Tumour Vasculature structure and function Flashcards
What is normal tissue composed of?
Linear blood vessel lined by smooth layer of endothelial cells with pericytes. ECM of loose network of collagen and other fibres, containing few fibroblasts and macrophages. Lymph vessels also present.
What are the components of tumor structure?
Solid tumours composed of parenchyma and stroma (vasculo-connective tissue). Stroma is not neoplastic.
How is tumor tissue characterized?
Characterised by loss of normal tissue organisation of parenchyma and stroma, with rapid proliferation of stroma leading to imperfect blood vessel architecture.
What are the characteristics of tumor blood vessels?
Blood vessels are leaky and irregularly shaped with sac-like formations, dead ends, and highly activated endothelia. They exhibit inefficient blood flow and decreased vessel stability due to few pericytes.
What happens to lymph vessels in tumors?
Lack lymph vessels leads to inefficient removal of interstitial fluid and soluble proteins.
How does the ECM differ in tumor tissue compared to normal tissue?
Tumor tissue has a denser network of collagen fibres in ECM, making it more rigid than normal tissue.
What is the tumor microenvironment like?
It is hostile, characterized by O2 depletion and nutrient/energy deprivation, with significant variation in parameters over time and between individual tumors.
What are the functions of endothelial cells in normal vasculature?
Endothelial cells provide barrier functions, cell trafficking, perfusion and permeability, blood pressure regulation, and coagulation.
What role do pericytes play in normal vasculature?
Pericytes give stability to normal vasculature but are only loosely attached in tumors, causing instability.
What are the types of capillaries?
Non-fenestrated (continuous), fenestrated, and discontinuous capillaries, differing in structure and location.
What is the process of angiogenesis?
Angiogenesis involves sprouting, bridging, and intussusception, producing daughter vessels from mother vessels.
What is the angiogenic switch in tumors?
In cancer, the angiogenic switch is not turned off, resembling a ‘wound that never heals’ and is important for tumor progression.
What are the two main sources of blood vessels in tumors?
Vessels recruited from pre-existing vasculature and new vessels formed due to angiogenic response.
How do tumor blood vessels differ from normal blood vessels?
Tumor blood vessels are leaky, immature, multilayered, and undergo constant remodelling.
What is chronic hypoxia?
Chronic hypoxia occurs due to oxygen diffusion gradients, causing cells to stop replicating and become quiescent.
What is the role of HIF in hypoxia?
HIF accumulates in hypoxic cells, binds to hypoxia response elements (HREs), and recruits transcriptional co-activators to activate target genes.
What are tumor-associated macrophages (TAMs)?
TAMs are key components of the tumor microenvironment, attracted by hypoxia and producing growth factors that induce angiogenesis.
What are the main actions of the VEGF family?
VEGF family induces angiogenesis, increases permeability, causes vasodilation, and influences immune cell maturation.
What is the significance of VEGF-A?
VEGF-A primarily affects angiogenesis and vasculogenesis, with at least six isoforms differing in function.
What are the activators of angiogenic growth factors?
Activators include acidic and basic FGFs, PDGF, TGF-a, TGF-b, TNF-a, and angiogenin.
What are some inhibitors of angiogenesis?
Inhibitors include angiostatin, endostatin, platelet-factor 4, prolactin, thrombospondin, and TIMPs.
What methods are used to investigate hypoxia?
Methods include EF5 localization, CD-31 staining, and measuring acute and chronic hypoxia using short half-life drugs.
How do hypoxic cells respond to chemotherapy?
Hypoxic cells are more resistant to chemotherapy due to acidosis and upregulation of H ion pumps.
What are therapeutic targets related to hypoxia?
Targets include hypoxia-dependent drugs, HIF stability modulation, and VEGF inhibitors like Bevacizumab.
What is important to eradicate in cancer treatment?
All hypoxic cells, as these lead to recurrence.
Higher metastatic risk.
What are hypoxia dependent drugs?
Hypoxic activated prodrugs (HAPs) that are activated in hypoxic conditions.
What is the aim regarding HIF stability in hypoxic cells?
To make HIF unstable or mimic VHL.
What is an example of a VEGF inhibitor?
Bevacizumab (Avastin).
What methods are used for studying structure?
Light and electron microscopy, injection of agents, vascular casts, radiography or angiography, intravital microscopy.
What are some agents used in the injection method for studying structure?
India ink, macromolecules, labelled RBC, colloidal carbon.
Invasive and destructive.
What are vascular casts made from?
Silicone rubber or vinyl acetate.
Invasive, disturbs system, destructive.
What are the requirements for intravital microscopy?
Animal model, molecular probe, equipped microscope, image processing and analysis algorithms.
What is the window chamber model?
An immune compromised animal has a surface layer scraped away and replaced with a glass window to view injected vessels.
How is tumour blood flow measured?
Inhalation of marked CO2 with PET, isotope clearance, thermal washout, relative distribution of cardiac output.
What is the simplified equation for blood flow rate?
Flow rate = pressure difference / resistance from vessels.
How does blood flow rate change with increasing tumour size in rodent models?
Blood flow rate decreases due to reduction in density of vascular bed.
What factors affect tissue oxygenation?
Oxygen availability and tissue respiration rate.
What causes acidosis in tumours?
Hypoxia leading to increased acidosis from high metabolic rates and inadequate transport of H+.
What are some effects of acidosis on tumour cells?
Inhibits cell proliferation, DNA synthesis, glycolysis, decreases radiosensitivity, modulates drug toxicity.
What are obstacles to treatment delivery in tumours?
Physiological barriers, heterogeneity of distribution, difficulty in transporting agents across vessel walls.
What are anti-angiogenic strategies?
Block activators of angiogenesis, matrix breakdown, receptor antagonists, signal transduction pathways, endothelial cell function.
What is the normalisation window in anti-angiogenic drugs?
A treatment window where cancer cells are more vulnerable to therapies, but prolonged use can induce resistance.
What are vascular disrupting agents (VDAs)?
Agents that exploit differences between tumour and normal endothelium to induce selective vascular dysfunction.
What effects do VDAs have on tumours?
Cause vessel congestion and occlusion, leading to massive tumour cell necrosis while leaving a viable rim.
