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Martin Almquist, Elin Isaksson, and Naomi Clyne

Renal hyperparathyroidism (rHPT) is a complex and challenging disorder. It develops early in the course of renal failure and is associated with increased risks of fractures, cardiovascular disease and death. It is treated medically, but when medical therapy cannot control the hyperparathyroidism, surgical parathyroidectomy is an option. In this review, we summarize the pathophysiology, diagnosis, and medical treatment; we describe the effects of renal transplantation; and discuss the indications and strategies in parathyroidectomy for rHPT. Renal hyperparathyroidism develops early in renal failure, mainly as a consequence of lower levels of vitamin D, hypocalcemia, diminished excretion of phosphate and inability to activate vitamin D. Treatment consists of supplying vitamin D and reducing phosphate intake. In later stages calcimimetics might be added. RHPT refractory to medical treatment can be managed surgically with parathyroidectomy. Risks of surgery are small but not negligible. Parathyroidectomy should likely not be too radical, especially if the patient is a candidate for future renal transplantation. Subtotal or total parathyroidectomy with autotransplantation are recognized surgical options. Renal transplantation improves rHPT but does not cure it.

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W P Bocchinfuso and K S Korach

Introduction Estrogen has been thought to be required for the development, differentiation and function of the female reproductive tract (George & Wilson 1988). It promotes the proliferation of the uterine and vaginal epithelium and ovarian follicular development (Canez et al. 1992); the development of the mammary gland, external genitalia, appropriate reproductive sexual behavior, and other secondary sexual characteristics (George & Wilson 1988). In more non-traditional target tissues, estrogen action has been shown to influence bone development, lipid metabolism and cardiovascular function (Auchus & Fuqua 1994, Ciocca & Vargas Roig 1995). The biological actions of estrogens, particularly 17β-estradiol(estradiol), are mediated through the estrogen receptor, which functions as a ligand-inducible transcription factor and is a member of the nuclear receptor superfamily that bind steroids, thyroid hormone, retinoids, prostanoids and vitamin D1 (Tsai & O'Malley 1994). Like other nuclear receptors, the estrogen receptor is composed of distinct functional domains (Fig. 1)
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K W Colston

INTRODUCTION Over the past two decades much has been learned about the metabolism and actions of vitamin D. Considered to be a dietary requirement essential for the prevention of rickets in the early years of this century, it is now clear that vitamin D is normally synthesized in adequate amounts in the skin by the actions of ultraviolet light. An exciting new area of research in the vitamin D field has opened up with the discovery of new target tissues, novel mechanisms of action and the synthesis of new analogues of vitamin D with tissue-selective actions and potential as therapeutic agents in a wide variety of clinical situations. This development has arisen from the realization that, in addition to its classical role as a calciotrophic hormone, the physiologically active metabolite of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), has a wide range of biological effects in haemopoietic and
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Jessica Svedlund, Elham Barazeghi, Peter Stålberg, Per Hellman, Göran Åkerström, Peyman Björklund, and Gunnar Westin

Primary hyperparathyroidism (pHPT) resulting from parathyroid tumors is a common endocrine disorder with incompletely understood etiology. In renal failure, secondary hyperparathyroidism (sHPT) occurs with multiple tumor development as a result of calcium and vitamin D regulatory disturbance. The aim of this study was to investigate a potential role of the histone 3 lysine 27 methyltransferase EZH2 in parathyroid tumorigenesis. Parathyroid tumors from patients with pHPT included adenomas and carcinomas. Hyperplastic parathyroid glands from patients with HPT secondary to uremia and normal parathyroid tissue specimens were included in this study. Quantitative RT-PCR, western blotting, bisulfite pyrosequencing, colony formation assay, and RNA interference were used. EZH2 was overexpressed in a subset of the benign and in all malignant parathyroid tumors as determined by quantitative RT-PCR and western blotting analyses. Overexpression was explained by EZH2 gene amplification in a large fraction of tumors. EZH2 depletion by RNA interference inhibited sHPT-1 parathyroid cell line proliferation as determined by tritium–thymidine incorporation and colony formation assays. EZH2 depletion also interfered with the Wnt/β-catenin signaling pathway by increased expression of growth-suppressive AXIN2, a negative regulator of β-catenin stability. Indeed, EZH2 contributed to the total level of aberrantly accumulated transcriptionally active (nonphosphoylated) β-catenin in the parathyroid tumor cells. To our knowledge EZH2 gene amplification presents the first genetic aberration common to parathyroid adenomas, secondary hyperplastic parathyroid glands, and parathyroid carcinomas. This supports the possibility of a common pathway in parathyroid tumor development.

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D M Peehl and D Feldman

Prostate cancer is a leading cause of cancer-related deaths in many countries. Premalignant lesions and invasive cancer occur more frequently in the prostate than in any organ other than the skin. Yet, the incidence of clinically detected prostate cancer is much lower than the histopathological incidence. The slow growth of prostate cancer and the low incidence of clinically manifest disease in some geographical locations or racial/ethnic groups suggest that prostate cancer can be controlled, perhaps by dietary factors. Vitamin D and retinoids have emerged as leading candidates both to prevent and to treat prostate cancer. Many of the activities of these compounds, established from epidemiological studies, research with cell culture and animal models, and clinical trials, are consistent with tumor suppressor effects. However, retinoids may have additional tumor enhancer properties that balance or negate anti-cancer activity. This perhaps explains the overall lack of protective effects of vitamin A compounds against prostate cancer found in epidemiological studies, and the minimal efficacy of retinoids in clinical trials to treat prostate cancer. While current efforts focus on developing strategies to use vitamin D compounds to control prostate cancer, the possibility exists that prostate cancer cells may become resistant to tumor suppressor effects of vitamin D. Analyses of experimental model systems show that prostate cancer cells become less sensitive to vitamin D through loss of receptors or signaling molecules that mediate vitamin D's actions, or through changes in metabolic enzymes that synthesize or degrade vitamin D compounds. The potential promise of exploiting vitamin D to control prostate cancer is tempered by the possibility that prostate cancer, perhaps even at early stages, may develop mechanisms to escape tumor suppressor activities of vitamin D and/or retinoids.

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Fábio Pereira, María Jesús Larriba, and Alberto Muñoz

The most active vitamin D metabolite, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3), is a pleiotropic hormone with wide regulatory actions. Classically, vitamin D deficiency was known to alter calcium and phosphate metabolism and bone biology. In addition, recent epidemiological and experimental studies support the association of vitamin D deficiency with a large variety of human diseases, and particularly with the high risk of colorectal cancer. By regulating the expression of many genes via several mechanisms, 1,25(OH)2D3 induces differentiation, controls the detoxification metabolism and cell phenotype, sensitises cells to apoptosis and inhibits the proliferation of cultured human colon carcinoma cells. Consistently, 1,25(OH)2D3 and several of its analogues decrease intestinal tumourigenesis in animal models. Molecular, genetic and clinical data in humans are scarce but they suggest that vitamin D is protective against colon cancer. Clearly, the available evidence warrants new, well-designed, large-scale trials to clarify the role of vitamin D in the prevention and/or therapy of this important neoplasia.

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Srilatha Swami, Aruna V Krishnan, Jasmaine Williams, Abhishek Aggarwal, Megan A Albertelli, Ronald L Horst, Brian J Feldman, and David Feldman

Abstract

Obesity is an established risk factor for postmenopausal breast cancer (BCa), insulin resistance, and vitamin D deficiency, and all contribute to increased synthesis of mammary estrogens, the drivers of estrogen receptor-positive (ER+) BCa growth. As both dietary vitamin D and calcitriol treatments inhibit breast estrogen synthesis and signaling, we hypothesized that vitamin D would be especially beneficial in mitigating the adverse effects of obesity on ER+BCa. To assess whether obesity exerted adverse effects on BCa growth and whether vitamin D compounds could reduce these unfavorable effects, we employed a diet-induced obesity (DIO) model in ovariectomized C57BL/6 mice. Breast tumor cells originally from syngeneic Mmtv-Wnt1 transgenic mice were then implanted into the mammary fat pads of lean and obese mice. DIO accelerated the initiation and progression of the mammary tumors. Treatments with either calcitriol or dietary vitamin D reduced the adverse effects of obesity causing a delay in tumor appearance and inhibiting continued tumor growth. Beneficial actions of treatments with vitamin D or calcitriol on BCa and surrounding adipose tissue included repressed Esr1, aromatase, and Cox2 expression; decreased tumor-derived estrogen and PGE2; reduced expression of leptin receptors; and increased adiponectin receptors. We demonstrate that vitamin D treatments decreased insulin resistance, reduced leptin, and increased adiponectin signaling and also regulated the LKB1/AMPK pathway contributing to an overall decrease in local estrogen synthesis in the obese mice. We conclude that calcitriol and dietary vitamin D, acting by multiple interrelated pathways, mitigate obesity-enhanced BCa growth in a postmenopausal setting.

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Carlien Leyssens, Lieve Verlinden, and Annemieke Verstuyf

The active form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is mostly known for its importance in the maintenance of calcium and phosphate homeostasis. However, next to its classical effects on bone, kidney and intestine, 1,25(OH)2D3 also exerts antineoplastic effects on various types of cancer. The use of 1,25(OH)2D3 itself as treatment against neoplasia is hampered by its calcemic side effects. Therefore, 1,25(OH)2D3-derived analogs were developed that are characterized by lower calcemic side effects and stronger antineoplastic effects. This review mainly focuses on the role of 1,25(OH)2D3 in breast, prostate and colorectal cancer (CRC) and the underlying signaling pathways. 1,25(OH)2D3 and its analogs inhibit proliferation, angiogenesis, migration/invasion and induce differentiation and apoptosis in malignant cell lines. Moreover, prostaglandin synthesis and Wnt/b-catenin signaling are also influenced by 1,25(OH)2D3 and its analogs. Human studies indicate an inverse association between serum 25(OH)D3 values and the incidence of certain cancer types. Given the literature, it appears that the epidemiological link between vitamin D3 and cancer is the strongest for CRC, however more intervention studies and randomized placebo-controlled trials are needed to unravel the beneficial dose of 1,25(OH)2D3 and its analogs to induce antineoplastic effects.

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K W Colston and C M√∏rk Hansen

It is now well established that, in addition to its central role in the maintenance of extracellular calcium levels and bone mineralization, 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), the active form of vitamin D, also acts as a modulator of cell growth and differentiation in a number of cell types, including breast cancer cells. The anti-proliferative effects of 1,25(OH)(2)D(3) have been linked to suppression of growth stimulatory signals and potentiation of growth inhibitory signals, which lead to changes in cell cycle regulators such as p21(WAF-1/CIP1) and p27(kip1), cyclins and retinoblastoma protein as well as induction of apoptosis. Such studies have led to interest in the potential use of 1,25(OH)(2)D(3) in the treatment or prevention of certain cancers. Since this approach is limited by the tendency of 1,25(OH)(2)D(3) to cause hypercalcaemia, synthetic vitamin D analogues have been developed which display separation of the growth regulating effects from calcium mobilizing actions. This review examines mechanisms by which 1,25(OH)(2)D(3) and its active analogues exert both anti-proliferative and pro-apoptotic effects and describes some of the synthetic analogues that have been shown to be of particular interest in relation to breast cancer.

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William H Chong, Alfredo A Molinolo, Clara C Chen, and Michael T Collins

Tumor-induced osteomalacia (TIO) is a rare and fascinating paraneoplastic syndrome in which patients present with bone pain, fractures, and muscle weakness. The cause is high blood levels of the recently identified phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 (FGF23). In TIO, FGF23 is secreted by mesenchymal tumors that are usually benign, but are typically very small and difficult to locate. FGF23 acts primarily at the renal tubule and impairs phosphate reabsorption and 1α-hydroxylation of 25-hydroxyvitamin D, leading to hypophosphatemia and low levels of 1,25-dihydroxy vitamin D. A step-wise approach utilizing functional imaging (F-18 fluorodeoxyglucose positron emission tomography and octreotide scintigraphy) followed by anatomical imaging (computed tomography and/or magnetic resonance imaging), and, if needed, selective venous sampling with measurement of FGF23 is usually successful in locating the tumors. For tumors that cannot be located, medical treatment with phosphate supplements and active vitamin D (calcitriol or alphacalcidiol) is usually successful; however, the medical regimen can be cumbersome and associated with complications. This review summarizes the current understanding of the pathophysiology of the disease and provides guidance in evaluating and treating these patients. Novel imaging modalities and medical treatments, which hold promise for the future, are also reviewed.