calcitriol and Neoplasm-Metastasis

Breast cancer metastasis to the bone continues to be a major health problem, with approximately 80% of advanced breast cancer patients expected to develop bone metastasis. Although the problem of bone metastasis persists, current treatment options for metastatic cancer patients are limited. In this study, we investigated the preventive role of the active vitamin D metabolite, 1α,25-dihydroxyvitamin D (1,25(OH)2D), against the metastatic potential of breast cancer cells using a novel three-dimensional model (rMET) recapitulating multiple steps of the bone metastatic process. Treatment of MCF10CA1a and MDA-MB-231 cells inhibited metastasis in the rMET model by 70% (±5.7%) and 21% (±6%), respectively. In addition, 1,25(OH)2D treatment decreased invasiveness (20 ± 11% of vehicle) and decreased the capability of MCF10CA1a cells to survive in the reconstructed bone environment after successful invasion through the basement membrane (69 ± 5% of vehicle). An essential step in metastasis is epithelial-mesenchymal transition (EMT). Treatment of MCF10CA1a cells with 1,25(OH)2D increased gene (2.04 ± 0.28-fold increase) and protein (1.87 ± 0.20-fold increase) expression of E-cadherin. Additionally, 1,25(OH)2D treatment decreased N-cadherin gene expression (42 ± 8% decrease), a marker for EMT. Collectively, the present study suggests that 1,25(OH)2D inhibits breast cancer cell metastatic capability as well as inhibits EMT, an essential step in the metastatic process.

Topics: Anticarcinogenic Agents; Antigens, CD; Biomarkers, Tumor; Bone Neoplasms; Breast; Breast Neoplasms; Cadherins; Cell Line; Cell Line, Tumor; Cell Proliferation; Cell Survival; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Neoplastic; Humans; Kinetics; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasm Proteins; Vitamin D

With the recent advance in breast cancer therapy, the survival rate of breast cancer patients has improved greatly. In spite of the progress, 25-50% of breast cancer patients eventually will develop metastasis. Due to limited early detection methods, metastasis is usually diagnosed at the late stages beyond recovery likely due to resistance to currently available breast cancer therapies. Thus, a new strategy to prevent cancer cell growth and repress tumor metastasis is desirable. The active form of vitamin D3, 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], has anti-invasion and anti-migration properties in pre-clinical studies, yet its clinical application has been hampered by its hypercalcemic side effect. Previously, we have demonstrated that a new class of less-calcemic vitamin D analog, 19-nor-2α-(3-hydroxypropyl)-1α,25-dihydroxyvitamin D3 (MART-10), is 1000-fold more active than 1α,25(OH)2D3 in suppressing MCF-7 cells growth through cell cycle arrest and apoptosis induction. In the current study, we show for the first time that MART-10 is more active than 1α,25(OH)2D3 in preventing MCF-7 cell invasion and migration likely mediated through the upregulation of E-cadherin, and the downregulation of Snail, Slug, and Twist, the transcription factors implicated in epithelial-mesenchymal transition (EMT), as well as MMP-13. Based on the current in vitro and the highly anti-tumor characteristics of MART-10 in a pancreatic xenograft model, MART-10 is deemed as a promising candidate for breast cancer treatment. Further in vivo animal study comparing MART-10 with 1α,25(OH)2D3 and other potent and less calcemic analogs of vitamin D is warranted.

Topics: Antigens, CD; Antineoplastic Agents; Breast Neoplasms; Cadherins; Cell Movement; Cholecalciferol; Epithelial-Mesenchymal Transition; Female; Gene Expression; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; MCF-7 Cells; Neoplasm Invasiveness; Neoplasm Metastasis; Nuclear Proteins; Snail Family Transcription Factors; Transcription Factors; Twist-Related Protein 1; Vitamin D

To determine the cause of refractory hypercalcemia in a patient with metastatic renal cell carcinoma.. We describe the clinical, pathologic, and immunostain findings in a patient with metastatic renal cell carcinoma and hypercalcemia of malignancy refractory to intravenous bisphosphonates.. A 57-year-old man with a remote history of clear cell renal cell carcinoma was referred to our clinic for evaluation of resistant hypercalcemia 12 years after nephrectomy. The patient had simultaneous elevation of serum 1,25-dihydroxyvitamin D and parathyroid hormone-related peptide. Computed tomographic scan of the chest and abdomen demonstrated numerous ring-enhancing lesions in the liver, and histologic examination of a biopsy specimen revealed liver tissue infiltrated by a malignant neoplasm composed of cells with clear and eosinophilic cytoplasm, arranged in tubules and nests. Findings were morphologically consistent with renal cell carcinoma of clear cell type, and positive immunostaining with the epithelial markers EMA and CAM 5.2 were supportive of the morphologic impression of renal cell carcinoma. The tumor showed expression of 25-hydroxyvitamin D 1alpha-hydroxylase by immunostaining. After failing to respond to intravenous bisphosphonates, the hypercalcemia improved with prednisone treatment.. In some patients with renal cell carcinoma, hypercalcemia of malignancy is associated with simultaneous elevation in serum 1,25-dihydroxyvitamin D and parathyroid hormone-related peptide. As our case exemplifies, it is imperative to identify such patients because hypercalcemia due to elevated 1,25-dihydroxyvitamin D levels may respond better to glucocorticoid treatment than to the conventional bisphosphonate therapy.

Topics: Carcinoma, Renal Cell; Humans; Hypercalcemia; Kidney Neoplasms; Male; Middle Aged; Neoplasm Metastasis; Parathyroid Hormone-Related Protein; Up-Regulation; Vitamin D