In vivo luminescent imaging of cyclosporin A-mediated cancer progression in rats

Transplantation. 2006 Jun 15;81(11):1558-67. doi: 10.1097/01.tp.0000209448.50238.de.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • 4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide
  • Benzamides
  • Dioxoles
  • Receptors, Chemokine
  • Tgfb1 protein, rat
  • Transforming Growth Factor beta
  • Transforming Growth Factor beta1
  • Cyclosporine