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Cancer Biology
Metastasis
Dr Tim Meyer
Metastasis-case history
 65



year old woman
2 cm lump right breast
Lumpectomy and axillary lymph node
dissection
Histology
• Invasive ductal adenocarcinoma
• 2/16 lymph nodes positive

Staging investigations – no distant
metastasis
Metastasis-case history
 Treatment


3

– curative intent
Radiotherapy to right breast
Adjuvant Tamoxifen
years later complains of pain left leg
Bone scan
Metastasis-case history
 Re-staging
investigations – no visceral
disease
 Treatment



– palliative intent
Radiotherapy to left femur
Second line hormone therapy
bisphosphonate
Metastasis-Questions
 How
do tumours metastasize?
 Why
do certain tumours preferentially
home to certain sites?
 At
what stage does metastasis occur ?
How does metastasis occur ?
 Three



routes of spread
Direct seeding of body cavities or surfaces
Lymphatic
Heamatogenous
Basement Membrane
Primary Tumour
Extracellular Matrix
Basement Membrane
Adhesion to and Invasion
of Basement Membrane
Intravasation
Haematogenous
spread
Adherence to
Basement Membrane
and Extravasation
Metastasis
Molecular Changes
 Alteration
in expression of adhesion
molecules
 Expression
of proteolytic enzymes
 Expression
of growth factors
Metastasis – Adhesion molecules

Integrins

Cadherins

Selectins

Immunoglobulins
Alteration in cell adhesion-Integrins
•Cell : ECM interactions
•Cell : Cell (heterotypic)
•Trans-membrane glycoprotien
•α and β subunit
•Over 20 members
Integrins-α and β subunit pairings
Changes in integrins in cancer
 Collagen
receptors such as α2β1 down-
regulated
 α4β1
and αvβ3 up-regulated in melanoma
E-cadherin
 Epithelial
cell adhesion molecule
 Down-regulated in many human cancers
 Mutated in hereditary gastric cancer
Proteolytic Enzymes

Serine proteases
 uPA, elastase, plasmin

Matrix metalloproteinases
 Gelatinase, collagenase, stromolysin,
matrilysin

Cysteine proteases
 Cathepsin B and L
Invasion - Altered expression of proteolytic enzymes
•Cancer cell intravasates into vessels (blood or lymphatic) by digesting the basement
membrane of the blood vessel with serine and matrix metalloproteases;
MMP’s (Zn2+-dependent) proteases e.g.
Cancer cell
UrokinasePlasminogen
activator
Plasminogen
Plasmin(S)
+ve
Pro-MMP
Active MMP
-ve
TIMPs
•then “migrates” in the blood stream
Laminin
Fibronectin
Collagen
Opportunities for therapy
 Inhibition

eg Inhibition of αvβ3 integrin
 Inhibition

of adhesion
of proteolysis
eg inhibitors of MMPs
Why do certain tumours preferentially
home to certain sites?
 Anatomy
 Tropism
Anatomy

Local lymph nodes

Portal circulation


GI tumours
metastasize to the
liver
Caval circulation

Lung metastasis
But
 Millions
of cancer cells shed daily in to
circulation but < 0.1% form mets
 Rarely
get cardiac or skeletal muscle mets
from any tumour
 Metastatic
disease with ‘no primary’
Tropism – seed and soil
 Endothelial
cells on target organ may
express receptors for which tumour cells
express ligands
 Target organs may secrete chemoattractants or chemotactic molecules
 Target organs may secrete factors that
stimulate proliferation of tumour cells
Chemokines and chemokine
receptors
• Originally
discovered as leukocyte
chemoattractants
•Promote cellular transformation, tumour
growth, homing, invasion and metastasis
•CXR4 expressed by tumours and CXCL12
expressed on many tissues
Taken from: Nature Immunology, Vol 2, no. 4
When Does Metastasis Occur ?
Tumor “stem-cell”
TUMOR CELL HETEROGENEITY
Autocrine
Growth-loop
Metastatic
Non-proliferative
Growth Factor
Independent
Non-antigenic
Fidler 1977
B16 melanoma cells
Single cell clones
A molecular signature of metastasis in
primary solid tumours
Ramaswamy et al nature genetics 2003
 12

metastatic adenocarcinomas
6 sites
 64
unmatched primary
adenocarcinomas
 Microarray
expression
for differential gene
Testing of metastasis ‘signature’
 62

stage I and II lung cancers
Identified two sets using the signature and
compared outcome using hierarchical
clustering using 128 genes and a refined pool
of 17 genes.
Primary tumour black
Mets in red
 Suggests
that metastasis genes are
present in the bulk of the primary
tumour and acquired early.
 Could
explain why some tumours
metastasize early.
New model?
Metastasis
mutations
Benign
Cell cycle, survival, growth
control mutations
Metastatic
Conclusion
 Metastasis
is the cause of death in most
cancer patients
 Multi-step process

Changes in adhesion, proteolysis and growth
factor expression
 Sites
influenced by anatomy and tropism
 The evolution of the metastatic phenotype
is uncertain