Involvement of liver-associated immunity in hepatic metastasis formation.
OBJECTIVE
Hepatic metastasis formation and prevention were studied from the viewpoint of liver-associated immunity.


METHODS
RCN-9, a colonic cancer cell line derived from Fischer rats, and its subclone RCN-H4, in which the cancer is highly metastatic to the liver, were used. Fischer rats that were inoculated with parent RCN-9 colonic cancer cells (5 x 10(6)) via the portal vein showed liver metastasis in less than 60% of the animals. In contrast, all rats (100%) that received RCN-H4 produced multiple liver metastases. To investigate the difference of hepatic metastasis formation, we assessed the susceptibility of both cell lines against hepatic sinusoidal lymphocytes (HSL) by 51Cr-release assay, and the expression of MHC class I and class II of both cell lines by flow cytometry. In addition, we examined whether activation of HSL by interleukin-12 (IL-12) can prevent liver metastasis of highly metastatic clone RCN-H4.


RESULTS
The RCN-H4 clone showed decreased susceptibility to lysis by natural cytotoxic cells in HSL. This decrease in cell susceptibility was attributable to an increase in cell surface expression of MHC class I antigen. Administration of IL-12, a potent NK/CTL stimulatory cytokine, augmented the cytotoxic activity against the RCN-H4 clone and prevented liver metastasis of RCN-H4 inoculated into the portal vein.


CONCLUSIONS
Liver metastasis formation is positively correlated with the strength of the hepatic immune system which mainly consists of ontogenetically primitive T cells. As these effectors exert their cytotoxicity in a MHC-nonrestricted fashion, tumor cells that highly express MHC class I antigen can readily avoid hepatic surveillance and apt to cause liver metastasis. Augmentation of the hepatic immune system, for instance, with IL-12 administration, can prevent liver metastasis even in tumor cells with a high potential for liver metastasis.
Okuno
K
K
First Department of Surgery, Kinki University School of Medicine, Osaka, Japan. okuno@surg1.med.kindai.ac.jp
Hirai
N
N
Lee
Y S
YS
Kawai
I
I
Shigeoka
H
H
Yasutomi
M
M
D000230:Adenocarcinoma / Q000276:immunology / Q000473:pathology / Q000556:secondary*; D000818:Animals; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007109:Immunity / Q000502:physiology*; D018664:Interleukin-12 / Q000494:pharmacology; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary*; D008214:Lymphocytes / Q000187:drug effects / Q000502:physiology; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; D018664:Interleukin-12