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