Tumour-stroma interactions Flashcards
define the tumour microenvironment
defined as all the non-transformed elements residing within or in the vicinity of the tumour
Cancer cells, immune cells, CAFs, vasculature, extracellular matrix, growth factors
define the tumour microenvironment
defined as all the non-transformed elements residing within or in the vicinity of the tumour
Cancer cells, immune cells, CAFs, vasculature, extracellular matrix, growth factors
define the tumour microenvironment
defined as all the non-transformed elements residing within or in the vicinity of the tumour
Cancer cells, immune cells, CAFs, vasculature, extracellular matrix, growth factors
what does the tumour microenvironment provide the tumour?
soluble factors, ECM degrading enzymes, angiogneic factors, oxygen etc
what is the stroma?
– all the elements in the host that support the tissue
* cell types and ECM that support the function of any particular organ
* fibroblasts, adipocytes, macrophages, pericytes
* provide growth factors, cytokines, and extracellular matrix components
* Not cancerous themselves, but support tumour growth, influence therapeutic intervention, modulate gene expression
what is the tumour stroma?
Stroma becomes reactive during cancer, like a wound, wards off the danger. Host cell types infiltrate the area and try to limit damage from the rest of the body
* during cancer → stroma becomes ‘reactive’ or ‘activated’
* consists of the non-malignant cells of the tumour and extracellular matrix
* may act as a physical barrier preventing spread of tumour or therapeutic intervention
* Or may facilitate metastasis by providing growth factors, secreting ECM, or degrading ECM
what factors in the tumour microenvironment influence cell motility/metastasis?
- Hypoxia and ROS
- Cancer associated macrophages
- Cancer associated fibroblasts
- endothelial precursor cells
- ECM stiffness
- Acidity
what are the types of ECM components?
- fibrous structural proteins (collagen types, elastins)
- Protein-polysaccharide complexes to embed and regulate structural proteins (proteoglycans – decorin, biglycan, lumican) * contain glycosaminoglycan (GAG) polysaccharides
- Adhesive glycoproteins (fibronectin, laminin, tenascin) – attach to cell surface integrin receptors
what are the types of ECM rich environment present within tissues?
Basement membrane (basal lamina)
Interstitial matrix (between cells)
what are the features of the basement membrane?
- more compact and less porous
- underlying epithelial & endothelial cells, acts as barrier
- type IV collagen, laminin, fibronectin
- supports the epithelial monolayer
what are the features of the interstitial matrix?
- highly charged, hydrated, and provides tensile strength to tissues
- fibrillar collagen (type I), proteoglycans, fibronectin, tenascin-C
- connective tissue layer, contains vessel immune cells
rich in proteoglycans, brings the charge
what are the features of the interstitial matrix?
- highly charged, hydrated, and provides tensile strength to tissues
- fibrillar collagen (type I), proteoglycans, fibronectin, tenascin-C
- connective tissue layer, contains vessel immune cells
rich in proteoglycans, brings the charge
what is desmoplasia?
(desmoplastic response)
- Secondary to the formation of the cancer
- Forms around tumour and consists of cancer-associated fibroblasts
- Usually associated with malignant tumours (poor prognosis)
- Growth of hard, fibrous tissue - rich in collagen and other types of extracellular matrix as well as fibroblast cell types
what are the functions of ECM in cancer?
- barrier function can limit spread or can influence access to therapy
- can provide achorage, which can promote proliferation and cell survival
- provide functional ECM fragments (after degradation can signal)
- signal reservoir
- co receptor activating signals
- function as receptor and signal presenter
- tracks for migration
- biomechanical force
what is the transformation event that causes collagen remodelling/ ECM rigitity (in mammary gland)
loss of epithelial polarity and disruption of gland morphology
collagen realigment from wavey organisation to parallel filaments
what is the transformation event that causes collagen remodelling/ ECM rigitity (in mammary gland)
loss of epithelial polarity and disruption of gland morphology
collagen realigment from wavey organisation to parallel filaments
Increase in ECM tension and focal adhesion formation signals to what oncogene?
INcreasing ECM tension leads to an increase in focal adhesions which activates mroe focal adhesion kinase to signal to oncogene Akt contributing to tumour cell survival/ proliferation and cell migration and invasion
what signalling cascade and protein activation happens when focal adhesion kinase activates Akt?
akt is a protooncoprotein
akt inhibits apoptosis by binding to bax. (preventing it from making holes in the membrane)
akt activate protein synthesis - activates mTOR via Rheb to interact and activate with S6K which binds to large ribosome subunit to activate translation of mrna to protein.
may lower concentration of FOXO ( a substrate of ubiquitin ligase) by ubiquitinating it causing degredation by the proteosome - in this was akt prevent FOXO ( atumour suppressor gene) from inhibiting proliferation
as cancer progresses what three stages of ECM/collagen does it go through
Normal ECM (TACS-1) wavy collagen
Predisposed (TACS-2) prealigned collagen
Desmoplastic ECM (TACS-3) aligned collagen
TACS - tumour associated collagen signature
what changes are induced by the hypoxic tumour core
Hypoxic core causes upregulation of hypoxia inducible factor 1a (HIF1a)
which causes overexpression of plasma membrane receptor (eg Met receptor) or angiogenic factors (VEGF) - increasing sensitivity to growth factors such as HGF (ligand for MetR)
leading to ECM degradation, dissociation from tumout (EMT), seek O2 rich regions (chemotaxis) and blood vessel formation
what happens when the hypoxic tumour core upregulates hypoxia inducible factor 1 alpha?
HIF1a accumulates in the nucleus and activates transcription by binding to Hypoxia Response Elements
HIF1a regulates Lysyl oxidase (LOX). Upregulation in hypoxic conditions causes moxidation of peptidyl-lysine residues resulting in reaactive aldehydes, leading to inter and intramolecular covalent crosslinks on collagen and elastin promoting ECM stiffening and tumour invasion
ECM stiffening results in increased integrin signalling and focal adhesion formation, enhanced P13 kinase anctivity and increased cell invasion
whats the state of Hif1a in normal conditions
Hypoxia inducible factor 1 alpha
in normal condition HIF1a is kept at low levels as it is hydroxylated and ubiquitylated by VHL targetting it for degredation by the proteosome
it is regulated by intracellular oxygen levels -> as levels of oxygen decrease, Hif1a is not degraded by the proteosome and accumulates in the cell
what does LOX do under hypoxic conditions?
Oxidises peptidyl lysin residues
resulting in reactive aldehydes
leading to inter and intra molecular covalent crosslinks between colagen fibres and other ECM molecules (elastin)
promoting ECm stiffening and tumour invasion
what is the ‘warburg’ effect?
- First described by Otto Heinrich Warburg in 1924
- It was observed that cancer cells produce energy by a high rate of glycolysis
- Production of lactic acid by tumour cells due to anaerobic glycolysis rather than oxidative phosphorylation for energy production – cancer cells rely on glycolysis even if oxygen is available
- High lactate leads to a high proton concentration → therefore an acidic environment
what type of cancer imaging is based on cancer cell metabolic activity?
Positron emission tomography (PET) with 2-deoxy-2-[fluorine-18]fluoro-D-glucose (18F-FDG)
– measures gamma radiation from radioactive isotope (an analog of glucose, taken up by the cell but cant be metabolise along the whole pathway)
* Exploits cancer cells increased glucose uptake and glycolytic activity
what are 3 benefits of Positron emission tomography with 2-deoxy-2–[fluorine-18]fluoro-D-glucose (18F-FDG) ?
- Observes metabolic abnormalities before phenotypic changes
- Sensitive technique
- Can be used to monitor patient’s response to chemotherapy based on metabolic activity (responders and non-responders) - before any reduction in tumour size occurs (faster identification of progress)
what contributes to the acidic external pH of solid tumours?
increased metabolism of glucose as well as poor fluid and gas exchange
whaat does the acidic microenvironment activate/induce
- Activates stress pathways (Reactive oxygen species), inflammatory response – inducing chromosomal instability
- stimulates the secretion of lysosomal proteases (cysteine cathepsins) and active collagenases (matrix metalloproteinases)
whaat does the acidic microenvironment activate/induce
3
- Activates stress pathways (Reactive oxygen species), inflammatory response – inducing chromosomal instability
- stimulates the secretion of lysosomal proteases (cysteine cathepsins) and active collagenases (matrix metalloproteinases)
- can influence TGFbeta1 activity - increase activity of signalling wihtin the cells
what is the external and internal pH in acute acidosis
breast duct
external pH ~6.8
internal pH ~ 7.4
what are the external and internal pH in normal breast duct?
physiolgical pH
external ~ pH7.4
internal ~pH7.2
what are the external and internal pH in chronic acidosis?
invasive stages
external pH ~6.7
internal pH ~7.2
how are cancer associated fibroblasts different from normal fibroblasts
- are activated by tumour derived growth factors (TGFb1, PDGF, bFGF) or from EMT
- increased proliferation rate, enhanced ECM production - enhanced tumourigenesis
- express high levels of alpha smooth muscle actin, fibroblast specific protein 1, extracellular matrix (periostin, tenascin-C), fibroblast activation protein FAP
- secrete growth factors - promoting paracrine signalling
give an example of a growth factor secreted by cancer associated fibroblasts
Stroma derived factor 1 (SDF-1a)/CXCL12 interacts with CXCR4 (receptor) on tumour cells and promotes cell migration
what components are present at the tumour invasive front
CAFs and ECM
CAFs sit at edge of the tumour and help spread towards to vasculature
what 2 ways can SDF-1 signalling be activated
an autocrine signalling loop with itself
TGFbeta1 signalling
what are the downstream affects of SDF-1 paracrine signalling (binding with CXCR4)
activation of ERK1/2, P13K/Akt, PLCgamma all contributing to cell proliferation/surival and cell motility
the autocrine and paracrine signalling of SDF-1 contribute to which two parts of tumourigenesis
autocrine signalling loop - drives differentiation /activation of fibroblasts
paracrine signalling contributes to tumour progression
the autocrine and paracrine signalling of SDF-1 contribute to which two parts of tumourigenesis
autocrine signalling loop - drives differentiation /activation of fibroblasts
paracrine signalling contributes to tumour progression
what are the roles of cancer associated fibroblasts in tumours?
- Tumour angiogenesis - via release of growth factors and recruiting endothelial presursor cells
- extracellular matrix remodelling ( + exposure of cryptic binding sites allowing alternative interactions) promoting cancer cell migration
- extracellular matrix stiffening via modulation of intracellular adhesion and cell contractility - disrupts tissue organisation and promotes cell migration
- tumour related inflammation via recruitment and modulation of immune cells - pro-inflammatory signalling, inhibition of natural killer cell and CD8+ ,cytotoxic T lymphocyte function
how does the tumour storma influence cancer therapy?
- Ligands derived from activated fibroblasts may signal to receptor (e.g. receptor tyrosine kinases) on tumour cells (paracrine signalling) – leading to therapeutic resistance (e.g. pro-survival signalling)
- Impaired drug delivery – * Density of the tumour stroma * Lack of vasculature * inefficient blood flow
o Release of pro-inflammatory cytokines, such as TNFa, may also promote survival and resistance to chemotherapy
