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
