world cancer report - iarc

laminin, entactin and also heparan sulfate
proteoglycans. Interactions of tumour
cells with the basement membrane have
been considered to comprise three steps,
which can readily be demonstrated in
vitro: adhesion, matrix dissolution/proteolysis
and migration [6].
Epithelial cells are normally polarized and
firmly attached to each other via desmosomes,
tight junctions and intercellular
adhesion molecules such as E-cadherin,
and also bound to the basement membrane
via other adhesion molecules
including integrins. Changes in cell-cell
and cell-matrix adhesive interactions are
common in invasive cancer (Cell-cell communication,
p109). Indeed, E-cadherin
may be designated a tumour suppressor
gene, since its loss or functional inactivation
is one of the most common characteristics
of metastatic cancer, and its reintroduction
into cells can reverse the
malignant phenotype. The adenomatous
polyposis coli gene (APC), which is mutated
in many inherited and sporadic colon
cancers, normally regulates the expression
of β-catenin, a protein which interacts
with E-cadherin. Mutations in APC
(or β-catenin) increase cellular levels of
the latter and facilitate interactions with
transcription factors such as T-cell factor/lymphoid
enhancer factor (TCF/LEF)
which drive the expression of genes
involved in inhibiting apoptosis and stimulating
cell proliferation. Other genes
commonly lost in cancers (e.g. DCC,
Deleted in Colon Carcinoma) also encode
adhesion molecules.
Integrins
Integrins are heterodimeric proteins that
mediate adhesion between cells and the
extracellular matrix or other cellular elements.
Ligand specificity is determined by
the subunit composition; many integrins
bind multiple substrates and others are
more selective. Far from being an inert
“glue”, they are capable of transmitting
important signals regulating cell survival,
differentiation and migration [7]. Many differences
in integrin expression between
benign and malignant cells have been documented,
but the patterns are complex. In
addition, their expression and binding
affinity can be profoundly influenced by
the local microenvironment and soluble
factors, enabling the tumour cell to
respond to different conditions encountered
throughout the metastatic cascade.
Other molecules involved in adhesion
Other adhesion molecules implicated in
cancer progression include selectins such
as sialyl Le x and members of the
immunoglobulin superfamily, including
intercellular adhesion molecules (ICAM-1,
ICAM-2, VECAM and PECAM). The latter
are upregulated on activated endothelial
cells, and can interact with integrins on
leukocytes and circulating tumour cells,
assisting their arrest and extravasation.
CD44 is another adhesion molecule uti-
lized during lymphocyte “homing”, and a
change from the standard “epithelial” pattern
to expression of splice variants associated
with haematopoietic cells has
been proposed to assist carcinoma cells
in haematogenous dissemination. Thrombospondin
may mediate adhesion between
circulating tumour cells, platelets
and endothelial cells, promoting embolization
(vessel obstruction) and arrest.
Tumour cells then gain access to the subendothelial
basement membrane when
endothelial cells retract in response to
these emboli, and can adhere to exposed
proteins. Synthetic peptides containing
sequences of amino acids which compete
with binding to laminin or fibronectin can
inhibit colonization of the lung by intra-
Fig. 3.44 MRI scan showing skeletal metastases in a patient with a primary prostatic carcinoma (front
and back views). Some of the larger metastases are marked by arrows. Note the numerous metastases
in the ribs and in the spine.
Invasion and metastasis 121