Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy

Transplantation. 2002 May 27;73(10):1565-72. doi: 10.1097/00007890-200205270-00008.

Abstract

Background: Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine.

Methods: A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kip1, cyclin D1) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum.

Results: Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kip1, reduced cyclinD1, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells.

Conclusions: Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adenocarcinoma / drug therapy*
  • Adenocarcinoma / immunology
  • Adenocarcinoma / pathology
  • Animals
  • Antibiotics, Antineoplastic / pharmacology*
  • B-Lymphocytes / immunology
  • Cadherins / genetics
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Cell Cycle Proteins / genetics
  • Cyclin D1 / genetics
  • Cyclin-Dependent Kinase Inhibitor p27
  • DNA Primers
  • Disease Progression
  • Genes, Tumor Suppressor
  • Immunosuppression*
  • Immunosuppressive Agents / pharmacology*
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / pathology
  • Killer Cells, Natural / immunology
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Sirolimus / pharmacology*
  • T-Lymphocytes / immunology
  • Tacrolimus / pharmacology
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins / genetics

Substances

  • Antibiotics, Antineoplastic
  • Cadherins
  • Cdkn1b protein, mouse
  • Cell Cycle Proteins
  • DNA Primers
  • Immunosuppressive Agents
  • Tumor Suppressor Proteins
  • Cyclin D1
  • Cyclin-Dependent Kinase Inhibitor p27
  • Sirolimus
  • Tacrolimus