RRC ID 73435
Author Ohsawa I, Murakami T, Uemoto S, Kobayashi E.
Title In vivo luminescent imaging of cyclosporin A-mediated cancer progression in rats.
Journal Transplantation
Abstract 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.
Volume 81(11)
Pages 1558-67
Published 2006-6-15
DOI 10.1097/01.tp.0000209448.50238.de
PII 00007890-200606150-00010
PMID 16770245
MeSH Adenocarcinoma / chemistry Adenocarcinoma / genetics Adenocarcinoma / pathology* Animals Benzamides / pharmacology Blotting, Western Cell Adhesion Cell Line, Tumor Cell Movement / drug effects Colonic Neoplasms / immunology Colonic Neoplasms / pathology* Cyclosporine / adverse effects* Cyclosporine / pharmacology* Dioxoles / pharmacology Disease Progression Gene Expression Regulation, Neoplastic / drug effects Image Processing, Computer-Assisted / methods* Killer Cells, Natural / drug effects Killer Cells, Natural / pathology Liver Neoplasms / genetics Liver Neoplasms / immunology Liver Neoplasms / secondary Luminescence Lymphatic Metastasis / immunology Male Neoplasm Metastasis / pathology Rats Rats, Inbred F344 Receptors, Chemokine / analysis Receptors, Chemokine / genetics Reperfusion Injury / pathology Reverse Transcriptase Polymerase Chain Reaction Transforming Growth Factor beta / analysis Transforming Growth Factor beta / genetics Transforming Growth Factor beta1
IF 4.546
Human and Animal Cells RCN-9(RCB0511)