Improvements in immunosuppressive drug therapy have increased chances for long-term survival after organ transplantation, but because of the indefinite immunosuppression, many physicians now encounter transplant recipients who have life-threatening complications, including cancer. With regard to de novo neoplasms, immunosuppressed organ allograft recipients have an increased risk for developing several types of malignancies, of which skin cancer is the most common (1–3). To put the problem in perspective, studies indicate that the long-term incidence (20 years) of skin cancer approaches 50% in regions of low sun exposure and 80% in regions of high exposure (4). Furthermore, an Australian study reported that approximately one quarter of deaths in renal transplant recipients after 10 years were caused by cancer (3). This is substantial considering the fact that patients receiving nonrenal transplants (e.g., heart and lung) tend to require higher immunosuppression, making them even more prone to cancer (3,5,6). Indeed, aggressiveness of the immunosuppressive regimen has been correlated with another transplant-related neoplasm, non-Hodgkin lymphoma (7). Recent reports, however, suggest that not all immunosuppressive drugs necessarily promote cancer in transplant recipients and that they may even have anti-neoplastic properties. In the following overview, we will focus the discussion on the pro- and anti-cancer properties of several key immunosuppressive substances.
The immunosuppressant cyclosporine A (CsA) has had a major impact on the outcome of organ transplantation (8). Much of this improvement can be attributed to the inhibitory effect of CsA on interleukin (IL)-2 expression and to the increase in transforming growth factor (TGF)-β1, a potent inhibitor of IL-2–stimulated T-cell proliferation (9,10). Unfortunately, cancer development with unusually aggressive phenotypes has been correlated with CsA immunosuppression (11–13). However, Hojo et al. (14) reported a mechanism for the heightened occurrence of malignancy, independent of host immunity, in which CsA induces TGF-β1–mediated phenotypic changes (including invasiveness of nontransformed cells) by a cell-autonomous mechanism. In our studies we observed a different lymphocyte-independent, tumor-promoting (colon adenocarcinoma) effect of CsA in mice. The effect we identified was related to enhancement of tumor angiogenesis in CsA-treated mice. Although the mechanism of the proangiogenic effect is not yet understood, tumor-bearing mice treated with CsA showed elevated expression of the angiogenesis stimulator vascular endothelial growth factor (VEGF) (15). Shihab et al. (16) have since confirmed the up-regulation of VEGF expression after CsA treatment in rats. IL-6 is another notable cytokine for this discussion because its production is increased in CsA-exposed Epstein-Barr virus (EBV)-infected B cells (17,18). Increased levels of IL-6 are capable of promoting B-cell activation, growth, and possibly immortalization (17). A high incidence of EBV-associated posttransplant lymphoproliferative disorder (PTLD) in CsA-treated transplant recipients correlates with this finding, although PTLD is not unique to CsA-based immunosuppressive therapy. In general, it is worth noting that the mechanistic studies mentioned here suggest that CsA promotes, rather than induces, tumor growth.
Other reports suggest that CsA promotes tumor formation in transplant recipients. For example, Herman et al. (19) showed that a higher cancer incidence with CsA treatment in kidney transplant recipients is caused by a dose-dependent reduction in DNA repair capability. A dose-dependent effect was also shown in a clinical study by Dantal et al. (20), in which the risks and benefits of two long-term maintenance regimens of CsA in kidney-allograft recipients were compared. In this study, the low-dose regimen was associated with fewer malignant disorders but more frequent rejection; in contrast, normal-dose CsA yielded less rejection but a higher incidence of cancer. A study by Tremblay et al. (21) also showed an increased incidence of cancer in renal transplant recipients in the CsA era. In liver transplantation for hepatocellular carcinoma, it was recently reported that recurrence-free survival after transplantation is significantly affected by the cumulative CsA dose given (22). These results correlate with experiments by Freise et al. (23) showing that CsA treatment in rats increases hepatocellular carcinoma recurrence after liver transplantation. It is also worth noting that the risk of certain cancers in patients receiving CsA immunosuppression can be potentiated by additional risk factors. For example, a recent study by Marcil and Stern (24) showed that the risk of squamous cell cancer of the skin is increased by CsA treatment in patients with psoriasis who are exposed to ultraviolet-A light. These results are corroborated by data showing a dramatically increased incidence of skin cancer in sun-exposed Australian patients in comparison with European patients receiving immunosuppression (4). However, notwithstanding these experimental and clinical studies, a general pro-neoplastic effect of CsA remains open to discussion (Fig. 1). For instance, it can also be argued that CsA inhibits multidrug resistance in cancer cells (25) and can even be combined with cytotoxic drugs such as paclitaxel to inhibit tumor growth in some cases (26). With this counterpoint in mind, more needs to be learned about cancer in the context of CsA therapy.
Less data are available for the calcineurin inhibitor FK506 (tacrolimus) compared with the data on CsA. However, recent experimental studies demonstrate a higher proliferation rate of human hepatoma cells in the presence of tacrolimus (27). This finding is consistent with the observation that after liver transplantation, patients on either tacrolimus or CsA-based immunosuppressive regimens show a similar elevation in tumor incidence (28). Furthermore, direct evidence of a neoplastic potential is suggested by tacrolimus stimulation of TGF-β1 expression (29), similar to the pro-metastatic mechanism described for CsA (14). In summary, a growing body of evidence indicates that calcineurin inhibitors as a group are associated with posttransplant malignancy. This side effect seems mainly linked to aberrant production of cytokines that regulate processes promoting tumor growth, metastasis, and angiogenesis (Fig. 1). However, a direct cause-and-effect relationship between calcineurin inhibitor use and promotion of cancer will continue to be a subject for debate.
MAMMALIAN TARGET OF RAPAMYCIN INHIBITORS
Rapamycin (sirolimus) is an immunosuppressive agent that forms a complex with the FK binding protein complex (FKBP-12), binding with high affinity to the mammalian target of rapamycin (mTOR). Rapamycin and derivatives, including CCI-779 and RAD001, inhibit mTOR, down-regulating p70S6 kinase activity and subsequent translation of specific mRNAs required for cell-cycle progression from the G1 to S phase. This action, which effectively blocks IL-2 stimulation of lymphocyte proliferation, is the basis for its immunosuppressive activity. Experimentally, mTOR inhibitors were found in early studies by Eng et al. (30) to also suppress the growth and proliferation of colon-38 tumor cells in mice, but only at high doses of drug (100–400 mg/kg/day). Interest in its anti-cancer potential waned, and the drug was later successfully developed as an immunosuppressive agent. However, more recent studies have revived rapamycin’s anti-cancer potential. For example, CCI-779 (a rapamycin ester) inhibits the growth in mice of human tumor xenografts deficient in PTEN, a molecule that normally inhibits signaling through the PI3 kinase and p70S6 kinase cell proliferation pathway (Fig. 2). Furthermore, lower doses of CCI-779 are required to inhibit PTEN−/− tumor growth than for PTEN+/+ tumors, suggesting PTEN deletion sensitizes cells to growth arrest elicited by mTOR inhibition (31). Although CCI-779 administered alone results in growth inhibition, CCI-779 treatment combined with androgen withdrawal led to tumor regression in an androgen-dependent prostate cancer xenograft lacking PTEN (32). The effect on the PI3 kinase and p70S6 kinase signaling pathway is not confined to PTEN deletion, because tumors overexpressing another molecule related to this pathway, myr-Akt (a membrane-targeted, activated allele of Akt/PKB), are also sensitive to CCI-779. Low doses of rapamycin (1 ng/mL) reverse the transformation of chicken embryo fibroblasts expressing a PI3k homolog or Akt (33). It has also been reported that effects of rapamycin on other molecules may inhibit cancer. For example, rapamycin reportedly up-regulates E-cadherin, which increases cell adhesiveness and thus theoretically reduces the metastatic potential of cancer (34). In this same study, rapamycin inhibited tumor growth and metastasis in the presence or absence of CsA. Rapamycin-induced increases in the expression of inhibitors of cell-cycle (e.g., p27kip1) controlling cyclin molecules may also slow tumor cell growth (35). In vivo studies show that CCI-779 arrests the growth of various human tumor cells with different potencies (IC50 of ∼1 nM to >1 μM) (36). Thus, rapamycin-based compounds have anti-neoplastic properties, and at least one mode of action could be related to multiple effects on tumor cell metastasis and proliferation (Fig. 2).
Excessive growth of EBV-transformed B lymphocytes is often the cause of PTLDs. Another rapamycin analog, RAD001 (everolimus), which is presently being evaluated for preventing allograft rejection, has an antiproliferative effect on EBV-transformed B lymphocytes in culture and in a mouse model (37,38). The effect seems to result in a rapamycin-like blockage of cells in the mid-to-late phase of G1, with evidence of apoptosis (37). In a recent study by Nepomuceno and colleagues (39), rapamycin was shown to effectively inhibit the growth of EBV-associated B-cell lymphomas in mice by reducing IL-10 secretion, which prevents constitutive STAT1 and STAT3 activation associated with these types of malignancies (40). Thus, with further experimentation, rapamycin and its analogs may prove to be useful in the prevention or treatment of PTLD.
Notwithstanding the reported direct effects on tumor cells, our research group has recently shown that rapamycin has a potent anti-cancer effect through a previously unrealized, indirect mechanism. In different mouse models we have shown that rapamycin has inhibitory effects on the development of cancer by blocking angiogenesis (15). This effect was correlated with rapamycin impairment of VEGF production and blockage of VEGF-induced vascular endothelial cell stimulation. Consistent with this hypothesis, rapamycin caused tumors to regress only after they became increasingly dependent on angiogenesis. This observation is in keeping with the low-dose, delayed effects on tumors typically seen with other reported antiangiogenic treatment protocols (41,42). The effects of rapamycin on VEGF-induced angiogenesis have now been independently confirmed (43). A major point, and a distinct advantage from a clinical perspective, is that effective doses of rapamycin for immunosuppression coincide with doses required for the antiangiogenic effect, thus potentially allowing for simultaneous treatment of organ rejection and cancer. This is likely no coincidence, because IL-2 triggering of lymphocyte proliferation and VEGF-induced angiogenesis occurs through the same principal intracellular PI3 kinase and p70S6 kinase signaling pathway (Fig. 2), which is blocked by rapamycin at doses in the 1 to 10 nM range. In summary, considering all the available experimental data, there is convincing evidence (Fig. 2) indicating that rapamycin, or its analogs, may be capable of reducing the problem of cancer in organ transplant recipients.
Clinical studies testing the potential anti-neoplastic effects of rapamycin in transplant recipients are in progress or are being initiated. However, most cancer statistics have been extracted from clinical trials originally designed with other primary objectives. In a multicenter analysis of patients after kidney transplantation, rapamycin has already given some indication of its potential in decreasing the incidence of malignancies (American Transplant Congress 2002, abstract 58). In this study, analyzing for neoplasms 2 years after transplantation, 5% of patients receiving CsA therapy developed malignancy, whereas none of the patients receiving sirolimus developed cancer. Furthermore, sirolimus conversion after an initial 3-month course of CsA resulted in an approximately 5% lower cancer occurrence rate in patients receiving combined sirolimus and CsA therapy, but the results were not statistically significant with the numbers available. However, when the incidence of skin cancer was studied, rapamycin significantly reduced the risk, even in the presence of CsA. In a single-center study, Campistol et al. collected cancer-related data of 160 renal transplant recipients (up to 5 years) receiving sirolimus-based immunosuppression or sirolimus in association with calcineurin inhibitors. No malignancy was reported in the calcineurin-free sirolimus treatment group, whereas 12 malignancies were reported among those receiving calcineurin inhibitor therapy (American Transplant Congress 2002, abstract 1013). This observation is consistent with recent data from Kahan et al. (44), in which their 10-year follow-up data of renal transplant recipients receiving a CsA-sirolimus immunosuppressive strategy show an overall low malignancy rate and a particularly low rate of PTLD (0.4%), renal cell carcinoma (0.2%), and skin cancer (1.9%), compared with other immunosuppressive regimens. Together, the present studies suggest a potential beneficial effect of mTOR inhibition on cancer development in transplant recipients, but more complete and specifically designed long-term clinical studies are needed to come to more firm conclusions.
FTY720: ANOTHER AGENT WITH DUAL PROPERTIES?
FTY720 is a synthetic structural analog of myriocin that shares structural and functional homology with sphingosine-1-phosphate (S1P), a natural ligand to several G-protein–coupled receptors. FTY720, combined with CsA or everolimus, is being tested for the treatment of allograft rejection (45); however, its apparent mode of action may open up other possibilities for its use, including cancer treatment. Mechanistically, FTY720 has a novel action characterized by sequestration of lymphocytes into secondary lymphoid organs, without affecting lymphocyte functions or properties (46). FTY720 acts as an agonist and signals the S1P receptor family (S1P4 and S1P5) on lymphocytes, increasing their intrinsic mobility and responsiveness to chemokines (47), directing them to peripheral lymphoid tissues.
It has also been hypothesized that the FTY720-related decrease in lymphocyte number is caused by death of lymphocytes, because more than 4 μM of the drug induces apoptosis (48). Recent data published by Wang et al. (49) also demonstrate that FTY720 induces several cancerous cell lines to undergo apoptosis at high doses, whereas normal cells are resistant to the drug, even at high concentrations. This same group has shown that FTY720 can induce invasive cancer cells to undergo apoptosis at concentrations exceeding 5 μM, indicating that high doses of FTY720 might be used to treat cancer (50). Experimentally, Azuma et al. (51) showed that 5 mg/kg per day dosing of FTY720 suppresses tumor growth in a murine breast cancer model. In addition, tumor metastasis was inhibited at lower FTY720 doses (2 mg/kg/day), resulting in prolongation of animal survival. In these studies, FTY720 (2 μM) was suggested to prevent adhesion and migration of tumor cells to extracellular matrix proteins, and to reduce expression of integrins on cancer cells. Further mechanistic considerations include that FTY720 in leukemia cells decreases the activation of Akt, mentioned earlier as an intracellular signaling molecule promoting survival, growth, and protein synthesis in various cancer cells (52). In this same study, BAD, a downstream proapoptotic protein, is shown to be dephosphorylated and activated by FTY720, potentially promoting cancer cell apoptosis. Additional mechanistic studies show that FTY720 may exert anticarcinogenic effects against prostate cancer cells by various potentially interrelated means, ranging from mitogenic signaling modulation and cell-cycle regulation to induction of apoptosis (53). Of particular relevance to this overview, a recent study by Tanaka et al. (50) showed that FTY720 prevents cancer progression induced by CsA. The authors demonstrated that the morphologic changes in cancer cells induced by CsA could be reversed by combination with FTY720. In conclusion, FTY720 deserves further testing related to reducing cancer in transplant recipients.
CORTICOSTEROIDS, AZATHIOPRINE, AND MYCOPHENOLATE MOFETIL: A RELATIONSHIP TO CANCER?
Corticosteroids have been used for many years as part of most immunosuppressive regimens. It is well known that steroids are actually used to treat certain types of cancer, including lymphomas, but steroids themselves have also been associated with the occurrence of cancer (54). For example, and of particular interest in organ transplantation, there is an increased incidence of Kaposi sarcoma in patients who are chronically treated with steroids (55). The mechanism of this effect is unclear, but it is known that steroid inhibition of TGF-β enhances the growth of Kaposi sarcoma cells (56). However, because corticosteroid therapy is used only to support other immunosuppressive therapy against transplant rejection, its effect alone on cancer development in this situation is difficult to assess. Moreover, the undoubtedly complex, “double-edged” nature of corticosteroid pro- and anti-cancer effects is beyond the scope of the present overview.
Azathioprine (AZA) disrupts the synthesis of DNA and RNA, causing effective immunosuppression by interfering with lymphocyte proliferation. From another perspective, cancer cells could also be considered vulnerable to its action because AZA disrupts cell division. With regard to cancer and AZA use, some of the most useful data come from the pre-CsA era when the drug was used alone to treat a wide variety of autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. In 1966, Jensen and Soborg (57) were already aware of deleterious effects of AZA on DNA and were suspicious of the possible risk for malignancy when using the drug as an immunosuppressant. Indeed, the fear of promoting malignancies became more of a reality a few years later with reports of post-AZA treatment cancer, particularly lymphomas (58). Other early clinical data confirmed an increased lymphoma incidence with AZA, even after short-term use (59). In addition to the increased risk for lymphomas, AZA has also been correlated with induction of a broad variety of solid neoplasms, including squamous cell carcinoma (60,61), urinary bladder tumors (62), breast cancer (63), and brain tumors (64). However, with the more recent use of new combined immunosuppressive regimens, the effects of less intensive use of AZA on tumor development in a transplant situation become difficult to assess. McGeown et al. (65) showed in a follow-up study of 1,000 renal transplant recipients that patients on CsA regimens had a greater cumulative incidence of tumors after transplantation than those on AZA regimens. In a historical retrospective study, AZA-treated patients demonstrated a lower incidence of Kaposi sarcoma in comparison with CsA-based immunosuppression (66); however, a recent analysis of 50 transplant recipients in Turkey with cancer indicates a significantly increased Kaposi sarcoma rate when AZA is combined with CsA (67). Taking these data together, a clear correlation of less intensive AZA use with cancer development in transplant recipients has not been established.
The substance MMF has recently been established as an effective immunosuppressive agent in organ transplantation. In addition to its well-documented immunosuppressive effects through blockage of the de novo purine synthesis pathway, it may also possess some anti-neoplastic properties. Indeed, there is some evidence in the literature that an antitumor effect may exist, including that the substance was originally developed as an anti-neoplastic agent (68) and has been shown to inhibit some tumor cell lines (69–71). Clinically, there are reported cases of posttransplant Kaposi sarcoma regression after conversion of CsA immunosuppression to MMF (72,73), but another study hints that MMF might actually cause a higher incidence of Kaposi sarcoma (74). The most extensive study to date on MMF and cancer was presented at the American Transplant Congress 2003 by Robson et al. (abstract 139). A prospective observational cohort study from the United Network for Organ Sharing (8,246 patients) and Collaborative Transplant Study registries (4,123 patients) showed that MMF treatment did not significantly affect the incidence of PTLD according to an analysis of the United Network for Organ Sharing data; however, there was a significantly lower rate of PTLD after analyzing the Collaborative Transplant Study data. Further analysis of data from both registries revealed a small, but significant, decrease in the development of any malignancy in patients receiving MMF. In summary, although MMF may play some positive role against cancer in transplant recipients, the effects in this regard are just beginning to be assessed.
Contrary to the view that immunosuppressants promote cancer, new data indicate that some of these substances may actually be used to treat cancer. Therefore, we may already possess some therapeutic tools to simultaneously address the risk of allograft rejection and cancer in transplant recipients. New clinical studies designed primarily for this purpose will be essential to document the potential anti-cancer activities of selected immunosuppressive agents.
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