world cancer report - iarc

Target Example of agent Comments
Adhesion/attachment RGD-toxin constructs and RGD-targeted Have not reached clinical trials
gene therapy
Table 3.7 Therapeutic agents directed towards stroma-tumour interactions.
growth in the liver where there are high
concentrations of its ligands. All of these
require proteolytic cleavage for activation.
Other enzymes which have been implicated
in metastasis include the cysteine proteinases,
notably cathepsins B and D. For
most of the enzymes described, there are
active research programmes seeking
selective inhibitors (some of which have
reached phase II and III clinical trials) to
prevent or treat metastatic disease.
Motility, coupled with proteolysis, is the
basis of tumour cell invasion, and is also
important during intravasation and
extravasation of blood and lymphatic vessels.
Many motility factors have been
described which may be tumour- or hostderived.
Many growth factors, such as
Anti-avfl3 monoclonal antibody Cytostasis in patients; anti-tumour and
(Vitaxin, Medi522) anti-angiogenic in animal models
Proteolysis Matrix metalloproteinase inhibitors Cytostatic in patients; rare occurence of
tumour partial regressions; stromal fibrosis;
activity seen in multiple animal models and
in combination with chemotherapy; new agents
with varied MMP specificity under development
Motility No selective agents
Signal pathways Squalamine (NHE-3 inhibitor) Selective for endothelial cells
PDGFR, KDR and EGFR small molecule Active in vitro in animal models; preclinical
inhibitors activity in combinations; phase I trials
completed for several agents, some tumour
stabilization or regression
Anti-EGFR monoclonal antibody Neutralizing antibody; active in vitro in
(C225) animal models; phase I trials ongoing
Anti-VEGF antibody Blocking antibody; active in vitro in animal
models; preclinical activity alone and in
combination; phase I-III trials ongoing
CAI (non-voltage-gated Ca ++ uptake Active in vitro in animal models; preclinical
inhibitor) activity in combinations; phase I trials of single
agents and combinations, some tumour
stabilization or regression
Extracellular matrix Pirfenidone Suppresses stromal/inflammatory cell
Remodelling by stromal expression of TGF-β
Phase I trials for pulmonary fibrosis
transforming growth factor alpha, epidermal
growth factor and platelet-derived
growth factor, can induce chemotactic
responses in tumour cells expressing the
cognate receptors. Scatter factor (also
known as hepatocyte growth factor, HGF)
is a potent host-derived motility factor,
and tumour cells themselves secrete a
variety of autocrine motility factors including
autotaxin and neuroleukin/phosphohexose
isomerase.
Organ preference of metastases
The organ distribution of metastases
depends on the type and location of the
primary tumour, with 50-60% of the secondary
sites being dictated by the
anatomical route followed by the dissemi-
nating cells. Most metastases occur in
the first capillary bed or lymph node
encountered. The number of involved
nodes is a key prognostic factor for many
cancers, and this has led to efforts to
identify “sentinel” lymph nodes in order
to improve predictions of cancer spread.
Lymphatic channels present less of a
challenge to tumour cell entry than capillaries
since they have scanty basement
membrane. Once in the lymphatics,
tumour cells are carried to the subcapsular
sinus of draining nodes, where they
may arrest and grow, succumb to host
defences, or leave the node via the efferent
lymphatics. The propensity for a
tumour cell to generate a lymphatic
metastasis may depend upon its ability to
Invasion and metastasis 123