In vivo luminescent imaging of cyclosporin A-mediated cancer progression in rats.
BACKGROUND
Immunosuppressed individuals undergoing organ transplantation are at increased risk of recurrences of initial cancers, although how immunosuppressive therapy increases early cancer metastasis remains unclear.


METHODS
The metastatic fate of luciferase-expressing rat metastatic colon cancer cells (luc-RCN-H4) injected intravenously into the liver of syngeneic and allogeneic rats was examined in the presence of the immunosuppressant cyclosporin A (CsA) by in vivo luminescent technique. With respect to potential tumor-progressing factors, contribution of chemokine receptors and transforming growth factor (TGF)-beta1 to early metastasis was evaluated using their specific signaling inhibitors.


RESULTS
F344 rats injected in the liver with luc-RCN-H4 cells did not always exhibit the formation of tumors and showed a dormant state as long as 60 days after inoculation without CsA. However, CsA released early luc-RCN-H4 cells from dormancy within 2 weeks at nearly 100% in liver and preferentially promoted metastasis to the lymph nodes (approximately 40%). A similar dissemination occurred even in minor histocompatibility complex-disparate hosts. As a tumor-progressing factor, RCN-H4 cells aberrantly expressed chemokine receptors CXCR4 and CCR7. The chemokine receptor (CXC) R4-specific antagonist AMD3100 decreased early metastasis of luc-RCN-H4 cells in rats with ischemic liver conditions (P<0.05), but CsA treatment did not enhance early adhesion. Use of CsA was able to facilitate TGF-beta1 expression and the subsequent TGF-beta-mediated random migration was blocked by the use of the specific signaling inhibitor SB431542 in vitro.


CONCLUSIONS
Whereas the chemokine receptor expression by cancer cells is implicated with early organotropic dissemination even under CsA-mediated immune suppression, rather, CsA enhances the late-phase progression after tumor adhesion through TGF-beta1 expression.
Ohsawa
Ichiro
I
Division of Organ Replacement Research, Center for Molecular Medicine, Jichi Medical School, Tochigi, Japan.
Murakami
Takashi
T
Uemoto
Shinji
S
Kobayashi
Eiji
E
D000230:Adenocarcinoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology*; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D003110:Colonic Neoplasms / Q000276:immunology / Q000473:pathology*; D016572:Cyclosporine / Q000009:adverse effects* / Q000494:pharmacology*; D004149:Dioxoles / Q000494:pharmacology; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007091:Image Processing, Computer-Assisted / Q000379:methods*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000276:immunology / Q000556:secondary; D049449:Luminescence; D008207:Lymphatic Metastasis / Q000276:immunology; D008297:Male; D009362:Neoplasm Metastasis / Q000473:pathology; D051381:Rats; D011916:Rats, Inbred F344; D019707:Receptors, Chemokine / Q000032:analysis / Q000235:genetics; D015427:Reperfusion Injury / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000235:genetics; D053773:Transforming Growth Factor beta1
C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D004149:Dioxoles; D019707:Receptors, Chemokine; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D016572:Cyclosporine