Y. Yonemura et al., A POSSIBLE ROLE OF CYTOKINES IN THE FORMATION OF PERITONEAL DISSEMINATION, International journal of oncology, 11(2), 1997, pp. 349-358
The earliest event in the formation of peritoneal dissemination is con
sidered through the process of the attachment of intraperitoneal free
cancer cells to the submesothelial basement membrane, exposed after co
ntraction of mesothelial cells. We studied the mechanisms of the contr
action of mesothelial cells using a. highly metastatic sell line (MKN-
45-P) to the peritoneum. Four hours after intraperitoneal inoculation
of MKN-45-P, mouse mesothelial cells began to contract, and submesothe
lial basement membrane was widely exposed after 24 h. The same changes
developed four hours after i.p. injection of IL-6, TNF-alpha and IL-8
, and were most prominently observed in mice treated with IL-8. Howeve
r, no significant changes were observed after treatment of HGF, EGF an
d TGF-beta. Furthermore, IL-1 alpha, IL-6, IL-8, TNF and EGF increased
the number of intercellular gaps of a human mesothelial cell monolaye
r, which was incubated on Matrigel coated dishes. Normal mesothelial c
ells form a contiguous monolayer of closely apposed polygonal cells, e
ach of which had prominent and peripheral bands of F-actin. After incu
bation with IL-1 alpha, IL-6, IL-8, TNF and EGF, peripheral actin band
s became indistinct and the central stress fibers became numerous. How
ever, no significant changes were found in mesothelial cells, which we
re treated with TGF-beta and HGF. In addition, the number of attached
MKN-45-P cells on a mesothelial cell monolayer after treatment of IL-1
alpha (0.1-1 ng/ml), IL-8 (10-100 ng/ml), and TNF-alpha (100 ng/ml) w
as significantly larger than that of control and TGF-beta significantl
y reduced the number of attached cells. Concentration of IL-8 in the s
erum-free medium of MKN-45-P cells was high (3.4 ng/ml), but IL-1 alph
a, IL-6, TNF-alpha, TGF-beta, EGF and HGF could not be detected. None
of these cytokines were detected in the conditioning medium of human m
esothelial cells. Based on these results, mesothelial cell contraction
may be mediated by IL-1 alpha, IL-6, IL-8, TNF-alpha, and EGF, and th
ese cytokines may be produced from cancer cells and/or intraperitoneal
inflammatory cells. In contrast, TGF-beta have an inhibitory effect o
n the mesothelial cell contraction and attachment of cancer cells to a
mesothelial monolayer. The attachment of free cancer cells on the per
itoneum may be controlled with these cytokines.