Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS-2/8 Chondrosarcoma Cells
Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS-2/8 Chondrosarcoma Cells
复制标题
核视黄酸受体γ的选择性激动剂抑制HCS-2/8软骨肉瘤细胞的生长
DOI：
10.1002/jor.24555
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发表时间：
2019
期刊：
影响因子：
2.8
通讯作者：
M. Iwamoto.M. Enomoto-Iwamoto.
中科院分区：
文献类型：
--
作者：
W. P. Shield;3rd;A. Cellini;H. Tian;K. Wilson;Y. Dan;J. M. Abzug;S. Garcia;N. Moritani;I. Alferiev;M. Chorny;M. Takigawa;V. Y. Ng;M. Iwamoto.M. Enomoto-Iwamoto.
软骨肉瘤是第二常见的原发性骨肉瘤。软骨肉瘤的治疗仅限于手术，因为这种癌症具有放射和化疗抗性。软骨肉瘤的理想治疗是耐受性良好的微创局部或全身治疗方式，以在切除局部、不可切除的局部或转移性疾病之前停止或减缓肿瘤生长。帕罗伐汀是一种核维甲酸受体γ（RARγ）激动剂，在动物模型中对异位骨化和骨软骨瘤有治疗作用，且无严重不良反应。我们假设RARγ的选择性激动剂对软骨肉瘤有抑制作用。免疫组化染色显示所有软骨肉瘤标本均表达RARγ。从低级别人软骨肉瘤建立的HCS-2/8软骨肉瘤细胞系用于检查RARγ激动剂的作用。在HCS 2/8沉淀培养物中，当与对照组相比时，RARγ激动剂处理减小了质量大小并且显著降低了总糖胺聚糖、蛋白质量和软骨基质分子的基因表达水平。用RARγ激动剂的全身性处理显著抑制了体内HCS-2/8细胞移植物的生长。此外，局部注射RARγ激动剂负载的聚乳酸纳米颗粒诱导移植物的质量大小消退。组织学分析表明RARγ激动剂处理抑制细胞增殖活性并刺激肿瘤的包裹。这些发现表明RARγ激动剂，包括帕罗伐汀，可能对低级别软骨肉瘤具有抗肿瘤作用。© 2019骨科研究学会。出版社：Wiley Periodicals，Inc. J Orthop Res 38：1045 - 1051，2020
Chondrosarcoma is the second most common primary bone sarcoma. Treatment of chondrosarcoma is limited to surgery due to radiation and chemotherapy resistance of this cancer. An ideal treatment for chondrosarcoma would be a well‐tolerated, minimally invasive local or systemic treatment modality to halt or slow tumor growth prior to resection of local, unresectable local, or metastatic disease. Palovarotene, an agonist of nuclear retinoic acid receptor γ (RARγ) has shown therapeutic action for treatment of heterotopic ossification and osteochondroma without serious adverse effects in animal models. We hypothesized that selective agonists of RARγ would have an inhibitory effect on chondrosarcoma. All human chondrosarcoma specimens expressed RARγ as determined by immunohistochemical staining. The ΗCS‐2/8 chondrosarcoma cell line, established from low‐grade human chondrosarcoma, was used to examine the actions of RARγ agonists. In ΗCS2/8 pellet cultures, RARγ agonist treatment reduced the mass size and significantly decreased total glycosaminoglycan, protein amounts, and gene expression levels of cartilage matrix molecules when compared with control groups. Systemic treatment with RARγ agonists significantly inhibited the growth of ΗCS‐2/8 cell transplants in vivo. Furthermore, local injection of RARγ agonist‐loaded poly‐lactic acid nanoparticles induced regression of the mass size of the transplants. Histologic analysis demonstrated that RARγ agonist treatment inhibited cell proliferation activity and stimulated encapsulation of the tumor. These findings indicate that RARγ agonists, including palovarotene, may have an anti‐tumor effect on low‐grade chondrosarcomas. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1045‐1051, 2020