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.
Fábio Pereira, María Jesús Larriba, and Alberto Muñoz
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.
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.
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.
María Rodríguez-Sanz, Daniel Prieto-Alhambra, Sonia Servitja, Natalia Garcia-Giralt, Laia Garrigos, Jaime Rodriguez-Morera, Joan Albanell, Maria Martínez-García, Iria González, Adolfo Diez-Perez, Ignasi Tusquets, and Xavier Nogués
The aim of the study was to evaluate the progression of bone mineral density (BMD) during 3 years of aromatase inhibitors (AI) therapy in actual practice conditions. This prospective, clinical cohort study of Barcelona–Aromatase induced Bone Loss in Early breast cancer (B-ABLE) assessed BMD changes during 3 years of AI treatment in women with breast cancer. Patients with osteoporosis (T score < −2.5 or T score ≤ −2.0) and a major risk factor and/or prevalent fragility fractures were treated with oral bisphosphonates (BPs). Of 685 women recruited, 179 (26.1%) received BP treatment. By the third year of AI therapy, this group exhibited increased BMD in the lumbar spine (LS; 2.59%) and femoral neck (FN; 2.50%), although the increase was significant only within the first year (LS: 1.99% and FN: 2.04%). Despite BP therapy, however, approximately 15% of these patients lost more than 3% of their baseline bone mass. At 3 years, patients without BP experienced BMD decreases in the LS (−3.10%) and FN (−2.79%). In this group, BMD changes occurred during the first (LS: −1.33% and FN: −1.25%), second (LS: −1.19% and FN: −0.82%), and third (LS: −0.57% and FN: −0.65%) years of AI treatment. Increased BMD (>3%) was observed in just 7.6% and 10.8% of these patients at the LS and FN, respectively. Our data confirm a clinically relevant bone loss associated with AI therapy amongst nonusers of preventative BPs. We further report on the importance of BMD monitoring as well as calcium and 25-hydroxy vitamin D supplementation in these patients.
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.
Srilatha Swami, Aruna V Krishnan, Jasmaine Williams, Abhishek Aggarwal, Megan A Albertelli, Ronald L Horst, Brian J Feldman, and David Feldman
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.
Johan O Paulsson, Ninni Mu, Ivan Shabo, Na Wang, Jan Zedenius, Catharina Larsson, and C Christofer Juhlin
Telomerase reverse transcriptase (TERT) promoter mutations have been linked to adverse clinical parameters in thyroid cancer, but TERT-expressing tumours are not always mutated. Little is known regarding other TERT-related genetic aberrations. To delineate the role of TERT gene aberrancies in follicular thyroid tumours, 95 follicular carcinomas (FTCs), 43 follicular adenomas (FTAs) and 33 follicular tumours of uncertain malignant potential (FT-UMPs) were collected. The tumours were assayed for TERT expression, TERT promoter mutations, TERT promoter hypermethylation and TERT gene copy number (CN) alterations and the results were compared to clinical parameters. Cases with mutation, detectable mRNA expression, CN gain or hypermethylation were classified as TERT aberrant, and these aberrancies were regularly found in FTC and FT-UMP but uncommonly found in FTA. In total, 59% FTCs and 63% FT-UMPs exhibited one or more of these TERT gene aberrancies. Moreover, 24 out of 28 FTCs (86%) with TERT expression displayed an evident TERT gene aberration, and statistics showed an increased risk for relapse in FTCs with TERT expression, CN gain or hypermethylation. We conclude that TERT expression in follicular thyroid tumours is coupled to promoter mutations, CN gain and increased promoter methylation. The molecular similarities regarding TERT aberrations between the FTC and FT-UMP groups indicate that a significant subset of FT-UMP cases may display future recurrences. TERT aberrancies are thus promising as future additional markers for determining malignant potential of follicular thyroid tumours.
Maria Denaro, Clara Ugolini, Anello Marcello Poma, Nicla Borrelli, Gabriele Materazzi, Paolo Piaggi, Massimo Chiarugi, Paolo Miccoli, Paolo Vitti, and Fulvio Basolo
Noninvasive encapsulated follicular variants of papillary thyroid carcinomas have been recently reclassified as noninvasive follicular thyroid neoplasms with papillary-like nuclear features (NIFTPs). NIFTPs exhibit a behavior that is very close to that of follicular adenomas but different from the infiltrative and invasive follicular variants of papillary thyroid carcinomas (FVPTCs). The importance of miRNAs to carcinogenesis has been reported in recent years. miRNAs seem to be promising diagnostic and prognostic molecular markers for thyroid cancer, and the combination of miRNA expression and mutational status might improve cytological diagnosis. The aim of the present study was to evaluate the miRNA expression profile in wild-type, RAS - or BRAF-mutated NIFTPs, infiltrative and invasive FVPTCs, and follicular adenomas using the nCounter miRNA Expression assay (NanoString Technologies). To identify the significant Kyoto Encyclopedia of Genes and Genomes (KEGG) molecular pathways associated with deregulated miRNAs, we used the union of pathways option in DNA Intelligent Analysis (DIANA) miRPath software. We have shown that the miRNA expression profiles of wild-type and mutated NIFTPs could be different. The expression profile of wild-type NIFTPs seems comparable to that of follicular adenomas, whereas mutated NIFTPs have an expression profile similar to that of infiltrative and invasive FVPTCs. The upregulation of 4 miRNAs (miR-221-5p, miR-221-3p, miR-222-3p, miR-146b-5p) and the downregulation of 8 miRNAs (miR-181a-3p, miR-28-5p, miR-363-3p, miR-342-3p, miR-1285-5p, miR-152-3p, miR-25-3p, miR-30e-3) in mutated NIFTPs compared to wild-type ones suggest a potential invasive-like phenotype by deregulating the specific pathways involved in cell adhesion and cell migration (Hippo signaling pathway, ECM-receptor interaction, adherens junction, regulation of actin cytoskeleton, fatty acid biosynthesis and metabolism).
E Saggiorato, R De Pompa, M Volante, S Cappia, F Arecco, A P Dei Tos, F Orlandi, and M Papotti
The distinction of benign from malignant follicular thyroid neoplasms remains a difficult task in diagnostic fine-needle aspiration cytology, and some discrepant results have been reported for the individual immunocytochemical markers of malignancy proposed so far. The aim of this study was to test if the combined use of a panel of markers could improve the diagnostic accuracy in the preoperative cytological evaluation of ‘follicular neoplasms’ in an attempt to reduce the number of thyroidectomies performed for benign lesions. The immunocytochemical expression of galectin-3, HBME-1, thyroperoxidase, cytokeratin-19 and keratan-sulfate was retrospectively analyzed in 125 consecutive fine-needle aspiration samples (cell blocks) of indeterminate diagnoses of ‘follicular thyroid neoplasm’, and compared with their corresponding surgical specimens, including 33 follicular carcinomas, 42 papillary carcinomas and 50 follicular adenomas. Statistical analysis on each marker confirmed that galectin-3 and HBME-1 were the most sensitive (92% and 80% respectively) and specific (94% and 96% respectively) molecules. The use of these two markers sequentially in non-oncocytic lesions (testing HBME-1 as a second marker whenever galectin-3 proved negative) increased the sensitivity and specificity up to 97% and 95% respectively. In oncocytic lesions, HBME-1 proved to be less sensitive, and the sequential combination of galectin-3 and cytokeratin-19 reached 100% of both specificity and sensitivity. Our data showed that, as compared with the use of single markers, the sequential combination of two markers represents the most accurate immunohistochemical panel in managing patients with a fine-needle aspiration biopsy diagnosis of ‘follicular neoplasms’, especially in otherwise controversial categories such as oncocytic tumours. The combination of three or more markers did not substantially improve the diagnostic accuracy of the test.