world cancer report - iarc

Fig. 3.45 Location of metastases at autopsy for
some common cancers, indicating that the site of
metastasis is not random.
Primary tumour Site of metastasis
Bronchial cancer Adrenal
(often bilateral)
Breast ductal Liver
carcinoma
Breast lobular Diffuse peritoneal
carcinoma seeding
Breast Bone, ovary
Lung Brain
Ocular melanoma Liver
Prostate Bone
Melanoma Brain
Table 3.6 Some sites of metastasis which are not
explicable by circulatory anatomy.
122 Mechanisms of tumour development
venously injected cells in experimental
models.
RHO
The RHO gene family of small GTPhydrolysing
proteins contains several
members known to be involved in cell
migration via regulation of actomyosinbased
cytoskeletal filament contraction
and the turnover of sites of adhesion.
Overexpression of RhoC alone in
melanoma cells is sufficent to induce a
highly metastatic phenotype [8].
Enzyme functions in invasion and
metastasis
Invasive tumour cells show increased
expression of many enzymes due to
upregulation of genes, enhanced activation
of pro-enzymes or reduced expression
of inhibitors such as tissue inhibitors
of metalloproteinases (TIMPs). In addition,
tumour cells may also induce expression
of enzymes by neighbouring host
cells and “hijack” these to potentiate
invasion.
Matrix metalloproteinases
One important group is the matrix metalloproteinases
(MMP). Different cancers
may show different patterns of expression;
for instance squamous carcinomas
frequently have high levels of gelatinase B
(MMP-9), stromelysins 1-3 (MMP-3,
MMP-10 and MMP-11, normally stromal
enzymes, but also expressed by these
carcinomas) and matrilysin (MMP-7).
Adenocarcinomas such as breast may
have increased levels of gelatinase A
(MMP-2) and colon carcinomas commonly
overexpress MMP-7. In addition, MT1-
MMP, which activates MMP-2, is often
upregulated in tumour and/or neighbouring
host tissues. The major substrate of
the gelatinases is collagen IV, a major
component of the basement membrane,
whereas the stromelysins prefer laminin,
fibronectin and proteoglycans, and can
also activate procollagenase (MMP-1),
which in turn degrades the fibrillar collagens
of the interstitial tissues. Urokinase
plasminogen activator (uPA) is also frequently
upregulated in cancer. It controls
the synthesis of plasmin, which degrades
laminin and also activates gelatinases.
Thus, upregulation of these enzymes in
cancers leads to proteolytic cascades and
potential for invasion of the basement
membrane and stroma.
Metalloproteinases also contribute to
tumour growth and metastasis by other
means [9]. During angiogenesis, “invasion”
of capillary sprouts requires local
proteolysis (mediated in part by upregulated
MMP-2 and MMP-9 together with
uPA) and in addition MMP-9 has been
implicated in the “angiogenic switch” by
releasing VEGF from sequestration in the
extracellular matrix [10]. Furthermore,
these proteases can contribute to the
sustained growth of tumours by the
ectodomain cleavage of membranebound
pro-forms of growth factors, and
the release of peptides which are mitogenic
and chemotactic for tumour cells.
Heparanase
Apart from the structural proteins cleaved
by metalloproteinases in the basement
membrane and extracellular matrix, the
other major components are glycosaminoglycans,
predominantly heparan
sulfate proteoglycan (HSPG). Heparanase
is an important enzyme which degrades
the heparan sulfate side-chains of HSPGs
and, like the proteases described above,
not only assists in the breakdown of extracellular
matrix and basement membrane,
but is also involved in the regulation of
growth factor and cytokine activity. Basic
fibroblast growth factor (bFGF, another
potent mitogen and chemotactic factor
for endothelial cells) and other heparinbinding
growth factors are sequestered by
heparan sulfate, providing a localized
depot available for release by heparanase.
Similarly, uPA and tissue plasminogen
activator (tPA) can be released from
heparan sulfate by heparanase, further
potentiating proteolytic and mitogenic
cascades.
Tissue-specific growth factors
Finally, it is possible that release of tissuespecific
growth factors may play a role in
organ selectivity of metastasis. For example,
colorectal carcinoma cells overexpressing
EGFR have a predilection for