Why hyperuricemia in cancer

Repurposing these existing drugs may therefore be a novel strategy for management of some refractory cancers, but the application of those drugs needs further analyses. Prospective study of serum uric acid levels and incident metabolic syndrome in a Korean rural cohort.

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Uric acid as a danger signal in gout and its comorbidities. Nat Rev Rheumatol. Front Immunol. Obesity and cancer: local and systemic mechanisms. Annu Rev Med. The prognosis of cervical cancer patients with hyperuricemia is much poorer than those with normouricemia. However, more relevant studies with large sample size are warranted for further elucidation.

In the present study, a total of patients with histologically diagnosed cervical cancer from to treated in our hospital were enrolled. Among them, 50 cervical cancer patients were subject to with hyperuricemia, while the other 50 patients with normouricemia were matched to patients with hyperuricemia by age. The mean level of serum uric acid of all cervical cancer patients was All patients had signed the informed consent prior to study inclusion. Blood samples were acquired by puncturing from peripheral venous 24—48 h prior to clinical treatment during routine preoperative assessment, and were used for evaluation of levels of uric acid in serum samples from patients with cervical cancer.

Serum uric acid was assayed by way of EDTA hydrazine on the autoanalyzer based on the basic protocols [ 28 ]. The association between hyperuricemia and cervical cancer outcome was investigated by overall survival estimation. In this study, overall survival was established as from time of making the definite diagnosis or accepting surgery to death or the final follow-up time.

We carried out the follow-up every six months up till to loss to follow-up, death, or follow-up for a total of 5 years. The latest follow-up time in this study was conducted in March, The association between hyperuricemia and the overall survival of patients with cervical cancer was estimated by the Kaplan—Meier curve analysis. In addition, we used the log-rank test to assess the survival rate of cervical cancer patients.

Cox regression analysis was used to determine the relative risk of mortality. Cervical cancer: Screening, management, and prevention. Nurse Pract. Evolution of cervical cancer screening and prevention in United States and Canada: implications for public health practitioners and clinicians. Prev Med. Evaluation of serum uric acid levels in patients with oral squamous cell carcinoma. Indian J Dent Res. Hyperuricemia has an adverse impact on the prognosis of patients with osteosarcoma.

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Acute hyperuricemic kidney failure: treatment by uricozyme [letter]. Nouv Presse Med ; 4 31 : Urate-oxidase prophylaxis of uric acid-induced renal damage in childhood leukemia. J Pediatr ; 1 : —5. Masera G, Jankovic M. Tumor lysis syndrome, case report and review of the literature. Ann Oncol ; 8 1 : Urate oxidase in prevention and treatment of hyperuricemia associated with lymphoid malignancies. Leukemia ; 11 11 : —6. Advances in the management of malignancy-associated hyperuricaemia.

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A micropuncture study of the early phase of acute urate nephropathy. J Clin Invest ; —9. They have postulated that leptin may directly impair UA excretion in the kidney and that in obesity elevated leptin levels may impair renal clearance of UA resulting in hyperuricemia. Hyperuricemic, leptin receptor deficient mice also show excessive hepatic XOR expression suggesting that leptin receptor signaling may also down regulate hepatic XOR expression [ 67 ].

Thus, leptin may affect SUA at both the level of production and renal clearance. There is also experimental evidence that UA may have a role in mediating leptin resistance. Recent studies have reported that elevated SUA precedes the development of MetS in humans [ 42 ], suggesting that it might precede the development of leptin resistance. Experimental studies found that lowering SUA pharmacologically improved features of MetS in rats in response to fructose feeding, including the development of insulin resistance, hypertriglyceridemia, and elevated blood pressure [ 19 ].

More recently, a pilot study found that lowering SUA in fructose-fed rats also reduced leptin expression in visceral fat tissues [ ]. Further studies will be required to determine if the reduced leptin expression would also translate into reduced leptin resistance.

The pro-tumorigenic role of leptin on breast, colon, prostate, and ovarian cancer in patients with obesity, MetS, and T2DM was recently reviewed [ 85 , , ]. While leptin is an apparent growth factor for BC that is elevated in BC patients [ 36 , ], its mechanism of tumor promotion remains equivocal [ 36 ].

Importantly, leptin receptors are expressed on many cancer cells including those of the breast [ ], and exposure of MCF-7 BC cells to leptin induced cell proliferation that was mediated in part by activation of MAPK [ ]. As described below, we speculate that leptin may further stimulate proliferation and tumorigenesis by down-regulating cancer cell XOR. Homeostasis of SUA in humans is maintained by the bidirectional flux of SUA in renal proximal tubule epithelial cells.

Presently, no less than 10 plasma membrane transport proteins have been found to contribute to UA movement into and out of the renal proximal tubule epithelial cells [ 68 ]. For many of these, a large array of accessory proteins has been identified that are required for co-transport function [ 68 ]. ABCG2 is an important efflux transporter of xenobiotic compounds, including many antineoplastic drugs, and its inhibition or mutation can improve cancer chemotherapy [ ].

Functional analysis confirmed the principal role of ABCG2 in normal physiology, independent of drug efflux, as that of UA efflux. Prospective analysis of the CA polymorphism in untreated patient populations, those not undergoing any chemotherapeutic drug treatment, demonstrated significant and markedly increased risk for developing nonpapillary renal cell carcinoma [ ], an increased risk and poor survival prognosis for patients with diffuse large B-cell lymphoma [ ], and increased risk and poor survival prognosis for patients with acute leukemia [ ].

These data strongly support the premise that hyperuricemia can be an important risk factor for cancer incidence and mortality, and they underscore the importance of conducting more expansive analysis of other UA transport proteins in diverse cancer settings.

Inflammatory stress induced by elevated intracellular UA may promote transformation, while elevated extracellular UA may further stimulate tumor cell proliferation, migration, and survival contributing to the development of highly aggressive cancer.

Hyperuricemia contributes to tumorigenesis by promoting both transformation and tumor cell proliferation, migration, and survival. High levels of extracellular UA present in the serum or in the local microenvironment of tumor cells exerts many pro-inflammatory effects that contribute to tumorigenesis.

Stimulation of cancer cells by UA further promotes proliferation, migration, and survival that mediates progression from early stage cancer to highly aggressive cancer. Although the increased cancer burden associated with hyperuricemia in obesity, T2DM, and MetS has suggested the relevance of modulating XOR activity in cancer therapy, presently available strategies may be inappropriate for many types of cancer. Allopurinol and febuxostat are FDA approved systemic pharmacological inhibitors that block XOR activity in all cells of the body [ 2 , ].

However, inhibition of XOR in tumor cells per se is a potentially confounding factor that limits current strategies for the pharmacological control of SUA in cancer management. Decreased or absent tumor cell XOR has been observed in the most aggressive human breast cancer [ ], gastric cancer [ ], colorectal cancer [ ], ovarian cancer [ ], non-small-cell lung cancer [ ], and in rat hepatic cancer [ , ]. For breast, gastric, colorectal, ovarian, and lung cancers in humans the decreased XOR activity was associated with worse clinical prognosis and unfavorable outcome reduced survival.

Poor XOR expression was also associated with poorly differentiated breast, gastric, and colorectal cancers and was associated with over two fold increased risk of distant metastasis.

While it has been suggested that the decreased purine catabolism and increased activity of salvage pathway enzymes would favor tumor cell growth [ , ], the decreased XOR activity observed in highly aggressive cancer cells appears to exert unexpected effects on cancer cell differentiation that also favors tumorigenesis and metastasis. XOR activity was found to modulate expression of the inhibitor of differentiation protein, Id1. Remarkably, epithelial XOR has now been found to modulate three of the critical signature genes mediating BC aggressiveness and metastasis: COX-2, MMP-1, and Id1 [ , ] consistent with the observed increase in clinical recurrence and metastasis in poor XOR expressing cancers.

These data indicate that systemic pharmacological inhibition of XOR with the goal of reducing SUA might exacerbate tumorigenesis or metastasis by inhibition of tumor cell XOR.

Little is known about the response of cancer cells themselves to UA. UA present in the tumor microenvironment may contribute to tumorigenesis or metastasis in ways that are distinct from the pro-inflammatory processes elicited by SUA. Exposure of human mammary cancer cells or mouse mammary epithelial cells in vitro to a wide concentration range of UA dose dependently increased migratory rate of both cells [ ].

Migratory rate of both cells was significantly increased at even low normal levels of UA. Thus, treatment of BC cells with exogenous UA in vitro appeared to replicate the state of cells from more aggressive tumors with increased metastasis that have been associated with aggressive breast and colorectal cancer in patients with MetS [ 23 , , ].

It was postulated that the high levels of SUA observed in obesity, T2DM, and MetS may repress tumor cell XOR and inhibit its function in promoting epithelial cancer cell differentiation [ ], and it has been shown that physiological levels of UA can indeed repress XOR activity [ ].

However, it can be imagined as well that highly aggressive tumor cells that are naturally deficient in XOR expression [ - ] may be both poorly set up to promote differentiation but still capable of responding to exogenous UA by increased aggressiveness.

Furthermore, we postulate that the elevated levels of leptin found in obesity, T2DM, and MetS may collaborate with UA and contribute to tumorigenesis and metastasis by down regulation of tumor cell XOR.

Elevated UA and reduced intracellular XOR contribute to tumor cell proliferation, migration, and survival. ROS scavenging properties of extracellular UA are postulated to promote cancer cell growth and survival in part by protecting cells from oxidative stress induced apoptosis.

This arises because tumor cells in general exhibit poor capacity to survive oxidative stress compared with normal cells and may therefore be protected by the antioxidant ROS scavenging properties of UA J-Shaped dose—response curve; [ 32 ].

Loss of XOR expression in the most aggressive cancer cells also contributes to tumor cell proliferation, migration, and survival. The diminished XOR expression found in aggressive cancer cells would result in shunting the XOR substrates hypoxanthine and xanthine into the salvage pathway, providing substrates for nucleotide synthesis, tumor growth, and proliferation. The independent effects of leptin on cancer cells notwithstanding [ 85 , ], the elevated levels of leptin observed in MetS associated cancer may also drive these processes both by inducing hyperuricemia and by down regulating cancer cell XOR.

Certain leukemias and the Tumor Lysis Syndrome are cancer states that are also associated with severe hyperuricemia. In these cases, the hyperuricemia arises as a result of cell lysis, release of purines, and subsequent UA accumulation. XOR plays a prominent role in both cancer types as the source of UA, and current therapies are directed at inhibition of XOR with allopurinol or Febuxostat and degradation of the SUA using recombinant uricase Rasburicase.

Recent reviews provide excellent discussion of both cancer states and therapeutic strategies for reducing the associated hyperuricemia [ , ]. At the present time, very little is known about the mechanisms by which UA may signal to cancer cells. However, some key observations have been generated from non-cancerous cells that may provide a useful background for further studies conducted on cancer cells themselves. Uptake of UA by primary renal proximal tubule epithelial cells PTEC of the rabbit inhibited in vitro cell proliferation that was mediated by at least two signaling mechanisms [ ].

Cells were mixed with control cells no UA and Lys light , proteins prepared, trypsin digested, fractionated by liquid chromatography-mass spectrometry LC-MS , and quantified by the relative ratio of isotopic peptide pairs. After correction for false discovery rate proteins of 13, peptides were found altered by exposure to UA. While details of this analysis remain to be fully deciphered, they establish the primacy of proliferation and apoptosis pathways regulated by UA in renal PTEC. While UA induced an apparent oxidative and nitrosative stress, it was also found subsequently to activate the inflammatory state of these cells [ 67 ].

UA at both normo- and hyperuricemic levels simultaneously increased steady state mRNA expression of the leukocyte chemokine MCP-1 and decreased expression of the anti-inflammatory protein adiponectin, and these data were largely replicated in an in vivo mouse model.

While XOR dependent redox mechanisms were implicated in adipogenesis, the potential impact of UA per se on adipocyte differentiation has not been determined. Although the identity of the UA transporter mediating the response to UA was not identified, GLUT9 is expressed on leukocytes and remains a reasonable candidate for this function [ ].

As an endogenous product of leukocytes, XOR activity exerts many effects on inflammatory potential, cytokine synthesis, and lipid uptake [ , , ]. Because treatment of mouse macrophages with oxonic acid, an inhibitor of uricase, replicated many of the effects of exogenous UA, it was postulated that intracellular UA was in part responsible for the effects of endogenous XOR generated UA on leukocyte function.

While the detailed mechanism by which UA contributes to intracellular signaling networks is unknown, it has been postulated to involve intracellular redox dependent mechanisms. These observations dovetail well with data generated in renal epithelial cells that identified several redox sensitive components of the upstream network mediating MAPK activation that are induced by UA [ 69 ]. Two risk factors for the development and progression of breast cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome.

To ameliorate inflammation, clinical trials abound that focus on COX-2 inhibition. The principal factors felt to mediate cancer risk from metabolic syndrome have included insulin resistance, high IGF1R signaling and higher tissue levels of estrogen for breast cancer. Hypothesis for the protumorigenic role of UA in the breast cancer microenvironment.

As observed in other inflammatory environments, UA at both normo- and hyperuricemic levels may simultaneously increase steady state mRNA expression of the leukocyte chemokine MCP-1 and decrease expression of the anti-inflammatory protein adiponectin.

Presently, the identity of the UA transporter mediating macrophage response to UA has not been identified. As an endogenous product of leukocytes, XOR activity may exert many effects on inflammatory potential, cytokine synthesis, and lipid uptake.

Together, these findings support the hypothesis that hyperuricemia might be partially responsible for the low grade inflammation present in the breast tumor microenvironment that contributes to tumor cell proliferation and metastasis. Significant side effects of systemic chronic inhibition of XOR have been recognized for many years. Confounding problems associated with chronic inhibition of XOR include diarrhea, diminished renal function, leukopenia, hypersensitivity reactions, vasculitis [ 3 ], and even exacerbation of vascular injury through recently identified effects on nitrite reduction [ ].

While the frequency of allopurinol hypersensitivity syndrome may be significantly reduced by avoiding the administration of allopurinol to subjects bearing the HLA-B58 haplotype [ ], it remains a serious syndrome with high mortality.

Systemic pharmacological inhibition of cancer cell XOR could theoretically exacerbate tumorigenesis, metastasis, and mortality. These unwanted side effects underscore the urgent need for mechanism based pre-clinical studies that can identify optimal strategies for management of hyperuricemia in relevant cancer models.

The authors declare no financial or non-financial competing interests. Johnson holds patent applications related to lowering uric acid in the treatment of metabolic syndrome, kidney disease and hypertension, and has consulted for Ardea, Novartis, Danone, and Astellas. He also holds a patent for the use of allopurinol to treat primary hypertension with the University of Washington and Merck, Inc. The authors contributed equally to the research, writing, and review of this manuscript.

All authors read and approved the final manuscript. National Center for Biotechnology Information , U. Journal List Clin Transl Med v. Clin Transl Med. Published online Aug Author information Article notes Copyright and License information Disclaimer. Corresponding author. Mehdi A Fini: ude. Received May 3; Accepted Jul This article has been cited by other articles in PMC.

Abstract Two risk factors for the development and progression of cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome. Review Hyperuricemia and cancer UA is derived exclusively from the oxidation of xanthine and hypoxanthine by XOR [ 1 ], and pharmacological inhibition of XOR has been used extensively for the management of hyperuricemic disorders such as gout, nephrolithiasis, some cases of acute and chronic kidney disease, ischemia-reperfusion disorders, and others [ 2 , 3 ].

Table 1 References demonstrating the specific association of SUA with cancer risk, recurrence, and mortality. Open in a separate window. SUA, inflammation, and cancer The association of elevated SUA with increased cancer risk and mortality predicts that diseases associated with hyperuricemia would also exhibit excess cancer risk and mortality. Adiponectin, SUA, and cancer Adiponectin is an anti-inflammatory protein whose levels are reduced in obesity, T2DM, insulin resistance, and MetS [ 70 ] and when reduced it has been associated with increased risk of diverse cancers [ 71 - 73 ].

Figure 1. Tumor cell XOR, UA, and cancer Although the increased cancer burden associated with hyperuricemia in obesity, T2DM, and MetS has suggested the relevance of modulating XOR activity in cancer therapy, presently available strategies may be inappropriate for many types of cancer. Figure 2. The special cases of leukemia and tumor lysis syndrome Certain leukemias and the Tumor Lysis Syndrome are cancer states that are also associated with severe hyperuricemia.

Renal epithelial cells Uptake of UA by primary renal proximal tubule epithelial cells PTEC of the rabbit inhibited in vitro cell proliferation that was mediated by at least two signaling mechanisms [ ]. UA as an Intracellular Redox Signal While the detailed mechanism by which UA contributes to intracellular signaling networks is unknown, it has been postulated to involve intracellular redox dependent mechanisms.

Conclusions Two risk factors for the development and progression of breast cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome.