T. Tani et al., PANCREATIC CARCINOMAS DEPOSIT LAMININ-5, PREFERABLY ADHERE TO LAMININ-5, AND MIGRATE ON THE NEWLY DEPOSITED BASEMENT-MEMBRANE, The American journal of pathology, 151(5), 1997, pp. 1289-1302
We studied the adhesion mechanism of pancreatic carcinoma using in vit
ro adhesion and migration assays of stable cell lines and tumors grown
from these cell lines in nude mice. We also compared the results with
the expression profiles of laminins and their receptors in pancreatic
carcinomas to evaluate the relevance of these mechanisms in vivo. All
of the cell Lines preferably adhered to laminin-5, irrespective of th
eir capability to synthesize laminin-5. Cell migration was studied in
the presence of hepatocyte growth factor, as it increased the speed of
migration manyfold. Herbimycin A treatment and antibodies against the
beta(1) and alpha(3) integrin subunits and laminin alpha(3) chain alm
ost entirely blocked cell migration of the BxPC-3 cell line, whereas m
igration was nearly unaffected by RGD peptide and only moderately inhi
bited by antibody against the alpha(6) integrin subunit. Indirect immu
nofluorescence microscopy of wounded BxPC-3 cells suggested a rapid en
docytosis of alpha(3) integrin subunit in the cells at the margin of t
he wound and a rapid, polarized rearrangement of the alpha(6) beta(4)
integrin. Especially HGF-treated cultures showed a prominent cytoplasm
ic reaction for laminin-5 at the margin of the wound. Xenografted cell
s formed tumors that produced and deposited the same laminin chains as
the in vitro cultures. Frozen sections of human pancreatic carcinomas
showed reactivity for laminin chains suggestive for expression of lam
inin-1 and laminin-5. Both xenografted tumors and human pancreatic car
cinomas also showed stromal reactivity for laminin-5. Electron microsc
opy of the human tumors suggested that this was due toan abundant redu
plication the basement-membrane-like material around the nests of mali
gnant cells. Our results suggest that pancreatic carcinomas synthesize
and deposit laminin-5 in the basement membrane in an abnormal manner.
Invading cells adhere to this newly produced basement membrane and mi
grate on it by using the alpha(3) beta(1) integrin receptor recognizin
g laminin-5.