Reference

Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells

All Rights Reserved. Retinoic acid inhibits angiogenesis and tumor growth of thyroid cancer cells. Hoffmann, Sebastian; Rockenstein, Andreas; Ramaswamy, Anette; Celik, Ilhan; Wunderlich, Anette; Lingelbach, Susanne; Hofbauer, Lorenz C.; Zielke, Andreas (Department of Surgery, Philipps-University of Marburg, Marburg 35043, Germany). Molecular and Cellular Endocrinology, 264(1-2), 74-81 (English) 2007 Elsevier Ltd. CODEN: MCEND6. ISSN: 0303-7207. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacology) The anti-proliferative effect of retinoic acid (RA) has been documented for various tumors. Some 40% of patients with advanced and poorly differentiated thyroid cancer have been shown to respond to RA with increased uptake of radioiodine. It has been suggested that these effects may be caused by redifferentiation. Presently, little is known about the effects of RA on tumor angiogenesis, a prerequisite for growth and metastatic spread. The aim of the current study was to det., whether tumor-induced angiogenesis of thyroid cancer is affected by RA. In vitro, the effect of 0.1/10 mM 13-cis RA on tumor cell no. (MTT assay) and secretion of VEGF (ELISA) was analyzed in three thyroid cancer cell lines (FTC 236, C634 and XTC), as well as in endothelial cells (HUVEC) over several passages. In vivo, tumor growth, VEGF-expression and microvessel d. (VSD) of RA treated thyroid cancer cells after xenotransplantation to nude mice was evaluated by morphometric anal. In vitro, thyroid cancer cell lines responded to RA with reduced proliferation, ranging from 26 to 34% after 2 wk of treatment and with up to 80% reduced secretion of VEGF. In vivo, tumor vols. of animals receiving RA were reduced by 33% (FTC 236), 27% (C643) and 6% (XTC), resp. VSD of exptl. tumors was diminished in the FTC 236 (25%) and the C643 cell line (15%), and almost unchanged in XTC tumors (7%). In vivo, VEGF-expression and apoptosis were not significantly affected by RA. In vitro, proliferation of HUVEC was inhibited by conditioned medium of C643 cells pretreated with RA (0.1/10 mM), as well as by administration of RA (0.1/10 mM). This study confirms thyroid tumor cell growth to be inhibited by RA. It demonstrates a decrease of in vitro VEGF accumulation and redn. of VSD in exptl. undifferentiated thyroid carcinoma, suggesting that reduced angiogenesis may be an important mechanism responsible for the therapeutic effect of RA in thyroid cancer. Moreover, a direct anti-proliferative effect of RA on human endothelial cells is suggested.

Retinoic acid receptor a expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status

Retinoic acid receptor a expression correlates with retinoid-induced growth inhibition of human breast cancer cells regardless of estrogen receptor status. Fitzgerald, patrick; Teng, Min; Chandraratna, Roshantha A. S.; Heyman, Richard A.; Allegretto, Elizabeth A. (Department Retinoid Research, Ligand Pharmaceuticals, Inc., San Diego, CA 92121, USA). Cancer Research, 57(13), 2641-2650 (English) 1997 American Association for Cancer Research. CODEN: CNREA8. ISSN: 0008-5472. DOCUMENT TYPE: Journal CA Section: 2 (Mammalian Hormones) Retinoic acid receptor (RAR) a has been shown to play a role in retinoid-induced growth inhibition of human breast cancer cell lines that express the estrogen receptor (ER). The dogma in the field has been that ER-pos. breast cancer cell lines respond to retinoid treatment because they express RARa, whereas ER-neg. breast cancer cell lines are refractory to retinoid treatment and have been thought to express little or no RARa. The authors set out to test several ER-neg. breast cancer cell lines for expression of RARa protein and responsiveness to retinoids in growth inhibition assays. Of six ER-neg. breast cancer cell lines that were tested, one (SK-BR-3) had high levels of RARa protein as measured by ligand-binding immunopptn. (~55 fmol/mg protein) and also displayed sensitivity to growth inhibition by retinoids (9-cis-retinoic acid; EC50, u2 nM). These cells were more sensitive than an ER-pos. cell line, T-47D, which expressed ~35 fmol RARa/mg total protein (9-cis retinoic acid; EC50, u50-100 nM). Another ER-neg. cell line, Hs578T, also expressed RARa (~23 fmol/mg) and was sensitive to retinoid-induced growth inhibition, albeit to a lesser extent than SK-BR-3 or T-47D cells. In contrast, the other ER-neg. cell lines tested expressed low (<10 fmol/mg) or no detectable levels of RARa protein and also did not respond to retinoids in growth inhibition assays. A RARa agonist displayed 100 times greater potency than a RARg agonist in growth inhibition of both T-47D and SK-BR-3 cells, suggesting RARa involvement in the process. Furthermore, a RARa antagonist completely abolished the growth inhibition induced by RAR agonists, implying that the activity of the agonists is exerted solely through RARa, not RARg, which is also expressed in both cell lines. Addnl., although retinoid X receptor (RXR) compds. are weakly active in growth inhibition of the RARa-pos. cell lines, they markedly increased the growth-inhibitory activity of RAR ligands. RXR compds. also potentiated the action of the antiestrogen 4-hydroxytamoxifen to inhibit the growth of T-47D cells. These findings have clin. ramifications in that patients with ER-neg. tumors that are RARa pos. may be candidates for retinoid therapy. Addnl., combinations of RXR ligands with RAR ligands (esp. RARa agonists) and/or antiestrogens may have utility in the treatment of breast cancer.