3.3 Angiogenesis and Contrast Agents

What are the components of a tumor’s microenvironment

extracellular matrix, fibroblasts, pericytes, innate immune cells, adaptive immune cells

what does the extracellular matrix determine

the arrangement of cells in tissues

what is the extracellular matrix compared to

scaffolding/skeleton

what type of ECM are epithelial tissues anchored by

basement membrane

when is a tumor considered invasive

when it breaks through the basement membrane

What are matrix metalloproteinases (MMPs)

ECM remodeling enzymes

What is the most common cell of connective tissue in mammals?

fibroblasts

what do fibroblasts do?

produce & arrange ECM, coordinate growth of other cells through growth factors, influence immune cell recruitment and activity, motile cells that move towards sites of injury

in some cancers there might be more ____ than cancer cells

fibroblasts

fibroblasts can help mediate what transition

epithelial to mesenchymal

What are the two general types of immunee cells

innate & adaptive

give some types of innate immune cells

macrophages, dendritic cells, natural killer cells

give one type of adaptive immune cell

T-cells

During ultrasound, what can a doppler shift be used to measure

blood velocity

in a doppler ultrasound, what can color show

direction information

Describe single photon emission computed tomography (SPECT)

older and can use same cameras as x-rays

describe positron emission tomography (PET)

requires detection of two photon

Where do SPECT and PET emit radiation from

within the body

What is the half life of SPECT radioisotope

6 hours

What is the half live of PET radioisotope

1.8 hours

what is a tracer in nuclear medicine

a contrast agent that emits a specific type of radiation which our machine is designed to detect

What do tracers target

specific biological functions

what is perfusion

blood flow + permeability

cancer angiogenesis is required for tumors larger than __

2 mm

what kind of cells form the new branch of vessels in cancer angiogenesis

endothelial

what kind of contrast agents are essential in cancer diagnosis

blood pool

How are blood pool agents delivered to the bloodstream

lesion

in what areas will blood pool agents concentrate

areas of high blood volume

How is delivery of blood pool agents controlled?

by how much blood is reaching target (blood flow) and diffusion out of the capillary (permeability)

Blood pool agents will only exit vasculature if vasculature is “____”

leaky

What are contrast agents

small molecules designed to increase contrast in the image, commonly injected intravenously (except for CT agents used to image gastrointestinal tract)

For CT contrast agents, what is the signal based on?

attenuation of X-rays and scales with Z3 (electron density)

CT contrast agents have a ___ atomic number than tissue

higher

What causes CT contrast enhancement

attenuation of x-rays caused by the contrast agent

What are two commonly used CT/X-ray contrast media?

barium sulfate (oral, rectal), iodine-based (IV, oral)

What type of agents are being phased out as CT hardware improves?

luminal

When did iodinated contrast agents start being used?

1950s

what is a drawback of ionic (carboxylic acids)

higher osmolarity and more side effects

describe non—ionic

newer, more expensive, safer

how are iodinated contrast agents most commonly delivered

intravenously

Degree of contrast enhancement is dependent on ___

time

what kind of modeling can be used to estimate delivery?

pharmacokinetic

what is multi-phase CT imaging useful for?

evaluating contrast wash-in and wash-out (blood kinetics of tumor)

What is the signal based on for MRI contrast agents

magnetic characteristics/properties of hydrogen (primarily in the form of water/fat)

What do MRI contrast agents manipulate?

the magnetic environment of nearby hydrogen nuclei

Unlike CT, ___ does not detect the contrast agent directly

MRI

What are two commonly used MRI contrast media

Gadolinium (paramagnetic), iron (ferromagnetic)

What does Gadoliniium do?

makes T1 images brighter

What does iron do as an MRI contrast agent?

makes T2 images darker

what is gadolinium?

a toxic metal in the lanthanide family that must be chelated to be safely administered

What is the drawback of gadolinium

can cause renal toxicity in patients with poor kidney function, may persist in brain for years (linear chelates)

what are the two types of chelates

linear or cyclical

TF2/FLAIR cannot distinguish tumor from ___

surrounding edema/swelling

Why is the blood-brain barrier a big challenge in the brain

it is impermeable

low-grade ____ do not typically take up contrast

gliomas

what is acute hypoxia (perfusion limited hypoxia)

temporary occlusion (blockage) of a blood vessel decreases the supply of oxygen to nearby cells

What is chronic hypoxia (diffusion limited hypoxia)

reduced oxygen levels for extended periods of time

what is the median oxygen concentration in normal tissues

40-60 mm of HG

what percentage of solid tumors have oxygen concentrations in the normal range?

<10%

half of all solid tumors have a median oxygen concentration less than __ mm of Hg

10

Regions of a tumor with less than __ mm of Hg are often termed the “hypoxic fraction”

5

What is bad about the hypoxic regions of a tumor?

they tend to be resistant to treatment

describe enhanced permeability and retention (EPR)

new blood vessels are leaky bc of incomplete walls, not much venous or lymphatic drainage, larger molecules end up being trapped inside tumor

What do EPR-targeted therapies do?

increased blood circulation time (less injections), reduces cardiac side-effects

new tumor blood vessels do not provide accurate and adequate _____

exchange

increased permeability with low ___ ___ lead to accumulation of fluid in the tumor mass

venous clearance

Increased fluid in tumors means an increase in ____ _____

interstitial pressure

What is the effect of high interstitial pressure in a tumor on drugs?

drugs get stuck inside the blood vessels and cannot diffuse deep into tumor mass

what kind of procedure can relieve the pressure gradient in tumor with high interstitial pressure?

debulking surgery

what is the primary signaling pathway that leads to angiogenesis in tumors (and in most normal tissues)

vascular endothelial growth factor (VEGF)

what secretes VEGF?

fibroblasts and/or tumor cells

where are the primary target for VEGF receptor expressed?

endothelial cells

what two things need to be in balance for stability of new blood vessels

pro-angiogenic and anti-angiogenic

what is the theory behind targeting angiogenesis

no angiogenesis = no blood supply to tumor = tumor should starve

explain the vasculature normalization hypothesis

normalization of the vasculature should improve radiotherapy and
chemotherapy
• Increase oxygen delivery by fixing acute hypoxia
• Increase delivery-efficiency of chemotherapie