A novel nude mouse model of liver metastasis and peritoneal dissemination from the same human pancreatic cancer line.
BACKGROUND
Recently, several mice models have been used for investigating cancer metastasis. However, there are no metastatic and peritoneal dominated variants from the same parental cell line.


OBJECTIVE
To elucidate the mechanisms of metastasis, we established highly liver metastatic and peritoneal disseminated models in nude mice, and then characterized several factors related to metastasis in these cells. We established a series of well-characterized sublines that showed metastatic potentials to different organ sites of nude mice. Two sublines were selected sequentially from the parental pancreatic cancer cell line, HPC-4, resulting in a highly liver metastatic cell line, HPC-4H4, and a highly peritoneal disseminated cell line, HPC-4P4a. Using these three cell lines, we investigated several biologic properties and mRNA levels of differentially expressed genes involved in cancer metastasis.


RESULTS
The tumorigenicity, the motile activity, and the adhesive activity of metastatic sublines were higher than those of parental HPC-4 cells. Macroscopic and microscopic findings and the DNA ploidy pattern were the same among the three cell lines. In addition, HPC-4H4 cells expressed clearly higher levels of vascular endothelial growth factor and IL-8 expression than did HPC-4P4a cells. In fluorescence-activated cell sorter analysis of adhesion molecules, the expression of integrin-alpha2 was enhanced in HPC-4 cells, integrin-alphavbeta5 was enhanced in HPC-4H4 cells, and integrin-alpha3 was enhanced in HPC-4P4a cells. Osteopontin, vascular endothelial growth factor, and hepatocyte growth factor were among the genes that were upregulated in HPC-4H4 cells compared with HPC-4P4a cells. HPC-4P4a cells did not metastasize to the liver by intrasplenic injection. Conversely, HPC-4H4 cells metastasized remarkably to the peritoneum by intraabdominal injection.


CONCLUSIONS
These sublines are the first reported liver metastatic and peritoneal disseminated models derived from the same parental cell lines. The results of our study suggest that the process of hematogenous metastasis is not the same as that of peritoneal dissemination.
Nishimori
Hidefumi
H
Department of Surgery 1, Sapporo Medical University School of Medicine, Sapporo, Japan.
Yasoshima
Takahiro
T
Hata
Fumitake
F
Denno
Ryuichi
R
Yanai
Yoshiyuki
Y
Nomura
Hiroki
H
Tanaka
Hiroshi
H
Kamiguchi
Kenjiro
K
Sato
Noriyuki
N
Hirata
Koichi
K
D000818:Animals; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000235:genetics; D002465:Cell Movement; D016207:Cytokines / Q000096:biosynthesis; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D008113:Liver Neoplasms / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000556:secondary*; D011003:Ploidies; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured
D015815:Cell Adhesion Molecules; D016207:Cytokines; D004273:DNA, Neoplasm; D012333:RNA, Messenger