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. This review proposes two new targets that may mechanistically integrate inflammation and metabolic syndrome, have been largely ignored, and are known to be druggable. Recent evidence has demonstrated that elevated serum uric acid (hyperuricemia) is associated with excess cancer risk, recurrence, and mortality. Although uric acid (UA) can function as a systemic antioxidant, its pro-inflammatory properties have been postulated to play an important role in the pathogenesis of cancer. Furthermore, obesity, Type 2 Diabetes Mellitus (T2DM), and the metabolic syndrome (MetS) are also associated with excess cancer, chronic inflammation, and with hyperuricemia, suggesting that UA may represent an important link between these disorders and the development of cancer. While pharmacological modulation of hyperuricemia could in principal augment anti-cancer therapeutic strategies, some cancer cells express low intracellular levels of the enzyme Xanthine Oxidoreductase (XOR) that are associated with increased cancer aggressiveness and poor clinical outcome. Thus, systemic pharmacological inhibition of XOR may worsen clinical outcome, and specific strategies that target serum uric acid (SUA) without inhibiting tumor cell XOR may create new therapeutic opportunities for cancer associated with hyperuricemia. This review will summarize the evidence that elevated SUA may be a true risk factor for cancer incidence and mortality, and mechanisms by which UA may contribute to cancer pathogenesis will be discussed in the hope that these will identify new opportunities for cancer management.
Highlights
Two risk factors for the development and progression of cancers that are amenable to life style modification are chronic inflammation and the metabolic syndrome
Leptin may affect serum uric acid (SUA) at both the level of production and renal clearance. These results suggest an additional link between SUA and cancer: with leptin regulating SUA levels in subjects with obesity, metabolic syndrome (MetS), and Type 2 Diabetes Mellitus (T2DM)
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
Summary
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. Realization of the important role played by UA as a signaling molecule mediating the inflammatory effects of hyperuricemia in adipocytes and leukocytes, as well as in signaling to cancer cells (Figure 3) has emphasized the relevance of managing UA therapeutically which could significantly improve treatment strategies for cancer that is associated with hyperuricemic disorders. 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 preclinical studies that can identify optimal strategies for management of hyperuricemia in relevant cancer models. 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.
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