Rapamycin blocks tumor progression

Unlinking immunosuppression from antitumor efficacy

Fu L. Luan, Minoru Hojo, Mary Maluccio, Kouzaburo Yamaji, Manikkam Suthanthiran

Research output: Contribution to journalArticle

206 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1565-1572
Number of pages8
JournalTransplantation
Volume73
Issue number10
Publication statusPublished - 27 May 2002
Externally publishedYes

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Sirolimus
Immunosuppression
Severe Combined Immunodeficiency
Renal Cell Carcinoma
Neoplasms
Cyclosporine
Cadherins
Pseudopodia
Transitional Cell Carcinoma
Kidney Neoplasms
Cyclin D1
G1 Phase
Organ Transplantation
Immunosuppressive Agents
Growth
S Phase
Urinary Bladder Neoplasms
Cell Adhesion
Natural Killer Cells
Immunity

ASJC Scopus subject areas

  • Transplantation
  • Immunology

Cite this

Rapamycin blocks tumor progression : Unlinking immunosuppression from antitumor efficacy. / Luan, Fu L.; Hojo, Minoru; Maluccio, Mary; Yamaji, Kouzaburo; Suthanthiran, Manikkam.

In: Transplantation, Vol. 73, No. 10, 27.05.2002, p. 1565-1572.

Research output: Contribution to journalArticle

Luan, FL, Hojo, M, Maluccio, M, Yamaji, K & Suthanthiran, M 2002, 'Rapamycin blocks tumor progression: Unlinking immunosuppression from antitumor efficacy', Transplantation, vol. 73, no. 10, pp. 1565-1572.
Luan, Fu L. ; Hojo, Minoru ; Maluccio, Mary ; Yamaji, Kouzaburo ; Suthanthiran, Manikkam. / Rapamycin blocks tumor progression : Unlinking immunosuppression from antitumor efficacy. In: Transplantation. 2002 ; Vol. 73, No. 10. pp. 1565-1572.
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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.",
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