Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy. Academic Article uri icon

Overview

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 date

  • May 27, 2002

Research

keywords

  • Adenocarcinoma
  • Antibiotics, Antineoplastic
  • Carcinoma, Renal Cell
  • Immunosuppression
  • Immunosuppression Therapy
  • Immunosuppressive Agents
  • Kidney Neoplasms
  • Sirolimus

Identity

Scopus Document Identifier

  • 0037182139

PubMed ID

  • 12042641

Additional Document Info

volume

  • 73

issue

  • 10