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Vitamin D3 Administration Induces Nuclear p27 Accumulation, Restores Differentiation, and Reduces Tumor Burden in a Mouse Model of Metastatic Follicular Thyroid Cancer

Department of Surgery (A.P.B.D.), University Health Network and Mount Sinai Hospital; Department of Medicine (S.E., P.H.), Mount Sinai Hospital; and Department of Pathology (W.L., S.L.A.), University Health Network, University of Toronto, Toronto, Ontario, Canada M5G 2M9

Address all correspondence and requests for reprints to: Dr. Sylvia L. Asa, Department of Pathology, 610 University Avenue, Suite 4-302, Toronto, Ontario Canada, M5G 2M9. E-mail: sylvia.asa{at}uhn.on.ca.

We have previously demonstrated in vitro that 1,25-dihydroxyvitamin D3 (calcitriol) treatment increases p27 expression and decreases cell proliferation in cultured thyroid carcinoma cell lines. We hypothesized that in vivo treatment with calcitriol would have a beneficial effect on thyroid carcinoma growth and progression. Five x 10⁶ WRO (human thyroid follicular carcinoma derived) cells were implanted in the neck in 4- to 5-wk-old female SCID mice in an orthotopic xenograft model. Animals (n = 15) were treated ip three times a week for 21 d with 0.75 µg/kg calcitriol or vehicle. Mice were killed 21 d after tumor implantation, tumor volume was measured, and excised tumor tissue was examined by light microscopy and immunohistochemistry for p27 and thyroglobulin reactivity. Average tumor volume in control mice after 21 d of vehicle treatment was 2002 ± 207 mm³ compared with a mean tumor volume of 1241 ± 115 mm³ in animals receiving calcitriol, reflecting a 38% reduction in tumor volume size (P < 0.003). Tumors from vehicle-treated animals demonstrated morphological features of epithelial malignancies with characteristics of insular carcinoma and multiple metastases to the lungs. Tumors excised from calcitriol-treated animals demonstrated signs of differentiation with restoration of thyroglobulin staining. This was associated with a marked accumulation of p27 immunoreactivity in the nuclear compartment. These studies demonstrate that in vivo calcitriol administration can effectively restore p27 accumulation in thyroid carcinoma cells, an effect associated with appreciably enhanced cellular differentiation, reduction in tumor burden, and prevention of metastatic growth.

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