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Block 2 Cancer > Metastasis > Flashcards

Metastasis Flashcards

1
Q 
What do these stand for?
MMP
EMT
CAM
VCAM
TAM
TABV
A
  • Matrix metalloprotinase
  • Epithelial mesenchymal transition
  • cell adhesion molecule
  • Vascular cell adhesion molecule
  • Tumor associated macrophage
  • tumor associated blood vessel
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2
Q

Metastasis

A

process by which tumor cells exit primary tumor and establish secondary tumors at distant sites; responsible for 90% human and animal cancer deaths

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3
Q

Metastasis setps

A
  1. Carcinoma in situ
  2. Angiogenesis and invasion
  3. intravasation
  4. Vascular arrest
  5. Extravasation
  6. Colonization
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4
Q

carcinoma in situ

A

will be developing additional mutations that allow next step (angiogenesis and invasion)

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5
Q

angiogenesis and invasion

A

mutations developed allow tumor cell to breach basement membrane, recruit new blood or lymphatic vessels, and invade surrounding tissues

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6
Q

intravasion

A

tumor cells enter circulation and travel to secondary sites

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7
Q

extravastate

A
  1. extravate as single cells

2. Proliferate intravascularly

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8
Q

colonization

A

tumor cells form secondarry tumors

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9
Q

risk of metastasis

A

higher with increased tumor size (tumors >2-3cm risk for metastasizing) but this isn’t only deciding factor of metastasis

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10
Q

Tumor microenvironment and metastasis

A

TME supports metastasis in many ways

  • facilitates epithelial to mesenchymal transition
  • promote tumor cell invasion and intravasation (including angiogenesis)
  • provide niche for generation of metastatic cancer stem cells by secreting factors that inhibit anti tumor immune response
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11
Q

to become invasive tumor cells alter

A
  • cell surface adhesion molecules and receptors including cadherins and integrins
  • increase their expression and secretion of proteases (matrix metalloproteinases) or secrete factors that induce cells of reactive stroma to upregultae and secrete these enzymes
  • produce factors that induced stroll cells to secrete chemokine and motility stumualating factors -> tumor cell migration
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12
Q

Invasion strategeies

A
  • Ameboid
  • Mesenchymal
  • Clusters/ cohorts
  • multicellular strands/ sheets
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13
Q

Ameboid/ Mesenchymal

A
  • this strategy used my lymphoid tumors and sarcomas

- these tumor cells lack cadherins and express low levels of integrins and proteases

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14
Q

Collective strategies

A

clusters/ multicellular sheets and strands

  • epithelial cancers use these
  • strong cell-cell interactions
  • high levels cadherins and gap junction proteins
  • elevated expression of integrin receptors and increased protease secretion
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15
Q

epithelial to mesenchymal transition

A

epithelial cells transiently change phenotype to acquire mesenchymal-like properties
- results in disillusion epithelial adherent and tight junctions, loss epithelial and expression of mesenchymal markers and enhanced protease secretion

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16
Q

EMT-TFs

A

EMT transcription factors mediate incomplete or partial EMT response; responsible for ability of carcinoma cells to degrade ECM and exhibit enhanced motility and invasiveness
- expression EMT-TFs by tumor cells induces specific markers and cell signaling pathways and antiapoptotic pro survival phenotype characteristic cancer stem cells

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17
Q

Leader cells

A
  • may undergo partial EMT to migrate and secrete EMC degrading proteases
  • EMT is a transient process only affects individual tumor cells
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18
Q

Pathways of metastatic spread

A
  1. Seeding of body caivities (carcinomatosis)
  2. Transplantations (contaminated donor organ or sx instrument)
  3. Hematogenous spread
  4. Lymphatic spread
19
Q

hypoxia

A

Central regions of large tumors most likely to be affected and become necrotic hence angiogenesis major inducer tumor angiogenesis b/c hypoxia promotes accumulation of HIF-1alpha
- hypoxia also promotes tumor progression and drug resistance

20
Q

HIF-1alpha

A

induces expression of VEGF -> angiogenesis

  • under normal conditions o2 dependent enzyme propel-hydroxylase promotes ubiquitinaition and proteasomal degradation of HIF-1alpha under hypoxic conditions prolyl-hydroxylasa inactive HIF-1alpha levels increase and induce transcription of VEGF
  • growth factors also increase levels HIF-1alpha
21
Q

Angiogenic switch

A

early stage non invasive tumors not highly vascularized bc presence basal lamina separating tumor from surrounding storma while invasive tumors display significant intra-tumor vascularization (this switch = antigenic switch)

22
Q

What causes angiogenic switch

A

they aren’t 100% sure but most likely

  • relative activities of angiogenic activators (VEGF) and inhibitors (angiostatin, endostatin)
  • breaching basement membrane
  • recruitment of tumor associated inflammatory cells
23
Q

tumor-TME interactions and angiogenesis

A

Tumors secret VEGF and other factors stimulating endothelial cell proliferation and migration but these factors = sequestered by ECM; tumor associated macrophages and mast cells secrete matrix metalloproteinases which partially degrade ECM -> release active VEGF
- macrophages and mast cells secrete additional factors that long with VEGF promote angiogenesis by stimulating endothelial cell survival, activation, proliferation, and migration (activated ECs recruit EC progenitors which mature to provide ECs for capillary sprouting)

24
Q

Tumor vasculature

A
  • is abnormal b/c driven by a single factor (VEGF) not combo of factors like physiological angiogenesis
  • vessels often irregularly shaped, dilated, and disorganized, and contain fewer pericytes (required for proper maintenance and fx of blood vessels)
  • capillaries v leaky -> variant o2 and nutrient profusion and making therapeutically effective drug level delivery and immune effector cell delivery challenging
  • hypoxic conditions persist
  • > additional angiogenesis and other events promoting tumor progression
25
Q

Anti-Angiogenic therapy

A

takes advantage of fact that tumor growth and survival dependent on adequate blood supply

  • usually combine with conventional chemo for best results but has limited impact
  • animal models not sufficient bc contain 1 type cell grow rapidly and are v dependent on angiogenesis while human tumors are slow growing and heterogenous with various dependencies upon angiogenesis so no way to know how dependent and if this therapy will work
26
Q

angiogenesis inhibitors

A
  • monoclonal antibody and receptor tyrosine kinase inhibitors that target VEGF and endothelial cell receptors which are activated during angiogenesis
  • tumors can use various methods to overcome VEGF specific blockade
27
Q

tumor overcoming VEGF specific blockade

A
  • expression of non-VEGF angiogenic factor by tumor or surrounding storms cells
  • employment of alternative angiogenesis independent mechanisms to vascularize tumor (ie co-opt existing capillaries)
28
Q

newer anti-angiogenic therapies

A

being designed to target tumor vasculature by blocking actions of multiple angiogenic factors and inflammatory cells

29
Q

alternative strategy to anti-angiogenic factors

A

normalize tumor vasculature to increase perfusion enhancing chemotherapeutic drug delivery and immune cell infiltration and prevent hypoxia driven tumor progressoin

30
Q

Tumors enter vasculature

A
  • passively (VEGF-induced blood vessels leaky and strucutrally abnormal can passively capture tumor penetrating cells)
  • actively- tumor cells migrate toward blood vessel bind endothelial cell basement membrane and secrete matrix metaloprotinases to degrade basal laimina, endothelia cell retraction allows tumor cell to move through gaps in endothelia lining
31
Q

Hazards of circulating tumor cells

A
  • physical forces when entering capillary can deform and shear cell (or capillary can burst)
  • hemodynamic and geometric forces can disrupt tumor cell membranes -> cell death
  • tumor cells often anchorage dependent so no ECM -> apoptosis
  • growth and survival factors provided by reactive stroma of primary tumor gone
  • tumor cells destroyed by natural killer cells
32
Q

protective microemboli

A

circulating tumor cells often avoid immune detection by associating with platelets which form protective micro emboli and secrete inhibitors of immune fx

33
Q

Ability of tumor to establish secondary tumors dependent upon

A
  1. Where tumor cells arrest in vasculature
  2. Microenviorment at secondary site
    * * specific tumor sites tend to metastasize to specific organs**
34
Q

Tumor cells arrest in vasculature

A
  1. Mechanical entrapment= passive process= tumor cells trapped in first capillary bed they encounter
  2. Site-specific mechanism= active process= tumor cells preferentially arrest in vasculature of specific organ based on tumor-endothelial cell interactions (many tumors utilize this, shown by Fidler’s experiments)
35
Q

Tumor-cell EC interactions

A

EC (endothelial cells) have cell adhesion molecules (CAMs) on their surfaces which interact with tumor cell surface molecules; can be constitutive or inducible

36
Q

constitutive EC CAMs

A

aka addressins

- these are continuously expressed on surface of ECs; pattern of expression generally tissue specific

37
Q

Inducible CAMs

A
  • expressed in response to single (often from tumor cell)

- members of selection (E and P selection) and Ig super family (ICAM-1, VCAM) of adhesion molecules

38
Q

extravasation as signal cell

A
  1. Adherent tumor cells promote retraction of endothelial cells
  2. Attach to subendotheilial BM
  3. infiltrate underlying tissue
39
Q

extravasation via intravascular proliferation

A

arrested tumor cells and associated cells proliferate within vessel -> vessel rupture and tumor cell infiltration

40
Q

Seed and Soil

A

stated metastasis wasn’t to random tumor cells grow preferentially at specific sites if conditions appropriate

41
Q

fates of tumor cell after infiltrating secondary site

A
  1. undergo apoptosis (bc lack supportive environment ie lack anchorage support and pro-survival signals)
  2. elimination by immune system
  3. enter state dormancy proliferate if proliferative and pro survival factors become available -> micromeststassi macrometastasis dependent on blood vessel recruitment
  4. successful colonization
42
Q

successful colinization

A

dependent upon favorable microenviorment. Primary tumor cell secretes factors and extracellular vesicles containing mRNAs, proteins, and miRNAs that can induce pre-metastiatic niche formation before tumor cell arrives. These factors can activate and mobilize bone marrow derived cells -> localized inflammatory response
- release growth factors, cytokines, protease active residents, remodeling ECM, and prepenivlnrment for tumor cells

43
Q

metastatic niche

A

establishment dependent upon interactions btwn infiltrating tumor cell and pre-conditioned tissue enivonrment

Block 2 Cancer (10 decks)

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