Rapamycin blocks tumor progression: unlinking immunosuppression from antitumor efficacy.
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.
Luan
Fu L
FL
Department of Transplantation Medicine, New York-Presbyterian Hospital, New York, NY 10021, USA.
Hojo
Minoru
M
Maluccio
Mary
M
Yamaji
Kouzaburo
K
Suthanthiran
Manikkam
M
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000276:immunology; D015820:Cadherins / Q000235:genetics; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D017931:DNA Primers; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007694:Killer Cells, Natural / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology; D016559:Tacrolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics
D000903:Antibiotics, Antineoplastic; D015820:Cadherins; C493961:Cdkn1b protein, mouse; D018797:Cell Cycle Proteins; D017931:DNA Primers; D007166:Immunosuppressive Agents; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1; D050760:Cyclin-Dependent Kinase Inhibitor p27; D020123:Sirolimus; D016559:Tacrolimus