Metastasis

Angiogenesis and Metastasis

I R Hart Institute of Cancer k.goodey@qmul.ac.uk
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

1. Primary tumours (10%) rarely kill, metastases do (90%) 5. 2. Primary tumour size often predicts for metastasis 3. Some tumours dont metastasize (skin SCC, brain glioblastoma) while others do, frequently (melanoma) 4. Some tumours have a propensity for specific tissue metastasis (breast, prostate - bone), while others are excluded from certain tissues - when considering blood flow as a single variable 6. Organ fibrosis is a significant risk factor for the development of aggressive cancers (hepatic cirrhosis, lung fibrosis) Micrometastases present at diagnosis - breast, colon - worse outcomes

Differences between Benign and Malignant Neoplasms

BENIGN 1.Often encapsulated 2.Well differentiated 3.Low mitotic rate 4.Noninvasive 5.Non-metastasising MALIGNANT Non encapsulated Poorly differentiated High mitotic rate Invasive Metastasising

Colonic adenoma: outgrowth rather than infiltrative

ANGIOGENESIS
for tumours to grow beyond about 2mm in 3-dimensions new blood vessels are required

Colonic carcinoma: infiltrative growth pattern

EMBRYONIC BLOOD VESSEL FORMATION

Vasculogenesis
- de novo organisation of blood vessels by in situ differentiation of mesoderm-derived endothelial cells e.g.dorsal aorta

Normal vessels
vein Capillary plexus

artery

lymphatic

Angiogenesis

- budding and branching of vessels from pre-existing vessels

Smooth muscle actin - pericytes PECAM-endothelial cells

Tumour blood vessels

The Angiogenic Switch

Balance between angiogenic stimulators and angiogenic inhibitors. Both types of peptides are contributed by tumour cells and host cells. Occurs at different times in different tumour types.
Smooth muscle actin - pericytes PECAM-endothelial cells

Angiogenic peptides

ANGIOGENESIS

Angiogenic peptides

Dissolution of basement membrane Endothelial cell migration Endothelial cell proliferation Vascular loop formation New B.M. deposition

PIGF VEGF-B VEGFR-1

VEGF-A VEGF-B

OV-VEGF VEGFR-2

VEGF-C VEGF-D

Antiangiogenic Therapy
VEGFR-3

sVEGFR-1 SS SS

NRP-1

NRP-1

P P

P P P1114L

Migration, permeability, DNA synthesis, survival

Target cells are more accessible and genetically stable than conventional cytotoxic agent targets As most adult endothelial cells are quiescent the potential for adverse effects is less May be particularly effective with other treatment modalities

angiogenesis

lymphangiogenesis

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 in vascular permeability of transplanted cancers within 6 hours which leads to vascular regression, these effects can last up to 72 hours following a single injection A4.6.1. also reduces IFP of tumour

Bevacizumab (Avastin)
Colorectal cancer Kabbinavar, 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 Med 349:427-434, 2003.

VEGFR INHIBITORS
Sorafenib ( Nexavar ) ~ VEGFR & PDGFR--Hepatocellular Carcinomas, but not reccommended by 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 and breast

LYMPHANGIOGENESIS
Are the identified lymphatics functional? How specific is LYVE-1 as a marker? How solid are the clinical data? Is there variation between tumour types?

Benign tumours are characterised 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 are characterised by:

Infiltration of malignant cells into surrounding tissues Invasion of neoplastic cells into blood and lymph vessels Spread of tumour cells to other parts of the body to establish secondary growths (metastasis)

Metastasis
secondary growth of a neoplasm at one or more locations distant from the primary site only occurs with malignant neoplasms spread may occur via
lymphatics blood vessels across mesothelial-lined cavities through cerebrospinal fluid

Metastasis: the spread of tumours

Invasion and Metastasis

Primary tumour Intravasation
detachment of tumour cells from each other attachment to extracellular matrix (ECM) via specific receptors degradation of ECM via secretion of collagenases and proteases locomotion through the ECM via secretion of motility factors vascular intravasation

Extravasation

interaction of tumour cells with host lymphocytes formation of tumour embolus adhesion to endothelium at a distant site via adhesion molecules vascular extravasation regrowth of metastatic clone

Secondary tumour

Patterns of Metastasis
carcinomas sarcomas

Epithelial Mesenchymal Transition (EMT) and Cancer Spread

via lymphatics (early) via bloodstream (late) via bloodstream (early)

lymph nodes liver & lungs lungs

bony metastasis

prostate, lung, thyroid, kidney, breast

preferential sites
bronchial carcinoma adrenal glands

Reviews 1. 2. 3. 4. J.P. Thiery and J.P. Sleeman Nature Rev. Mol. Cell Biol. 7:131-142, 2006 H. Peinado et al., Nature Rev. Cancer 7:415-428, 2007 A. Barrallo-Gimeno and M.A. Nieto. Development 132:3150-61, 2005 J.P. Thiery. Nature Rev. Cancer 2:442-54, 2002

Proteinases
Serine proteinases uPA, thrombin, Cathepsin G Cathepsin B, L. Cathepsin D Gelatinases, Collagenases

MMPs
family of related enzymes with shared domains degrade collagens and other matrix proteins Zinc dependent enzymes, work best at neutral pH

Cysteine proteinases Aspartyl proteinases Matrix metalloproteinases

generally secreted as inactive pro-enzymes all inhibited by TIMPs

Activation of pro-gelatinase A None of these trials provided positive results.

Pro-gelatinase Gelatinase A

However~ (1) Extensive homology between catalytic domains of MMPs, so none of the drugs were highly selective for specific MMPs;

pro-peptide

exposed catalytic site

(2) Entry criteria in these trials excluded patients with early stage cancer;
Taken from ~ Zucker and Cao, Cancer Biol Ther. (2009) 8: 2371! 2373.

Metastasis: the spread of tumours

(3) Unanticipated long-term drug intolerance reduced drug compliance; (4) Drug dosage based on short-term kinetic studies in healthy volunteers were not necessarily predictive of chronic therapeutic drug levels achieved in patients with cancer.

Primary tumour

Intravasation

Extravasation

Taken from ~ Zucker and Cao, Cancer Biol Ther. (2009) 8: 2371! 2373. Secondary tumour

Understanding the Biology

Might lead to effective treatments which appear to work through postulated mechanisms Might look likely to generate effective treatments but these are not as selective as thought or applied too late in the process

Suggested reading
Duffy MJ et al J Pathol. 214: 283293, 2008. Spaderna S et al Cancer Res. 68: 537-544, 2008. Eccles SA and Welch DR Lancet 369: 1742-1757, 2007. Scheel C et al Cancer Res. 67: 11476-11480, 2007.