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.
Jessica Svedlund, Elham Barazeghi, Peter Stålberg, Per Hellman, Göran Åkerström, Peyman Björklund, and Gunnar Westin
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.
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.
A G Mackay, E A Ofori-Kuragu, A Lansdown, R C Coombes, L Binderup, and K W Colston
The anti-tumour effect of EB 1089, a novel vitamin D analogue with reduced calcaemic activity, was examined in vivo using the N-methyl-nitrosourea-induced rat mammary tumour model. The vitamin D compound was given orally at a dose of 1 pg/kg body weight alone and in combination with tamoxifen (1 mg/kg). Effects were compared with oral tamoxifen treatment alone. EB 1089 significantly inhibited tumour progression compared with controls with a response rate of 58% and a regression rate of 92% As expected, tamoxifen at the dose given also caused significant inhibition of tumour progression with a response rate of 73%. Combination of these two compounds did not lead to a marked increase in their effectiveness. Histological examination of tumours from EB 1089-treated rats showed a marked reduction in cellularity and mitotic activity.
At the dose given, EB 1089 produced a significant rise in serum calcium concentration and urinary calcium excretion. Tamoxifen treatment alone did not significantly alter serum calcium levels. However, combined treatment with tamoxifen and EB 1089 led to a significant reduction in hypercalcaemia compared with EB 1089 alone. It is suggested that vitamin D analogues with reduced calcaemic activity may provide a new therapeutic strategy for certain malignancies, either alone or in combination with established treatment regimens.
Endocrine-Related Cancer (1996) 3 327-335
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.
W P Bocchinfuso and K S Korach
James Koh, Joyce A Hogue, Sanziana A Roman, Randall P Scheri, Hèléne Fradin, David L Corcoran, and Julie A Sosa
The clinical presentation of primary hyperparathyroidism (PHPT) varies widely, although the underlying mechanistic reasons for this disparity remain unknown. We recently reported that parathyroid tumors can be functionally segregated into two distinct groups on the basis of their relative responsiveness to ambient calcium, and that patients in these groups differ significantly in their likelihood of manifesting bone disability. To examine the molecular basis for this phenotypic variation in PHPT, we compared the global gene expression profiles of calcium-sensitive and calcium-resistant parathyroid tumors. RNAseq and proteomic analysis identified a candidate set of differentially expressed genes highly correlated with calcium-sensing capacity. Subsequent quantitative assessment of the expression levels of these genes in an independent cohort of parathyroid tumors confirmed that calcium-sensitive tumors cluster in a discrete transcriptional profile group. These data indicate that PHPT is not an etiologically monolithic disorder and suggest that divergent molecular mechanisms could drive the observed phenotypic differences in PHPT disease course, provenance, and outcome.
A Perren, S Schmid, T Locher, P Saremaslani, C Bonvin, P U Heitz, and P Komminoth
The tumorigenesis of sporadic endocrine tumors is still not fully understood. Activating point mutations of the serine/threonine kinase gene BRAF located on 7q34 are found in a wide range of malignancies, with the highest frequency (66%) occurring in malignant melanomas. Melanomas are tumors of neural-crest-derived cells as are medullary thyroid carcinomas, pheochromocytomas and paragangliomas. BRAF has not been examined in endocrine tumors of the diffuse neuroendocrine system or of neural-crest-derived cells.
We examined 130 endocrine tumors of the pancreas, parathyroid gland, adrenal medulla, paraganglia, lung and gastrointestinal tract as well as follicular and c-cell-derived thyroid tumors. We found a high rate of V559E mutations in papillary thyroid carcinomas (47%), one V599E mutation in a well-differentiated gastric endocrine carcinoma (malignant carcinoid), but no activating BRAF mutations in all other endocrine tumors examined. These results point towards different pathways in tumorigenesis of endocrine tumors of various localizations and only rare involvement of the MAP kinase (MAPK) pathway in a subset of malignant neuroendocrine tumors.
A Falchetti and M L Brandi
Multiple Endocrine Neoplasias type 1 (MEN 1) and type 2 (MEN 2) represent complex inherited (autosomal dominant traits) syndromes characterized by occurrence of distinct proliferative disorders of endocrine tissues, varying from hyperplasia to adenoma and carcinoma.
MEN 1 syndrome is characterized by parathyroid gland, anterior pituitary and endocrine pancreas tumors. Other endocrine and non endocrine tumors, such as carcinoids, lipomas, pinealomas, adrenocortical and thyroid follicular tumors, have been also described in MEN 1 patients occurring at higher frequency than in general population (Brandi ML et al. 1987). Recently also a spinal ependymoma has been found in a patient with MEN 1 syndrome (Kato H et al 1997)
MEN 2 syndromes recognize three main clinical entities, MEN 2A, characterized by medullary thyroid carcinoma (MTC), primary hyperparathyroidism (PHPT) and pheochromocytoma (PHEO); MEN 2B that exhibits MTC, usually developing sooner than the MEN 2A- associated one, pheochromocytoma, multiple neuromas of gastroenteric mucosa, myelinated corneal nerves (Gorlin RJ et al. 1968) and a typical marphanoid habitus; and familial medullary thyroid carcinoma only (FMTC) featuring by families with at least four members with MTC and no objective evidence of pheochromocytoma and parathyroid disease on screening of affected and at-risk members, as stated by the International RET Mutation Consortium (Larsson C et al. 1994).
This work was supported by grants of the Associazione Italiana per la Ricerca sul Cancro (to MLB), from CNR/PF ACRO (INV. 95.00316 PF 39) and by MURST 60% (to MLB).