Immunosuppressive Drugs and the Risk of Cancer after Organ Transplantation
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《新英格兰医药杂志》
Improvements in immunosuppressive therapy during the past decade have brought us closer to the day when long-term acceptance of organ allografts will be routine. These achievements, however, have run up against an important limitation: death of the recipient from cardiovascular disease, infection, and cancer.1 As compared with an age-matched healthy population or with patients undergoing dialysis, organ-transplant recipients have an increased incidence of cancer; one study found that after 20 years of immunosuppressive therapy, 40 percent of recipients had cancer.2 Further burdens are to be expected in an aging population of transplant recipients with well-functioning allografts.
The causes of the cancers that develop in allograft recipients include environmental and genetic factors, but the main instigator is chronic opportunistic infection by oncogenic viruses. After renal transplantation, the principal neoplasms and their associated viruses are lymphoproliferative disorders due to Epstein–Barr virus, Kaposi's sarcoma due to human herpesvirus 8 (HHV-8), and skin cancer due to human papillomavirus.3 The type of drugs used for the induction and maintenance of immunosuppression and the duration of treatment with these agents influence both the incidence and the type of cancer that develops. Cyclosporine, for example, accelerates the development of skin cancers and lymphoproliferative disorders, and immunosuppressive combinations such as a monoclonal antibody against the interleukin-2 receptor, tacrolimus, and mycophenolate mofetil have been associated with a further rise in the incidence of cancer. The extent of immunosuppression itself also directly influences the risk of cancer, as has been shown by the relation between the risk of cancer in renal-transplant recipients given high doses of cyclosporine, as compared with those given moderate doses.4
Immunosuppression does not entirely account for the causal link between immunosuppressive agents and cancer, however. There is compelling evidence that cyclosporine causes dramatic increases in metastases of carcinoma in laboratory animals lacking an immune system.5 In contrast, another immunosuppressive drug, sirolimus (rapamycin), has recently been shown to prevent tumors and even to cause established tumors to regress.6
In this issue of the Journal, Stallone et al. report the regression of cutaneous Kaposi's sarcoma in 15 kidney-transplant recipients after a switch from an immunosuppressive regimen based on cyclosporine and mycophenolate mofetil to a regimen based on sirolimus.7 A similar phenomenon was previously reported in two renal-transplant recipients.8 After the replacement of cyclosporine and mycophenolate mofetil with sirolimus, there were no episodes of renal-allograft rejection, yet the Kaposi's sarcoma lesions regressed in all 15 recipients. The expression of vascular endothelial growth factor (VEGF) and a VEGF receptor (Flk-1/KDR) was increased in samples of iatrogenic cutaneous Kaposi's sarcoma lesions, whereas the activation of Akt and p70S6 kinase was reduced. This observation suggests that sirolimus contributed to the regression of the lesions by inhibiting the Akt–p70S6 kinase signaling pathway.
Kaposi's sarcoma is an angioproliferative disease that frequently develops in organ-transplant recipients or in persons infected with human immunodeficiency virus type 1 (HIV-1). Its origin is still debated. Kaposi's sarcoma cells display markers of both endothelial and monocyte–macrophage lineages, and the HHV-8 genome is usually present in tumor cells. The development of Kaposi's sarcoma after transplantation seems to be related to the reactivation of latent HHV-8 infection or to the transfer of HHV-8–infected progenitor cells from the donor to the recipient. VEGF is a key player in Kaposi's sarcoma, and HHV-8 encodes a chemokine-like, G protein–coupled receptor (a homologue of the human interleukin-8 receptor CXCR2) that promotes the proliferation of endothelial cells through the activation of the VEGF receptor Flk-1/KDR. Kaposi's sarcoma cells produce abundant amounts of VEGF, and HIV-1–infected patients with Kaposi's sarcoma have increased levels of VEGF in serum. In animals inoculated with human cutaneous Kaposi's sarcoma, a serum antibody against VEGF blocks tumor development.9
Among the questions raised by the results of Stallone et al. is whether the Kaposi's sarcoma lesions regressed because sirolimus was given, because cyclosporine and mycophenolate mofetil were discontinued, or for both reasons. The evolution of Kaposi's sarcoma after transplantation varies, and reducing the level of immunosuppression (particularly that induced by cyclosporine) often halts the evolution of both cutaneous and visceral lesions without compromising graft function. Stallone et al. cite a 17 percent rate of remission of Kaposi's sarcoma after the discontinuation of cyclosporine,10 but this is probably an underestimate, particularly among patients whose lesions are restricted to the skin. Remission of Kaposi's sarcoma has been reported after the interruption of mycophenolate mofetil or cyclosporine. Since immune surveillance seems to play a major role in iatrogenic Kaposi's sarcoma, regression of the lesions associated with switching to sirolimus at doses that suppress the immune system suggests that the drug also has antitumor effects.
Calcineurin inhibitors such as cyclosporine and tacrolimus promote the spread of cancer in mice without an immune system, probably by increasing the production of growth factors (transforming growth factor , interleukin-6, and VEGF) that enhance angiogenesis, tumor growth, and metastasis.5 In such mice, sirolimus abolishes the tumor-promoting effects of calcineurin inhibitors. Moreover, in vitro sirolimus inhibits tumor growth, blocks the tumor cell cycle at the G1 checkpoint, and in some cases, enhances apoptosis and sensitivity to chemotherapy. Sirolimus forms a complex with the tacrolimus-binding protein and then binds mTOR (the mammalian target of rapamycin). This molecular unit down-regulates pathways of cell-cycle progression and shortens cell survival. The binding of various ligands to membrane receptors (e.g., interleukin-2 receptors and growth-factor receptors) activates mTOR signaling. In the upstream pathway, phosphatidylinositol-3'-kinase (PI3K) and Akt are key factors affecting the phosphorylation of mTOR. PI3K and Akt are proto-oncogenes, and genetic alterations resulting in excessive stimulation of the Akt–mTOR pathway are common in cancers.11 PTEN (a protein that down-regulates the PI3K–Akt pathway) is inhibited by deletions or mutations in many tumors with constitutive activation of the Akt–mTOR pathway and related downstream pathways (p70S6 kinase, 4E-binding protein 1, and c-myc). Taken collectively, the fact that signaling of mTOR — the molecular target of sirolimus — is frequently deregulated in cancer suggests a direct role for sirolimus in the restraint of cancer cells. This conclusion is consistent with observations that sirolimus not only directly inhibits the proliferation of tumor cells but also inhibits tumor neovascularization. In mice, sirolimus inhibits tumor progression through antiangiogenic activity related to impaired VEGF production and diminished responsiveness of endothelial cells to stimulation through the VEGF receptor.6 Interestingly, this activity is optimal at doses routinely used in immunosuppressive regimens.
The results presented by Stallone et al. strengthen the possibility that equilibrium between efficient immunosuppression and control over the development of cancer may be attainable, by showing that sirolimus has the potential to tilt the risk–benefit balance of immunosuppression toward benefit after transplantation. A retrospective analysis of more than 36,000 recipients two years after a first kidney transplantation yielded further encouraging data: a decrease of approximately 50 percent in the relative risk of cancer among patients given sirolimus, as compared with those given calcineurin inhibitors.12 Different groups are now studying the incidence of skin cancer as a primary end point in kidney-transplant recipients. The article by Stallone et al. is a potentially important contribution because it illustrates that unexpected effects of immunosuppressive drugs, such as the antitumor effect of sirolimus and the antiviral action of mycophenolate mofetil,13 can change the rules of the cat-and-mouse game played by the allograft recipient and antirejection drugs.
Source Information
From the Institut de Transplantation et de Recherche en Transplantation, INSERM Unité 463, Nantes University, Centre Hospitalier Régional Universitaire de Nantes, Nantes, France.
References
Soulillou JP, Giral M. Controlling the incidence of infection and malignancy by modifying immunosuppression. Transplantation 2001;72:Suppl:S89-S93.
London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP. Risk of neoplasia in renal transplant patients. Lancet 1995;346:403-406.
Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905-913.
Dantal J, Hourmant M, Cantarovich D, et al. Effect of long term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998;351:623-628.
Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999;397:530-534.
Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128-135.
Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317-1323.
Campistol J, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma. Transplantation 2004;77:760-762.
Samaniego F, Young D, Grimes C, et al. Vascular endothelial growth factor and Kaposi's sarcoma cells in human skin grafts. Cell Growth Differ 2002;13:387-395.
El-Agroudy AE, El-Baz MA, Ismail AM, Ali-El-Dien B, El-Dien AB, Ghoneim MA. Clinical features and course of Kaposi's sarcoma in Egyptian kidney transplant recipients. Am J Transplant 2003;3:1595-1599.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501.(Jacques Dantal, M.D., Ph.)
The causes of the cancers that develop in allograft recipients include environmental and genetic factors, but the main instigator is chronic opportunistic infection by oncogenic viruses. After renal transplantation, the principal neoplasms and their associated viruses are lymphoproliferative disorders due to Epstein–Barr virus, Kaposi's sarcoma due to human herpesvirus 8 (HHV-8), and skin cancer due to human papillomavirus.3 The type of drugs used for the induction and maintenance of immunosuppression and the duration of treatment with these agents influence both the incidence and the type of cancer that develops. Cyclosporine, for example, accelerates the development of skin cancers and lymphoproliferative disorders, and immunosuppressive combinations such as a monoclonal antibody against the interleukin-2 receptor, tacrolimus, and mycophenolate mofetil have been associated with a further rise in the incidence of cancer. The extent of immunosuppression itself also directly influences the risk of cancer, as has been shown by the relation between the risk of cancer in renal-transplant recipients given high doses of cyclosporine, as compared with those given moderate doses.4
Immunosuppression does not entirely account for the causal link between immunosuppressive agents and cancer, however. There is compelling evidence that cyclosporine causes dramatic increases in metastases of carcinoma in laboratory animals lacking an immune system.5 In contrast, another immunosuppressive drug, sirolimus (rapamycin), has recently been shown to prevent tumors and even to cause established tumors to regress.6
In this issue of the Journal, Stallone et al. report the regression of cutaneous Kaposi's sarcoma in 15 kidney-transplant recipients after a switch from an immunosuppressive regimen based on cyclosporine and mycophenolate mofetil to a regimen based on sirolimus.7 A similar phenomenon was previously reported in two renal-transplant recipients.8 After the replacement of cyclosporine and mycophenolate mofetil with sirolimus, there were no episodes of renal-allograft rejection, yet the Kaposi's sarcoma lesions regressed in all 15 recipients. The expression of vascular endothelial growth factor (VEGF) and a VEGF receptor (Flk-1/KDR) was increased in samples of iatrogenic cutaneous Kaposi's sarcoma lesions, whereas the activation of Akt and p70S6 kinase was reduced. This observation suggests that sirolimus contributed to the regression of the lesions by inhibiting the Akt–p70S6 kinase signaling pathway.
Kaposi's sarcoma is an angioproliferative disease that frequently develops in organ-transplant recipients or in persons infected with human immunodeficiency virus type 1 (HIV-1). Its origin is still debated. Kaposi's sarcoma cells display markers of both endothelial and monocyte–macrophage lineages, and the HHV-8 genome is usually present in tumor cells. The development of Kaposi's sarcoma after transplantation seems to be related to the reactivation of latent HHV-8 infection or to the transfer of HHV-8–infected progenitor cells from the donor to the recipient. VEGF is a key player in Kaposi's sarcoma, and HHV-8 encodes a chemokine-like, G protein–coupled receptor (a homologue of the human interleukin-8 receptor CXCR2) that promotes the proliferation of endothelial cells through the activation of the VEGF receptor Flk-1/KDR. Kaposi's sarcoma cells produce abundant amounts of VEGF, and HIV-1–infected patients with Kaposi's sarcoma have increased levels of VEGF in serum. In animals inoculated with human cutaneous Kaposi's sarcoma, a serum antibody against VEGF blocks tumor development.9
Among the questions raised by the results of Stallone et al. is whether the Kaposi's sarcoma lesions regressed because sirolimus was given, because cyclosporine and mycophenolate mofetil were discontinued, or for both reasons. The evolution of Kaposi's sarcoma after transplantation varies, and reducing the level of immunosuppression (particularly that induced by cyclosporine) often halts the evolution of both cutaneous and visceral lesions without compromising graft function. Stallone et al. cite a 17 percent rate of remission of Kaposi's sarcoma after the discontinuation of cyclosporine,10 but this is probably an underestimate, particularly among patients whose lesions are restricted to the skin. Remission of Kaposi's sarcoma has been reported after the interruption of mycophenolate mofetil or cyclosporine. Since immune surveillance seems to play a major role in iatrogenic Kaposi's sarcoma, regression of the lesions associated with switching to sirolimus at doses that suppress the immune system suggests that the drug also has antitumor effects.
Calcineurin inhibitors such as cyclosporine and tacrolimus promote the spread of cancer in mice without an immune system, probably by increasing the production of growth factors (transforming growth factor , interleukin-6, and VEGF) that enhance angiogenesis, tumor growth, and metastasis.5 In such mice, sirolimus abolishes the tumor-promoting effects of calcineurin inhibitors. Moreover, in vitro sirolimus inhibits tumor growth, blocks the tumor cell cycle at the G1 checkpoint, and in some cases, enhances apoptosis and sensitivity to chemotherapy. Sirolimus forms a complex with the tacrolimus-binding protein and then binds mTOR (the mammalian target of rapamycin). This molecular unit down-regulates pathways of cell-cycle progression and shortens cell survival. The binding of various ligands to membrane receptors (e.g., interleukin-2 receptors and growth-factor receptors) activates mTOR signaling. In the upstream pathway, phosphatidylinositol-3'-kinase (PI3K) and Akt are key factors affecting the phosphorylation of mTOR. PI3K and Akt are proto-oncogenes, and genetic alterations resulting in excessive stimulation of the Akt–mTOR pathway are common in cancers.11 PTEN (a protein that down-regulates the PI3K–Akt pathway) is inhibited by deletions or mutations in many tumors with constitutive activation of the Akt–mTOR pathway and related downstream pathways (p70S6 kinase, 4E-binding protein 1, and c-myc). Taken collectively, the fact that signaling of mTOR — the molecular target of sirolimus — is frequently deregulated in cancer suggests a direct role for sirolimus in the restraint of cancer cells. This conclusion is consistent with observations that sirolimus not only directly inhibits the proliferation of tumor cells but also inhibits tumor neovascularization. In mice, sirolimus inhibits tumor progression through antiangiogenic activity related to impaired VEGF production and diminished responsiveness of endothelial cells to stimulation through the VEGF receptor.6 Interestingly, this activity is optimal at doses routinely used in immunosuppressive regimens.
The results presented by Stallone et al. strengthen the possibility that equilibrium between efficient immunosuppression and control over the development of cancer may be attainable, by showing that sirolimus has the potential to tilt the risk–benefit balance of immunosuppression toward benefit after transplantation. A retrospective analysis of more than 36,000 recipients two years after a first kidney transplantation yielded further encouraging data: a decrease of approximately 50 percent in the relative risk of cancer among patients given sirolimus, as compared with those given calcineurin inhibitors.12 Different groups are now studying the incidence of skin cancer as a primary end point in kidney-transplant recipients. The article by Stallone et al. is a potentially important contribution because it illustrates that unexpected effects of immunosuppressive drugs, such as the antitumor effect of sirolimus and the antiviral action of mycophenolate mofetil,13 can change the rules of the cat-and-mouse game played by the allograft recipient and antirejection drugs.
Source Information
From the Institut de Transplantation et de Recherche en Transplantation, INSERM Unité 463, Nantes University, Centre Hospitalier Régional Universitaire de Nantes, Nantes, France.
References
Soulillou JP, Giral M. Controlling the incidence of infection and malignancy by modifying immunosuppression. Transplantation 2001;72:Suppl:S89-S93.
London NJ, Farmery SM, Will EJ, Davison AM, Lodge JP. Risk of neoplasia in renal transplant patients. Lancet 1995;346:403-406.
Kasiske BL, Snyder JJ, Gilbertson DT, Wang C. Cancer after kidney transplantation in the United States. Am J Transplant 2004;4:905-913.
Dantal J, Hourmant M, Cantarovich D, et al. Effect of long term immunosuppression in kidney-graft recipients on cancer incidence: randomised comparison of two cyclosporin regimens. Lancet 1998;351:623-628.
Hojo M, Morimoto T, Maluccio M, et al. Cyclosporine induces cancer progression by a cell-autonomous mechanism. Nature 1999;397:530-534.
Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med 2002;8:128-135.
Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients. N Engl J Med 2005;352:1317-1323.
Campistol J, Gutierrez-Dalmau A, Torregrosa JV. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi's sarcoma. Transplantation 2004;77:760-762.
Samaniego F, Young D, Grimes C, et al. Vascular endothelial growth factor and Kaposi's sarcoma cells in human skin grafts. Cell Growth Differ 2002;13:387-395.
El-Agroudy AE, El-Baz MA, Ismail AM, Ali-El-Dien B, El-Dien AB, Ghoneim MA. Clinical features and course of Kaposi's sarcoma in Egyptian kidney transplant recipients. Am J Transplant 2003;3:1595-1599.
Vivanco I, Sawyers CL. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2002;2:489-501.(Jacques Dantal, M.D., Ph.)