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intro to cancer > the non cellular stroma > Flashcards

the non cellular stroma Flashcards

1
Q

ECM

A

a reinforced composite of structural proteins that are organised as fibrillar structures embedded within a viscoelastic gel containing proteoglycans, glycoproteins, water, growth factors and other metabolites secreted by cell

provides structural support and biochemical signals for multicellular tissues

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2
Q

integrins

A

coordinate cell movement

  • new attachment proteins are established at the front a moving cell
  • old adhesions are released at the back
  • enables the cell to crawl forward
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3
Q

cell adhesion

A

fibronectin and integrins help cells attach to the ECM
- integrins function as heterodimers

  • integrins transmit tension from the ECM across the plasma membrane
  • integrins are anchored to the cytoskeleton
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4
Q

fibronectin in the ECM

A

serves as a molecule bridge between the integrins and the ECM
- has an ECM binding site and a cell attachment site

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5
Q

integrin regulation

A
  • regulated by signals from inside and outside the cell
  • acitivty regulation changes integrin conformation
  • on/ off integrins connections with the ECM enable cells to move through the tissue
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6
Q

stromal ECM

A
  • recruitment of stromal cells and generation og ECM are important rate- limiting steps in tumour formation
  • as tumour progression proceeds, the fibroblast rich stroma is replaced by myofibroblasts, which generate collagen rich desmoplastic stroma
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7
Q

remodelling of the ECM

A

ECM must be degraded to allow cells to pass between endothelial cells
two main groups of ECM degrading enzymes:
- matrix metalloproteinases require bound calcium or zinc for activity
- serine proteases have conserved serine residues in the active site

localised degradation of ECM maintains overall ECM structure, but created enough space for migrating cells to pass through

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8
Q

matrix metalloproteinases

A
  • activation of fibroblasts by TGD-beta, and conversion into myofibroblasts, induces release of MMPs

degradation of the ECMs: allows for structural remodelling of the ECM and releases a variety of tethered growth factors

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9
Q

how is the activity of ECM degrading proteases kept tightly localised

A
  • some proteases are secreted in an inactive form: a localised activator converts them to active form e.g. tissue plasminogen activator activates plasminogen to dissolve blood clots
  • some proteases are confined by cell surface receptors e.g. urokinase-type plasminogen activator found at growing tips of some migrating cells and is elevated in breast tumour tissue
  • some proteases are inhibited by the actions of locally secreted inhibitors e.g. tissue inhibitors of metallo proteinases
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10
Q

invadopodia

A
  • dynamic, actin-rich membrane protrusions that degrade ECM
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11
Q

examples of heterotypic cell communication using paracrine signalling

A

localised concentrations of PDGF required for recruitment of pericytes to capillaries

PDGF- beta is secreted by endothelial cells, and it gets sequestered into the ECM

mutant PDGF-beta that cant be retained in the ECM diffuses away from the endothelial cells

causes lack of structural support

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12
Q

hallmark of cancer - invasion

A

penetration of surrounding tissue and migration of cells into neighbouring tissue

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13
Q

metastatic cascade - invasion

A

changes in cell adhesion
-enhanced cancer cell migration
-extracellular matrix degradation

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14
Q

metastatic cascade - intravasation

A
  • basement membrane invasion
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15
Q

metastatic cascade - circulation

A

anchorage independent survival

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16
Q

metastatic cascade - extravasation

A
  • basement membrane invasion
17
Q

metastatic cascade - colonisation

A

cell adhesion and proliferation

18
Q

epithelial features

A
  • regular columnal morphology
  • high degree of cell adhesion
  • cell-cell junctions
  • specialised apical membrane
  • underlying basement membrane
  • cells relatively static
19
Q

mesenchymal features

A
  • irregular rounded or elongate morphology
  • loss of apico-basal polarity
  • front-back polarity
  • dynamic adhesions
  • lamellipodia and filopodia
  • cells highly motile
20
Q

epithelial to mesenchymal transition

A
  • assembly of cells into an epithelium is reversible
    -EMT found in developing tissues
  • EMT involved in cancer cell invasion
21
Q

EMT

A

epithelial cell - immotile, tight cell junctions, polarised cells

transformed epithelial cell: loss of polarity, loose cell -cell junctions, dysplastic growth

mesenchymal cell: migratory, loss of cell-cell junctions, dynamic cell-ECM adhesion

CAF: secretion of eco, organisation of ECM fibres,

22
Q

regulation of adherens junctions: proteolytic turnover 1

A

-Ecadherin protein half life of 5-10 hours: highly susceptible to proteolytic degradation

  • caspases are proteolytic enzymes activated during apoptosis: they degrade numerous essential proteins including beta-catenin and alpha-catenin
  • this leads to apoptotic cell death
23
Q

regulation of adherens junctions: proteolytic turnover 2

A

beta-catenin and E-cadherin are also substrates for calpain mediated proteolytic cleavage
- thus calpains may also modulate cadherin dependent cell-cell adhesions
-calpain is upregulated in breast tumour, renal cell carcinoma, cheonic lymphocytic leukemia B cells

24
Q

calpains in tumourigenesis

A
  • calpain is switched on in response to activation of the oncogene v-Src
  • calpain substrates involved in regulation of cell adhesion include c-Src, FAK, Stalin, paxillin, alpha-actinic, actin
  • calpain substrates involved in regulation of cell proliferation include p53, p27, cyclin D
  • calpain expression upregulated in renal cell carcinomas that metastasise to peripheral lymph nodes
  • calpain activity upregulated in breast cancer tissue
  • calpain - 2 proposed as a target for limiting prostate cancer invasion
25
Q

what calpain inhibitors suppress

A

cell migration and cell proliferation

26
Q

therapies targeting invasion

A

current therapies that impact tumour invasion upregulate the function of adherens junctions, promoting cell-cell adhesion and preventing tumor cell invasion
- mediated by upregulated E-cadherin, alpha catenin and beta catenin gene expression; dephosphorylation of beta - catenin, increased stabilisation of beta - catenin at cell-cell adhesions

27
Q

targeted therapies examples

A

aspirin - can restore E-cadherin dependent cell - cell adhesion
- MMP inhibitors inhibit tumour induced degradation of ECM proteins
- EGFR inhibitors inhibit tumour growth and metastasis
- VEGFR inhibitors inhibit angiogenesis, tumour growth and metastasis
- Src INHIBITORS INHIBIT TUMOUR GROWTH AND METASTASIS

intro to cancer (19 decks)

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