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

[email protected]

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



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.



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.



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



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



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



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.

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Angiogenesis and Metastasis 10.11 - Colour