L17 - TME and cell balancing tumour growth I Flashcards
Vasculature
- Blood vascular endothelial cells
- Pericytes
- Lymphatic endothelial cells
How do tumour endothelial cells differ from normal endothelial cells?
Express lower levels of adhesion molecules -impaired barrier function
Express higher levels of immune checkpoint molecules - immunosuppression
Pericytes: what are they, where are they located, what do they do, and how do they interact with tumours?
Surround blood vessels
Embedded in the basement membrane of vessels and adjacent to endothelial cells
Support the permeability and maturation of the vasculature
In tumours, impaired interaction of pericytes and endothelial cells contributes to a leaky and dysfunctional tumour vasculature
Also interact with other stromal cells and cancer cells via paracrine mechanisms
Modulation of the tumour microenvironment
Lymphatic endothelial cells
Form the walls of lymphatic vessels
Lymph ducts drain fluid between cells into venous circulation
Lymph ducts also allow antigen-presenting immune cells to access lymph nodes
A dissemination route for cancer cells in addition to blood vessels
Recently recognised as direct regulators of anti-tumour immunity
Can present tumour antigens but also immune checkpoint molecules
How far can tumours be away from vasculature while still surviving
Typicaqlly >200µm
Features of the low oxygen area between two pieces of vasculature
Anoxia:
* Low oxygen
* Low ATP
* Low Glucagon(?)
* High lactic acid
* Low pH
How do tumours still thrive in anoxic environments?
Early in tumour progression, clusters of tumour cells grow to ~0.2mm (the range that they can thrive away from vasculature)
Without vasculature, the resulting hypoxia would trigger p53-dependent apoptosis so tumour cells secrete VEGF
Though the VEGF molecules are unable to stimulate angiogenesis, eventually the cluster of tumour cells suddenly acquire the ability to induce neoangiogenesis - the angiogenic switch
Angiogenic switch
Accompanied by the release of matrix metalloproteinase 9 (MMP-9) from inflammatory cells (e.g. mast cells, macrophages) recruited to the tumour cells
MMP-9 cleaves components of the ECM, releasing VEGF for signalling to nearby cells
Intratumoural hydrostatic pressure
Often relatively high:
* Tumour-associated capillaries leak fluid into the parenchymal space of the tumour
* Expansion of cancer cell populations causes collapse of lymphatic vessels, disrupting fluid drainage within the cores of solid tumours
* PDGF released by many carcinoma cells induces contraction of stromal fibroblasts, squeezing out interstitial fluid
Complicates administration of anti-cancer drugs as they are not transferred down the pressure gradient from the circulation - drugs stay in the circulation