Pro- And Anti-Cancer Effects of Immunosuppressive Agents Used in Organ Transplantation

Guba, Markus; Graeb, Christian; Jauch, Karl‐Walter; Geissler, Edward K.

doi:10.1097/01.tp.0000120181.89206.54

Cited by 315 publications

(230 citation statements)

References 67 publications

(57 reference statements)

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“…It has been reported that the effective doses of RAPA for immunosuppression coincide with doses required for its antiangiogenic effects (6). This allows RAPA to be considered for the effective treatment of organ rejection, autoimmune diseases, and cancer.…”

Section: Discussionmentioning

confidence: 99%

“…The reasons for the high incidence of cancer in these individuals, including patients with organ transplant, are unknown, but have been postulated to include impaired immune surveillance, viral infections, or the direct effects of immunosuppressive agents (2,4,5). Nevertheless, some clues to the mechanisms underlying the development of posttransplantation cancer have recently emerged from clinical findings, including the observation that transplant patients receiving the mTOR 2 inhibitor rapamycin (RAPA) do not develop cancer at the same rate as those receiving other immunosuppressive agents such as calcineurin inhibitors (CNIs) (5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

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Altered VEGF mRNA Stability following Treatments with Immunosuppressive Agents

Basu

Datta

Zurakowski

et al. 2010

Journal of Biological Chemistry

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The high incidence of cancer and its aggressive progression is a common and major problem in patients receiving immunosuppressive therapy. The calcineurin inhibitors (CNIs) may have protumorigenic effects and can promote the overexpression of several molecules inducing tumor growth. We have recently demonstrated that CNIs can mediate the transcriptional activation of the angiogenic cytokine vascular endothelial growth factor (VEGF) and promote a rapid progression of human renal cancer. Here, we investigated whether the CNI cyclosporine (CsA) and the mTOR inhibitor rapamycin (RAPA) could alter the mRNA stability of VEGF in 786-0 and Caki-1 renal cancer cells. Following actinomycin D treatment, we observed that CsA increased, whereas RAPA decreased the VEGF mRNA stability as observed by real time PCR. It is established that the mRNA-binding protein HuR may play a critical role in VEGF mRNA stability. By using HuR-siRNA, we found that the knockdown of HuR significantly decreased the CNIinduced VEGF mRNA stability. By Western blot analysis, it has been observed that CNI treatment induced the translocation of HuR from the nucleus to the cytoplasm; CNIs also induced the association between HuR and PKC-␦ and promoted the phosphorylation of HuR. Finally, we found that the inhibition of PKC-␦ using a dominant negative plasmid significantly decreased the CsA-induced cytoplasmic translocation of HuR and VEGF mRNA stability. Together, targeting the pathways that promote CNI-induced transcription as well as the mRNA stability of VEGF might serve as novel therapeutics for the prevention and treatment of cancer in immunosuppressed patients.The development of cancer is a critical problem in patients treated with immunosuppressive agents (1-3). The reasons for the high incidence of cancer in these individuals, including patients with organ transplant, are unknown, but have been postulated to include impaired immune surveillance, viral infections, or the direct effects of immunosuppressive agents (2, 4, 5). Nevertheless, some clues to the mechanisms underlying the development of posttransplantation cancer have recently emerged from clinical findings, including the observation that transplant patients receiving the mTOR 2 inhibitor rapamycin (RAPA) do not develop cancer at the same rate as those receiving other immunosuppressive agents such as calcineurin inhibitors (CNIs) (5-9).Vascular endothelial growth factor (VEGF) is a 34 -45-kDa cytokine expressed by tumor cells, endothelial cells, leukocytes, and different other cell types (10 -12). It plays a major role in regulating the process of angiogenesis for the growth and progression of tumors (10). We have recently reported that CNIs may promote the overexpression of VEGF in human renal cancer, one of the major cancers in transplant patients (13). We have observed that CNI-induced VEGF overexpression is mediated through the transcriptional activation mechanism and can lead to a rapid progression of renal tumors (13).The regulation of VEGF expression in tumor cells is complex, inv...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Altered VEGF mRNA Stability following Treatments with Immunosuppressive Agents

Basu

Datta

Zurakowski

et al. 2010

Journal of Biological Chemistry

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“…In addition, rapamycin is shown to repress HIF-1␣ synthesis and expression of HIF-1 target genes including VEGF in these cells via targeting mTOR. Therefore, rapamycin is now considered to act as an antineoplastic agent, as well as an immunosuppressant (18,34). It appears to be obvious to hypothesize that rapamycin suppresses HIF-1␣ protein expression in T cells as well.…”

Section: Discussionmentioning

confidence: 99%

“…Rapamycin binds to FK506-binding protein 12, and this complex targets mTOR and inhibits T cell response to IL-2 to progress G 1 to S phase (17). On the other hand, it has been noticed that rapamycin suppresses the growth of certain tumors (18,19). For example, rapamycin inhibits metastatic tumor growth and angiogenesis in mouse model and this anti-angiogenic activity is shown to link to a decrease in production of VEGF (20).…”

mentioning

confidence: 99%

TCR Engagement Increases Hypoxia-Inducible Factor-1α Protein Synthesis via Rapamycin-Sensitive Pathway under Hypoxic Conditions in Human Peripheral T Cells

Nakamura

Makino

Okamoto

et al. 2005

The Journal of Immunology

135

117

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Peripheral T cells encounter rapid decrease in oxygen tension because they are activated by Ag recognition and migrate into inflammatory sites or tumors. Activated T cells, therefore, are thought to have such machineries that enable them to adapt to hypoxic conditions and execute immune regulation in situ. We have recently shown that survival of CD3-engaged human peripheral blood T cells is prolonged under hypoxic conditions and hypoxia-inducible factor-1 (HIF-1) and its target gene product adrenomedullin play a critical role for the process. It is also shown that hypoxia alone is not sufficient, but TCR-mediated signal is required for accumulation of HIF-1α in human peripheral T cells. In the present study, we showed that TCR engagement does not influence hypoxia-dependent stabilization but stimulates protein synthesis of HIF-1α, most possibly via PI3K/mammalian target of rapamycin system, and that expression of HIF-1α and its target genes is blocked by treatment with rapamycin. Since some of those gene products, e.g., glucose transporters and phosphoglycerokinase, are considered to be essential for glycolysis and energy production under hypoxic conditions and adequate immune reaction in T cells, this TCR-mediated synthesis of HIF-1α may play a pivotal role in peripheral immune response. Taken together, our results may highlight a novel aspect of downstream signal from Ag recognition by TCR and a unique pharmacological role of rapamycin as well.

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“…In addition, mTORIs also inhibit the translation of transcription factors resulting in reduced angiogenesis, preventing the multiprotein complexes (mTORC1 and mTORC2) pathway activation, thereby halting cell proliferation, particularly in the setting of cancer development (Guba et al 2004). MTORi have antineoplastic properties, and show promise in reducing cancer recurrence while permitting ongoing immunosuppression (Law 2005).…”

Section: The Role Of Components Of the Immunosuppressive Regimenmentioning

confidence: 99%

Cancer in the Transplant Recipient

Chapman

Webster

Wong

2013

Cold Spring Harbor Perspectives in Medicine

230

187

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Malignancy has become one of the three major causes of death after transplantation in the past decade and is thus increasingly important in all organ transplant programs. Death from cardiovascular disease and infection are both decreasing in frequency from a combination of screening, prophylaxis, aggressive risk factor management, and interventional therapies. Cancer, on the other hand, is poorly and expensively screened for; risk factors are mostly elusive and/or hard to impact on except for the use of immunosuppression itself; and finally therapeutic approaches to the transplant recipient with cancer are often nihilistic. This article provides a review of each of the issues as they come to affect transplantation: cancer before wait-listing, cancer transmission from the donor, cancer after transplantation, outcomes of transplant recipients after a diagnosis of cancer, and the role of screening and therapy in reducing the impact of cancer in transplant recipients.

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Pro- And Anti-Cancer Effects of Immunosuppressive Agents Used in Organ Transplantation

Cited by 315 publications

References 67 publications

Altered VEGF mRNA Stability following Treatments with Immunosuppressive Agents

Altered VEGF mRNA Stability following Treatments with Immunosuppressive Agents

TCR Engagement Increases Hypoxia-Inducible Factor-1α Protein Synthesis via Rapamycin-Sensitive Pathway under Hypoxic Conditions in Human Peripheral T Cells

Cancer in the Transplant Recipient

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