Angiogenesis and Metastasis 10.11 - Colour
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Transcript of Angiogenesis and Metastasis 10.11 - Colour
8/3/2019 Angiogenesis and Metastasis 10.11 - Colour
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Angiogenesis and Metastasis
I R Hart
Institute of Cancer
Metastatic Growth in the Liver
• > 90% human cancer is epithelial in origin• Metastasis accounts for 90% of cancer deaths•1 Kg metastatic burden is incompatible with life
Metastasis
1. Primary tumours (10%) rarely kill, metastases do (90%)
2. Primary tumour size often predicts for metastasis
3. Some tumours don’t metastasize (skin SCC, brainglioblastoma) while others do, frequently (melanoma)
4. Some tumours have a propensity for specific tissuemetastasis (breast, prostate - bone), while others areexcluded from certain tissues - when considering bloodflow as a single variable
5. “Micrometastases” present at diagnosis - breast,colon - worse outcomes
6. Organ fibrosis is a significant risk factor for thedevelopment of aggressive cancers (hepaticcirrhosis, lung fibrosis)
Differences between Benign andMalignant Neoplasms
BENIGN MALIGNANT
1.Often encapsulated Non encapsulated2.Well differentiated Poorly differentiated3.Low mitotic rate High mitotic rate4.Noninvasive Invasive5.Non-metastasising Metastasising
Colonic adenoma: outgrowth rather than infiltrative
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Colonic carcinoma: infiltrative growth pattern
ANGIOGENESIS
“for tumours to grow beyond about
2mm in 3-dimensions new blood
vessels are required”
EMBRYONIC BLOOD VESSELFORMATION
Vasculogenesis - de novo organisation of blood
vessels by in situ differentiation ofmesoderm-derived endothelial cellse.g.dorsal aorta
Angiogenesis - budding and branching of vesselsfrom pre-existing vessels
artery
vein
lymphatic
Smooth muscle actin - pericytes
PECAM-endothelial cells
Capillary plexus
Normal vessels
Tumour blood vessels
Smooth muscle actin - pericytes PECAM-endothelial cells
The Angiogenic Switch
• Balance between angiogenicstimulators and angiogenic inhibitors.
• Both types of peptides arecontributed by tumour cells and hostcells.
• Occurs at different times indifferent tumour types.
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Angiogenicpeptides
Angiogenicpeptides
ANGIOGENESIS
• Dissolution of basement membrane
• Endothelial cell migration
• Endothelial cell proliferation
• Vascular loop formation
• New B.M. deposition
SS SS
NRP-1 NRP-1
VEGFR-1 VEGFR-2 VEGFR-3
VEGF-A
VEGF-B
VEGF-C
VEGF-D
OV-VEGF
PIGF
VEGF-B
sVEGFR-1
P1114L
P PP PP P
Migration, permeability, DNA synthesis, survival
angiogenesis lymphangiogenesis
Antiangiogenic Therapy
• Target cells are more accessible andgenetically stable than conventionalcytotoxic agent targets
• As most adult endothelial cells arequiescent the potential for adverseeffects is less
• May be particularly effective withother treatment modalities
Bevacizumab
• Humanised mouse monoclonal Ab that neutralises
human VEGF• It is derived from A4.6.1 a mouse monoclonal Ab
against human VEGF
• In mouse injection of A4.6.1 causes decrease invascular permeability of transplanted cancers within6 hours which leads to vascular regression, theseeffects can last up to 72 hours following a singleinjection
• A4.6.1. also reduces IFP of tumour
Bevacizumab(Avastin)
Colorectal cancerKabbinavar, F et al J Clin Onc
21:60-65, 2003.
Hurwitz, H et al N Engl J Med
350:2335-2342.
Renal cancer
Yang, J C et al N Engl J Med349:427-434, 2003.
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VEGFR INHIBITORS
Sorafenib ( Nexavar ) ~ VEGFR &PDGFR--HepatocellularCarcinomas, but not reccommendedby NICE
Sunitinib ( Sutent ) ~ VEGFR &PDGFR--Renal Cell Carcinomas
LYMPHANGIOGENESIS
• VEGF-C/VEGF-D binding to VEGF-R3.• LYVE-1 as a marker of lymph vessels.• Experimentally VEGF-C has promoted
breast cancer metastasis.• Clinical correlations with metastatic
activity e.g. gastric,cervical andbreast
LYMPHANGIOGENESIS
• Are the identified lymphaticsfunctional?
• How specific is LYVE-1 as a marker?
• How solid are the clinical data?
• Is there variation between tumourtypes?
Benign tumours arecharacterised by:
• Localised• Usually grow slowly• Compress, rather than infiltrate, adjacent
tissue, often forming a capsule• Do not spread to distant sites generally do
not recur after removal• May be self limiting or regress• Have cellular structure resembling that of
the tissue of origin
Malignant tumours arecharacterised by:
• Infiltration of malignant cells intosurrounding tissues
• Invasion of neoplastic cells into bloodand lymph vessels
• Spread of tumour cells to other partsof the body to establish secondarygrowths (metastasis)
secondary growth of a neoplasm at one ormore locations distant from the primary site
through cerebrospinal fluid across mesothelial-lined cavities
only occurs with malignant neoplasms
lymphatics
spread may occur via
blood vessels
Metastasis
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Metastasis: the spread of tumours
Primary tumour
Secondary tumour
Intravasation
Extravasation
detachment of tumour cells from each other
degradation of ECM via secretion of collagenases and proteases
locomotion through the ECM via secretion of motility factors
vascular intravasation
formation of tumour embolus
attachment to extracellular matrix (ECM) via specific receptors
interaction of tumour cells with host lymphocytes
vascular extravasation
adhesion to endothelium at a distant site via adhesion molecules
regrowth of metastatic clone
Invasion and Metastasis
carcinomas via lymphatics (early) lymph nodes
sarcomas
prostate, lung, thyroid, kidney, breast
via bloodstream (early) lungs
bony metastasis
bronchial carcinoma adrenal glands
preferential sites
via bloodstream (late) liver & lungs
Patterns of MetastasisEpithelial Mesenchymal Transition (EMT)
and Cancer Spread
Reviews
1. J.P. Thiery and J.P. Sleeman Nature Rev. Mol. Cell Biol. 7:131-142, 2006
2. H. Peinado et al., Nature Rev. Cancer 7:415-428, 2007
3. A. Barrallo-Gimeno and M.A. Nieto. Development 132:3150-61, 2005
4. J.P. Thiery. Nature Rev. Cancer 2:442-54, 2002
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Proteinases
Serine proteinases uPA, thrombin,Cathepsin G
Cysteine proteinases Cathepsin B, L.
Aspartyl proteinases Cathepsin D
Matrix metalloproteinases Gelatinases, Collagenases
MMPs
• family of related enzymes with shared domains
• degrade collagens and other matrix proteins
• Zinc dependent enzymes, work best at neutral pH
• generally secreted as inactive pro-enzymes
• all inhibited by “TIMPs”
Activation of pro-gelatinase A
Pro-gelatinase Gelatinase A
pro-peptide exposedcatalytic
site
None of these trials provided positive results.
However~
(1) Extensive homology between catalyticdomains of MMPs, so none of the drugs werehighly selective for specific MMPs;
(2) Entry criteria in these trials excludedpatients with early stage cancer;
Taken from ~ Zucker and Cao, Cancer Biol Ther. (2009)8: 2371!2373.
(3) Unanticipated long-term drug intolerancereduced drug compliance;
(4) Drug dosage based on short-term kineticstudies in healthy volunteers were not
necessarily predictive of chronic therapeuticdrug levels achieved in patients with cancer.
Taken from ~ Zucker and Cao, Cancer Biol Ther. (2009) 8:2371!2373.
Metastasis: the spread of tumours
Primary tumour
Secondary tumour
Intravasation
Extravasation
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Understanding the Biology………
• Might lead to effective treatmentswhich appear to work throughpostulated mechanisms
• Might look likely to generateeffective treatments but these arenot as selective as thought or appliedtoo late in the process
Suggested reading
• Duffy MJ et al J Pathol. 214: 283-293, 2008.
• Spaderna S et al Cancer Res. 68:537-544, 2008.
• Eccles SA and Welch DR Lancet369: 1742-1757, 2007.
• Scheel C et al Cancer Res. 67:11476-11480, 2007.