack
  • Higher autocrine concentrations of promigratory factors
  • Allows passive transport of otherwise non-motile tumour
    cells
29
Q

Amoeboid migration

A
  • Alternate form of invasion
  • 30x faster than mesenchymal migration
  • Cells undergo shape changes to squeeze through the ECM rather than cut through it (protease
    independent)
  • Tumour cells may be able to switch between types of migration in vivo
  • May in part explain poor response of cancers to antiMMPs
30
Q

Three main pathways of tumour dissemination

A
  • Direct seeding of body cavity
  • Lymphatic spread
  • Haematogenous spread
31
Q

Direct seeding

A
  • Occurs when a cancer penetrates a body cavity
  • Pleural, pericardial, joint space
32
Q

Lymphatic spread

A
  • Dissemination via lymphatics typical of carcinomas (malignant epithelial neoplasms)
  • Tumour cells penetrate the thin walled lymphatic spaces
  • Lymphatics drain into lymph nodes where tumour may arrest and form a deposit
  • Patterns of nodal involvement follow the anatomical routes of lymphatic drainage
33
Q

Haematogeneous spread

A
  • Dissemination via blood vessels seen in carcinomas and
    sarcomas (connective tissue neoplasms)
  • Tumours typically penetrate venous spaces (thinner than arteries)
  • Tumour cells follow the venous flow of the neoplasm and often
    deposit in the first capillary bed they encounter
34
Q

Multitude of steps to successfully initiate a metastasis

A
  • Invade
  • Intravasate
  • Vascular dissemination
  • Extravasate
  • Colonise
  • Tumour cells require a specific genetic signature to negotiate these steps
35
Q

Primary tumours

A
  • Genetically unstable and become heterogeneous with multiple subclones of cells
  • Emergence of a subpopulation with most of the necessary genetic alterations for metastasis
  • Many of these genes are acquired at an early stage of tumour evolution
  • Additional genetic alterations are required to complete the metastatic phenotype
36
Q

Intravasation

A
  • Invasion into blood vessels involves penetration through the BM then adhesion to endothelium
  • Requires ECM integrin interactions and proteolytic enzymes
37
Q

Vascular dissemination

A
  • Few cancer cells survive once in bloodstream
  • Survival advantage if aggregated with platelets and fibrin
38
Q

What is vascular dissemination mediated by

A
  • Tumour cell release of platelet activating and procoagulant
    factors (e.g. ADP, tissue factor, thromboxane A2)
  • Expression of adhesion molecules (e.g CD44, surface mucins)
39
Q

Tumour-platelet thrombi

A
  • Shield tumour cells from the immune system
  • Reduce tumour cell exposure to mechanical sheer forces
  • Also facilitate extravasation
40
Q

Extravasation

A

Tumour cell arrest and extravasation at distant site
involves adhesion to endothelium, then egress through basement membrane

41
Q

What is extravasation facilitated by

A

Tumour-platelet thrombi as platelets express numerous endothelial and ECM adhesion molecules

42
Q

What does extravasation require

A

ECM-integrin interactions and proteolytic enzymes

43
Q

Colonisation

A
  • Often first site of metastasis is the first capillary bed
  • Certain cancers have a propensity to metastasize to certain sites
  • Stimuli for angiogenesis are necessarily induced by the tumour for survival
  • Lead to upregulation of angiogenic factors (e.g. VEGF
    and bFGF) and down regulation of antiangiogenic inhibitors (two key mechanism are hypoxia and angiogenic switch)
44
Q

Seed and soil hypothesis

A
  • Certain tumour cells (the seed) have a specific affinity for the milieu of certain organs (the soul
  • Metastases occurs when there is a match
45
Q

Example of seed and soil hypothesis

A

CD44 expressing tumours have propensity for LN deposition as LN venules express high levels of hyaluronate (the CD44 receptor)

46
Q

Another example of seed and soil hypothesis

A

Breast cancer cells overexpressing CXCR4 hone to
bone marrow where its ligand, SDF1, is highly expressed

47
Q

What are sites of metastasis determined by

A
  • The tumour cells
  • The microenvironment of the host tissue
  • Prevailing circulatory patterns
48
Q

What is required for a tumour to exceed 1-2mm in size

A
  • Vascularisation
  • Necessary for delivery of oxygen and nutrients and
    removal of waste products
49
Q

Process of vascularisation

A

Angiogenesis

50
Q

Angiogenesis

A

-Induced outgrowth of pre existing vessels
- Formation of new vessels from endothelial cells recruited from the bone marrow

51
Q

Hypoxia

A

Results in HIF-1 and HIF-2 expression, leading to transcription of pro-angiogenic factors

52
Q

Angiogenic switch

A

Genetic aberrations result in altered expression of pro- and anti-angiogenic factors

53
Q

Three examples of angiogenic switch

A
  • Activating mutations of RAS and MYC
  • MMPs release angiogenic factors sequestered in the ECM, e.g. bFGF
  • Mutant p53 does not induce synthesis of anti-angiogenic
    molecules, e.g. thrombospondin
54
Q

Angiogenesis inhibitors

A
  • Bevacizumab (VEGF inhibitor)
  • Associated with improved outcomes in brain, lung, colorectal and breast cancer

PATH3309 (12 decks)

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