L. Benjamin & E. Keshet

New blood vessel formation(revascularisation/angiogenesis)

• blood vessel structure (varies between tissues)

• Cellular mechanisms (capillary sprouting)

• Angiogenic factors (VEGF, FGF)

• Anti-angiogenic drugs• Applications (disease, tumours, regeneration)

New blood vessel formation(revascularisation/angiogenesis)

Blood vessel structure • Focus on capillaries:

–structure varies between tissues

• Endothelial cells• Pericytes • Smooth muscle cells

Cleaver 6 Melton, 2003

Blood brain barrier

Lymph nodes

CNS

High endothelial venules

Kidney glomeruli

Gastrointestinal tract

fenestrae

fenestrae

liver Large gaps

spleen Splenic sinus of red pulp

Phenotypes of differentiated endothelial cells

Ross & Rommel(1995) HISTOLOGY

Ross & Rommel(1995) HISTOLOGY

BLOOD

Leukocytes crossing between junctionsDejana E (2006) The transcellular railway: insights into leukocyte diapedesis

Nature 8:105-107

BLOOD

Leukocytes penetrating the endotheliumDejana E (2006) The transcellular railway: insights into leukocyte diapedesis

Nature 8:105-107

New blood vessel formation(revascularisation/angiogenesis)

• Blood vessel structure (varies between tissues)

• Cellular mechanisms (capillary sprouting)

• Angiogenic factors (VEGF, FGF)

• Anti-angiogenic drugs• Applications (disease, tumours, exercise, regeneration)

New blood vessel formation(revascularisation/angiogenesis)

Angiogenic factors • VEGF = ONLY mitogenic for endothelial cells• FGF = mitogenic for many cell types

• Angiopoietin GFs, MMPs, Exercise

Folkman J (2007)

Capillary sprouting = angiogenesis

Folkman J (2007)

BMDC recruitment in tumors

Angiogenic factors, cytokines initiate recruitment

BMDC mobilization

Transendothelial migration

Homing of BMDCs to tumor

Amplification of hematopoietic lineages

Folkman J (2007)

New blood vessel formation(revascularisation/angiogenesis)

• Anti-angiogenic drugs

3 general mechanisms of angiogenesis inhibitors

Folkman J (2007)

Anti-angiogenic factors and Genetics

e.g. Downs syndrome – increased circulating endostatin (~10 fold higher) results in decreased tumour incidence

Extra copy of chromosome 21

= extra copy of collagen 18

endostatin is an integral part of collagen 18 (cleaved fragment)

Putting the Bite on CancerQ: Is it true that sharks don't get cancer?

A: While it is not true that sharks do not develop cancer, they do have a remarkable cancer shield. Of the thousands of fish tumors in the collections of the Smithsonian Institution, only about 15 are from elasmobranchs (The Smithsonian is an amazing place - where else can one go to see thousands of fish tumors?), and only two of these are thought to have been malignant. 

Research by Dr. Robert Langer of M.I.T. and other workers has revealed a promising anti-tumor agent obtainable in quantity from shark cartilage. Shark cartilage, it turns out, contains a compound antagonistic to the effects of angiogenin, called 'angiogenin inhibitor' - which does just what it sounds like: inhibits the formation of new blood vessels so that the proto-tumor starves or 'chokes' in its own waste products.

The Silky Shark is 'hit' hard by the shark fin and shark cartilage industries -

Clincal trials indicate that shark fin extracts are NOT effective at slowing cancers Save the sharks!

Applications of drugs to influence angiogenesis

Diseases EYE. Macular degeneration - due to increased/inappropriate blood vessels: capillaries grow into the photoreceptors = block.

Curently use VEGF antibody every 4-5 weeks to block (= foreign protein). NEW = Viral delivery of soluble VEGF Receptor into the eye Piroska Rakoczy, Lions Eye Institute, UWA

Diabetic retinopathy (Type 1) treat with laser photocoagulation

UTERUS. Endometriosis / outside the uterus (increased blood vessels = block) CANCERS. Cancer and tumour growth (requires angiogenesis = block)

Dharma, A&HB, patent on anti-angiogenic factors

Tissue regeneration (requires angiogenesis = increase)

How deliver drugs specifically to target? Recombinant virus?

Angiogenesis = growth of blood vessel sprouts from capillary blood vessels

Depends on angiogenic factors and their inhibitors

Angiogenesis is required for • growth of many normal tissues– bone, prostate• repair of many damaged tissues• increase in adipose tissue• tumour growth

Folkman J (2007) Nature Reviews/ Drug discovery. April 6:273-286