L17 - TME and cell balancing tumour growth I

Question 1

Vasculature

Answer 1

• Blood vascular endothelial cells
• Pericytes
• Lymphatic endothelial cells

Question 2

How do tumour endothelial cells differ from normal endothelial cells?

Answer 2

Express lower levels of adhesion molecules -impaired barrier function

Express higher levels of immune checkpoint molecules - immunosuppression

Question 3

Pericytes: what are they, where are they located, what do they do, and how do they interact with tumours?

Answer 3

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

Question 4

Lymphatic endothelial cells

Answer 4

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

Question 5

How far can tumours be away from vasculature while still surviving

Answer 5

Typicaqlly >200µm

Question 6

Features of the low oxygen area between two pieces of vasculature

Answer 6

Anoxia:
* Low oxygen
* Low ATP
* Low Glucagon(?)
* High lactic acid
* Low pH

Question 7

How do tumours still thrive in anoxic environments?

Answer 7

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

Question 8

Angiogenic switch

Answer 8

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

Question 9

Intratumoural hydrostatic pressure

Answer 9

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