Impact of Acute Rejection Therapy on Infections and Malignancies in Renal Transplant Recipients

Jamil, Bilal; Nicholls, Kathy; Becker, Gavin J.; Walker, Rowan G.

doi:10.1097/00007890-199911270-00027

Cited by 85 publications

(59 citation statements)

References 16 publications

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“…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%

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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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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“…7,9 Nevertheless, recent studies clearly identified a major association between the use of CNI and the development and recurrence of different types of cancer in both transplant and nontransplant patients. 10 -14 The immunosuppressive effect of CNI may result in impaired immune surveillance for neoplastic cells 15,16 and may increase susceptibility to oncogenic viral infections. 12,17 CNI may also directly cause DNA damage to cells and interfere with normal DNA repair mechanisms 18 ; however, independent of these effects, it has been found that commonly used CNI cyclosporine (CsA) and FK506 may promote tumor growth through the induced expression of different genes, including TGF-␤, IL-10, and angiogenic cytokines (e.g., vascular endothelial growth factor).…”

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confidence: 99%

Calcineurin Inhibitors Modulate CXCR3 Splice Variant Expression and Mediate Renal Cancer Progression

Datta

Contreras

Grimm³

et al. 2008

Journal of the American Society of Nephrology

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Calcineurin inhibitors (CNI) are used to prevent inflammatory diseases and allograft rejection. However, little is known about the mechanism(s) underlying their ability to promote the development and recurrence of cancer. Recent studies suggested that the chemokine receptor CXCR3 may play important roles in tumorigenesis. CXCR3 has two splice variants with opposite functions: CXCR3-A promotes cell proliferation, and CXCR3-B inhibits cell growth. Here, we explored the effects of CNI on the expression and function of CXCR3 splice variants. Compared with normal renal tissues and renal epithelial cells, human renal cancer tissues and renal cancer cell lines demonstrated higher expression of CXCR3-A and markedly lower expression of CXCR3-B. In human renal cancer cells (786-0 and Caki-1) and renal epithelial cells, CNI markedly downregulated the expression of CXCR3-B, whereas expression of CXCR3-A was unchanged. This CNI-mediated downregulation of CXCR3-B resulted in increased proliferation and migration of renal cancer cells; CNI-mediated cell proliferation involved signaling through G i proteins, perhaps via CXCR3-A. Finally, it was observed that CNI treatment increased the growth of human renal tumors in vivo, and the expression of CXCR3-B was significantly decreased in these tumors. In summary, these observations suggest that CNI may mediate the progression of human renal cancer by downregulating CXCR3-B and by promoting proliferative signals, likely through CXCR3-A. Targeting CXCR3 splice variants or the signaling pathways downstream of CXCR3 receptors may provide a therapeutic strategy for the prevention of CNI-mediated renal cancer progression.

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“…CNI levels should be monitored closely in the setting of acute rejection, as nephrotoxicity is more common. Moreover, in the setting of antibody-depleting therapy, patients should be monitored closely for infectious complications [25]. Graft survival is negatively impacted by episodes of acute rejection [26].…”

Section: Acute Rejectionmentioning

confidence: 99%