the non cellular stroma Flashcards
ECM
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
integrins
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
cell adhesion
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
fibronectin in the ECM
serves as a molecule bridge between the integrins and the ECM
- has an ECM binding site and a cell attachment site
integrin regulation
- 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
stromal ECM
- 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
remodelling of the ECM
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
matrix metalloproteinases
- 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
how is the activity of ECM degrading proteases kept tightly localised
- 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
invadopodia
- dynamic, actin-rich membrane protrusions that degrade ECM
examples of heterotypic cell communication using paracrine signalling
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
hallmark of cancer - invasion
penetration of surrounding tissue and migration of cells into neighbouring tissue
metastatic cascade - invasion
changes in cell adhesion
-enhanced cancer cell migration
-extracellular matrix degradation
metastatic cascade - intravasation
- basement membrane invasion
metastatic cascade - circulation
anchorage independent survival
metastatic cascade - extravasation
- basement membrane invasion
metastatic cascade - colonisation
cell adhesion and proliferation
epithelial features
- regular columnal morphology
- high degree of cell adhesion
- cell-cell junctions
- specialised 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
epithelial to mesenchymal transition
- assembly of cells into an epithelium is reversible
-EMT found in developing tissues - EMT involved in cancer cell invasion
EMT
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,
regulation of adherens junctions: proteolytic turnover 1
-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
regulation of adherens junctions: proteolytic turnover 2
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
calpains in tumourigenesis
- 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
what calpain inhibitors suppress
cell migration and cell proliferation
therapies targeting invasion
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
targeted therapies examples
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
