‘Metastases’ are tumour implants discontinuous with the primary
Approximately 30% of newly diagnosed patients with solid tumours
present with metastases (1)
They are the major cause of cancer-related morbidity and mortality
Pathways of Spread (1)
(1) Seeding of the body cavities and surfaces
When a malignant neoplasm penetrates into a natural ‘open field’ eg.
(2) Lymphatic Spread
Most common pathway for the initial dissemination of carcinomas
Tends to follow the natural routes of lymphatic drainage
(3) Haematogenous Spread
Typical of sarcomas
More readily via venous (than arterial) system
Invasion & Metastasis
For tumour cells to break loose from the primary mass, enter the
blood/lymph vessels and produce a secondary growth they must
interact with the extracellular matrix (ECM) at several stages:
Breach the underlying basement membrane
Transverse the interstitial connective tissue
Penetrate the vascular basement membrane
Invasion of the ECM is an active process which involves:
Detachment of tumour cells from each other
Attachment to matrix components
Degradation of the ECM
Migration of tumour cells
Invasion & Metastasis cont.
Detachment of Tumour Cells
Normal cells are adhered to one another via transmembrane
Downregulation of E-cadherin expression in adenocarcinoma of the
Decreased ability for adherence and facilitation of detachment from the
6. Attachment of Matrix Components
Expression of integrins by tumour cells serve as receptors for ECM
Receptor-mediated attachment of tumour cells to laminin & fibronectin
Increased density of receptors = increased invasiveness
Invasion & Metastasis cont.
3. Degradation of ECM
1. Secretion of proteolytic enzymes by tumour cells
2. Induction of host cell protease synthesis (eg. type IV collagenase)
3. Cleavage of type IV collagen of the epithelial & vascular basement
6. Migration of Tumour Cells
1. Cleavage products of matrix components have growth-promoting,
angiogeneic and chemotactic activities
2. Promotion of migration of tumour cells through loosened ECM, and
through the degraded basement membrane
Lymph Node Metastasis
Motility towards lymphatic capillaries aided by lower interstitial fluid
pressures within the ECM, than in the tumour ~ ‘tide of fluid’ (2)
Having reached the lymphatic capillaries, tumour cells move along external
surface of the endothelium and invade into the lumen via interendothelial
The composition of lymphatic vessels makes it easy for fluid, particles and
cells to pass into the vessels (3)
Having gained access to the capillaries, the tumour cells embolise singly or
in clusters towards local lymph nodes
Some cells do not reach the nodes, but adhere to the lymphatic endothelium
and cause ‘in transit’ metastases (2)
Tumour cells enter the subcapsular sinus of the lymph node through the
afferent lymphatics and may either:
Invade the cortex of the node
Bypass the node via lymphpaticovenous connections
Travel directly into the efferent lymphatics and spread to further local nodes
Until recently lymphatic metastasis was believed to be a ‘passive process’ – it
has now become apparent that lymphangiogenesis can contribute actively to
tumour metastasis (4)
Studies describing lymphatic growth and development did not emerge until the
late 1990s due to a lack of defined lymphatic endothelial markers (5)
Widely established lymphatic endothelial markers include:
Vascular Endothelial Growth Factor-3 (VEGFR-3)– the first lymphangiogenic growth
Current knowledge does not yet provide a full understanding of their exact role
While the mechanisms of tumour lymphangiogenesis are not fully understood
or defined, multiple studies have established VEGF-C & -D as the main
regulator of lymphangiogenesis (6, 7, 8, 9, 10)
Over-expression of VEGF-C in animal tumour models has demonstrated strong
increases in lymphatic vessel formation and significant promotion of lymph
node metastases (7, 9).
Recently VEGF-C has also been shown to promote further metastasis from
regional to distal lymph nodes and organs (10)
It is proposed that tumour lymphangiogenesis increases the lymphatic vascular
area within or close to the tumour, and therefore increases contact between
tumour cells and the lymphatics ~ facilitating entry of malignant cells into the
lymphatic system, thereby promoting metastatic spread (5).
Colorectal cancer data is conflicting in human models, but it seems likely that
both VEGF-C/-D contribute to the disease course (5)
Anti-lymphangiogenic therapy is an important area for future research ~
assuming that restriction of lymphatic vessel growth associated with tumours
will prevent lymph node metastases
Lymph node metastases are a key event in colorectal tumour progression;
With lymph node metastases 5-year survival is reduced from 90% to 68%
VEGF-C/-D induced stimulation of VEGFR-3 represents a promising target
for anti-lymphangiogenic therapy
Blocking extracellular ligand-receptor interactions with neutralising monoclonal
antibodies to either receptors or ligands ~ demonstrated in some animal models
Soluble VEGFR-3-fc fusion protein has also been shown to inhibit
(1) Kumar, Abbas, Fausto (eds) (2005). Robbins and Coltran ~ Pathological Basis of Disease. 7th
Ed. Elsevier Saunders, Pennsylvania.
(2) Nathanson, SD. (2003). Insights into the Mechanisms of Lymph Node Metastasis. Cancer,
98; 2: 413-423.
(3) Swartz, MA. & Skobe, M. (2001). Lymphatic Function, Lymphangiogenesis, and Cancer
Metastasis. Microscopy Research and Technique, 55:92-99.
(4) Ji, RC. (2006). Lymphatic endothelial cells, tumour lymphangiogenesis and metastasis: New
insights into intratumoral and peritumoral lymphatics. Cancer Metastasis Rev, 25:
(5) Sundlisaeter, E. et al. (2007). Lymphangiogenesis in colorectal cancer – Prognostic and
therapeutic aspects. Int. J Cancer, 121: 1401-1409.
(6) Yoo, PS. et al (2007). A Novel In Vitro Model of Lymphatic Metastasis from Colorectal
Cancer. Journal of Surgical Research, ‘article in press’.
(7) Kawakami, M. et al (2005). Vascular Endothelial Growth Factor C Promotes Lymph Node
Metastasis in a Rectal Cancer Orthotopic Model. Surg Today, 35: 131-138.
(8) Akagi, K. et al (2000). Vascular endothelial growth factor C (VEGF-C) expression in human
colorectal cancer tissues. Br J Cancer, 83: 887-891.
(9) Skobe, M. et al (2001). Induction of tumour lymphangiogenesis by VEGF-C promotes breast
cancer metastasis. Nat Med, 7: 192-198.
(10) Hirakawa, S. et al (2007). VEGF-C-induced lymphangiogenesis in sentinel lymph nodes
promotes tumour metastasis to distant sites. Blood, 109: 1010-1017.