Y. Yonemura et al., MECHANISMS OF THE FORMATION OF THE PERITONEAL DISSEMINATION IN GASTRIC-CANCER, International journal of oncology, 8(4), 1996, pp. 795-802
To clarify the mechanisms of the formation of peritoneal dissemination
, a new animal model by the i.p. inoculation of highly metastatic gast
ric cancer cell line MKN-45-P was developed. Peritoneal dissemination
with bloody ascites was found in 100% of nude mice, injected 1x10(7) M
KN-45-P cells in suspension into the peritoneal cavity. By a highly se
nsitive method for specific detection of metastasized human tumor cell
s in nude mice using polymerase chain reaction, a human beta-globin-re
lated sequence in the DNA from various parts of the peritoneum was spe
cifically amplified and detected by gel electrophoresis and by a speci
fic oligonucleotide probe. Greater omentum showed a strong signal of t
he amplified fragments of human beta-globin gene from the 1st day and
the signals gradually increased. The signals in the gonadal fat, mesen
tery and ovarium could be weakly detected on the Ist day, transiently
decreased on the 3rd day, and then increased from the 7th day. In the
diaphragm, and abdominal wall, signals could be detected from the 7th
day. In contrast, small intestine and colon did not show any human bet
a-globin signals. In greater omentum and gonadal fat, cancer cells wer
e selectively detected in the milky spots stained by activated carbon
on the 3rd day. In the diaphragm, cancer cells adhered to the small po
res termed stomata, and invaded into the subdiaphragmatic lymphatic la
cunae connected with stomata. From the 3rd day, mesothelial cells of t
he abdominal cavity became round and separated, resulting in the expos
ure of the underlying connective tissue. MKN-45-P cells were found to
adhere to the naked areas of the submesothelial connective tissue. Fro
m these results, we conclude that the major metastatic route of the pe
ritoneum may be firstly through milky spots, secondly through the diap
hragmatic stomata, and thirdly by the adhesion to the naked connective
tissue exposed after shrinkage of the mesothelial cells. The third pr
ocess may be related to the interaction between some adhesion molecule
s and their ligands.