Oncology - Angiogenesis Flashcards
What is angiogenesis?
Angiogenesis is the formation of new blood vessels from existing ones.
Why is angiogenesis important in cancer?
Angiogenesis is crucial for tumor growth because it provides oxygen and nutrients to the tumor mass. Without angiogenesis, tumors remain avascular and slow-growing. It also plays a role in the spread of cancer (metastasis).
How is tumor growth affected by angiogenesis?
Before angiogenesis, tumors exist as avascular masses, limiting their growth. Angiogenesis allows blood vessels to infiltrate the tumor, leading to exponential growth. Tumors can be graded by their microvessel count (MVC), and higher MVC correlates with poorer survival rates.
How are endothelial cells implicated in cancer?
-Endothelial cells lay behind the blood vessels
-These cell have a high potential for cell division is tightly controlled - when blood vessels get damaged we need to repair them quickly so rapid division and are tightly controlled lots factors to control this. Cancer can form from endothelial cells as well as angiogenesis due to the quick cell division
-There are direct and indirect angiogenic factors
-There are also potent angiogenic inhibitors
What are some direct angiogenic factor, what do they do and what happens if we inhibit them?
- VEGF – vascular endothelial growth factor – permeability - essential for blood vessel growth, if we target this we can stop angiogenesis
- FGF – fibroblast growth factor (acidic and basic) – proliferation and differentiation endothelial cells
- PD-EGF – platelet-derived endothelial-cell growth factor – recruits smooth muscle cells
-These bind to tyrosine kinase receptors
What are some in-direct angiogenic factor, what do they do and what happens if we inhibit them?
Things that don’t directly act on endothelial cells, outside the body important in the remodeling of the tissue of the blood vessel that needs to grow
- EGF – epidermal growth factor
- TGF-alpha and beta - transforming growth factor – extracellular matrix
- TNF-alpha – tumor necrosis factor
- Prostaglandins and HETE
How do inhibitors of angiogenesis work?
- Stop endothelial cell division angiostatin, endostatin, retinoic acid
- Tissue inhibitors of metalloproteinases TIMP-1 +2, they act on direct factors such as stopping cell division or act indirect things like remodeling of extracellular matrix weakening the tissue
What are the steps involved in the angiogenic process?
The angiogenic process involves signals for new blood vessel formation by tumor as it becomes hypoxic, poor blood vessels formed and local capillaries form matrix metalloproteinases breaking down the extracellular matrix which allows formation of blood vessels results in exponential growth of tumor. endothelial cell proliferation, vascularization of the tumor, and eventual metastasis through leaky blood vessels
How can we target the angiogenesis process?
Notch1 and VEGRF2 extracellular signals unique to progenitor cells, potential selective target therapy. MMPs (inhibit) and TIMPs (induce) can also be targeted
How does metastasis occur?
Metastasis involves tumor cells leaving the primary site, invading local tissue with the help of MMPs, entering circulation, extravasating into target organ tissue, and proliferating to form secondary colonies. However there are other things going on as well e.g., hypoxic state results infmmation also clears up mess in extracellular matrix
What are the 3 main classes of anti-angiogenic drugs?
- Blocking growth factors – e.g., bevacizumab (Avastin)
- Block intracellular signalling – tyrosine kinase inhibitors e.g., sunitinib (Sutent), IFN-alpha
- Block intercellular signalling e.g., thalidomide.
- Other targets include basement membrane degradation (MMP inhibitors), migration inhibitors (endostatin) and immune stimulators (CMC101)
AVASTIN also used in wet-ARMD due to vascularization of eye
Where can anti-angiogenic drugs target?
Anti-angiogenic drugs can target signaling molecules, gene transcription, and microRNAs involved in angiogenesis.
What are examples of drugs that inhibit angiogenesis directly?
Examples include SU11248 (Sunitinib), angiostatin, endostatin, and Avastin (bevacizumab).
How does Avastin work?
Binds to VEGF, it sequesters VEGF in out blood preventing it from binding to the receptor, stopping the process of angiogenesis. It is a safe, effective and selective drug as it only binds to 1 signaling molecule.
How effective is Avastin?
Avastin’s efficacy in inhibiting vascularization can be visualized through CT scans, showing significant reduction or loss of vascularization in tumors, particularly in combination therapy with other drugs like carboplatin and Taxol.
