Inducing Angiogenesis W6 Flashcards by elizabeth burtonshaw-walker

What cells make up the tumour
microenvironment?

Immune cells
- mast
- bone marrow derived (BMDC)
- macrophage
- neutrophil
- myeloid derived supessor cells (MDSC)

Stromal cells
- fibroblast
- Mesinchinal stem cells (MSC)

Epithelial cells

Vascular cells
- endothelial
- pericyte

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MDSC

Heterogenous of myeloid origin

Increase levels of ROS

Can cause mutations

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MSC

Help 2 form metastatic niche for cells to break away and metastasise to other areas

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What is angiogenesis

the formation of new blood vessels from pre-existing ones

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Why Cancer Needs Angiogenesis

Tumors can’t grow beyond ~1–2 mm³ without a blood supply.

They need oxygen and nutrients—so they trigger angiogenesis to feed themselves.

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How Tumors Induce Angiogenesis - hypoxia

Low O2

As a tumor grows, inner cells become oxygen-starved.

This triggers HIF-1α to activate

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How Tumors Induce Angiogenesis - VEGF

VEGF is the key player in stimulating nearby blood vessels to grow toward the tumor.

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How Tumors Induce Angiogenesis - other angiogenic factors

FGF

PDGF

TGF-B

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How Tumors Induce Angiogenesis - matrix breakdown

Tumor and surrounding cells produce enzymes like MMPs to degrade the extracellular matrix, making room for new vessels.

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Why is angiogenesis bad

Provides nutrients & oxygen for rapid tumor growth.

Enables metastasis: new vessels give cancer cells routes to escape and spread.

The new vessels are often abnormal—leaky, disorganized—which also helps cancer cells get into circulation.

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What is TME

Tumor microenvironment

includes all the non-cancerous components surrounding a tumor that interact with it.

They can promote or suppress tumor progression.

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Key componants of TME

Cancer cells

stromal cells

Immune cells

Endothelial cells

ECM

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VEGF

Vascular endothelial growth factor

Signalling protein

Stimulates new growth of BV (angiogenesis)

Produced by cells when they need more O2

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How VEGF works

Stimulus like hypoxia causes the cell to release VEGF

Binds to VEGF receptors on endo cells

Activates a tyrosine kinase signalling cascade

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VEGF in cancer

Tunmors use VEGF-A to trigger BV growth so they can get nutrients and O2

New vessels allow invasion and metastasis

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What is TGF-B

Transforming growth factor beta

signaling protein that controls cell growth, immune responses, and tissue repai

TGF-B in cancer (advanced)

Main role : tumor promotor

enhances tumor invasion and metastasis

Promote angiogenesis via VEGF

Drives immunosupression

Helps create TME

TGF-B in cancer (early)

Main role : tumor suppression (inhibit growth )

Inhibit cell proliferation

Promote apoptosis

What is cell proliferation

process by which cells divide and multiply, increasing the total number of cells.

What is flux

generally refers to the flow or movement of something,

TME and flux

Always in a state of flux

Cancer stem cells (CSC)

possess similar properties to tissue stem cells

they can self-renew and differentiate

more resistant to conventional treatments (e.g., chemotherapy, radiation)

CSC and tumors

CSC can form tumors when transplanted in animals but normal stem cells cannot

Role of CSC in cancer

Tumor initiation - thought to be responsible for starting and maintaining the tumor

Metastasis - CSC can detach form primary tumor and strangle in blood to colonise distant sites

Recurrence - After initial treatments, non-CSCs might die, but CSCs survive and cause tumor relapse

Why chemotherapy doesn't always work

some cells might be more resistant to chemotherapy CSC have self-renewal properties cancer cells can mutate and evolve = genetic diversity within the tumor = some cells might survive chemotherapy while others die TME can shield cancer cells from chemo Hypoxia in TME can make cancer cells less responsive to chemo

How to get a CSC

Arise from normal stem cells or differentiates cells that have acquired genetic mutations to give them stem like properties

Targeting CSC

1. express certain cell surface markers that distinguish them ie CD44 Approach : Development of antibodies that specifically bind to these markers 2. They rely on specific signaling pathways for self-renewal etc Approach : Inhibiting these pathways could reduce CSC survival and proliferation. 3. The CSC niche provides them with support and protection. Approach : Targeting the niche can help disrupt the CSCs' survival and make them more vulnerable to treatment.

What else should we consider in the tumour microenvironment?

The oxygen concentration

Hypoxia and Normoxia in the TME

hypoxia (low oxygen) - due to rapid proliferation • Increased genetic instability • Poor immune response • Influence ECM Remodeling/Stiffness • HIF1-alpha expression results in altered angiogenesis • Less susceptibility to chemotherapy and radiation therapy Hypoxic tumors often have abnormal blood vessels that are tortuous, leaky, and inefficient in oxygen delivery. normoxia (normal oxygen levels) • Near blood vessel • Low HIF-1alpha expression • More susceptible to chemotherapy and radiation therapy

Apoptosis vs necrosis

Apoptosis: Programmed Cell Death Necrosis: Uncontrolled Cell Death

If cells are constantly exposed to an hypoxic environment….

Eventually get a mutation in ie P53

Growth of a tumor steps (3)

1. Normal BV, starting to be a small tumor, hasn’t started to invade 2. Tumor grows, new BV form 3. BV very invasive, metastasis

What is new BV formation called

Neoangiogenesis

Why is the angiogenic switch is necessary for tumour growth and metastasis

enabling them to grow beyond a small size and metastasize to other parts of the body. This switch refers to the transition from an avascular (no blood vessels) state to a vascularized state, where the tumor begins to form its own blood vessels to support its increased nutritional and oxygen demands.

How is angiogenesis induced - Key triggers

Hypoxia - As tumors grow, they can outgrow their blood supply, leading to areas of low oxygen VEGF - primary angiogenic factor responsible for inducing the formation of new blood vessels. Role of HIFs - key regulators in the response to low oxygen. HIF-1α, in particular, is a transcription factor that activates the transcription of multiple genes involved in angiogenesis.

Blood vessel organisation in normal versus tumour

Normal: - Well defined structure - proper vascular maturation - regulated blood flow - angiogenesis as a normal process Tumor : - disorganised structure - leaky and permeable - lack or pericyte coverage - impaired blood flow