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Inhibition of mTOR and HIF pathways diminishes chondro-osteogenesis and cell proliferation in chondroblastoma

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Tumor Biology

Abstract

Chondroblastoma (CBL) is a benign bone tumor occurring mostly in teenagers. Despite this, CBL can recur and metastasize after curettage, which may impede normal epiphysis. In search of a novel targeted therapy for CBL, we aimed at BMP-2, a factor critical for chondro-osteogenesis and chondrocyte proliferation. Two pathways upstream of BMP-2, the mTOR and HIF, were targeted with rapamycin (Rapa) and FM19G11 (FM), respectively. Using immunohistochemistry, we found BMP-2 was highly expressed in CBL tissues. CBL cells explanted and confirmed with higher BMP-2 level than normal cartilage. Protumorigenic effect of Rapa and FM on CBL cells were transduced via BMP-2. Combination of Rapa and FM conferred stronger inhibition of cell proliferation than either monotherapy and inhibited levels of chondro-osteogenic markers (Sox9, aggrecan, and type II collagen). To minimize the adverse effect of Rapa, we performed screening in essential amino acids and found leucine deprivation-sensitized CBL cells to Rapa. Combination treatment of low dose Rapa, FM, and leucine deprivation conferred compatible inhibitory effects on CBL cell proliferation, chondro-osteogenic potential, and tumorigenic capacity. We conclude that targeting BMP-2 using mTOR/HIF inhibition could potently curb the disease. Addition of low-leucine diet could lower the dose of rapamycin in chase for less toxicity.

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Acknowledgments

This study was supported, in part, by the Wuxi Health Bureau, no.YGZX1106.

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None.

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Authors and Affiliations

  1. Division of Orthopedics, Second People’s Hospital of Wuxi, Nanjing Medical University, Wuxi, 214000, People’s Republic of China

    Xiao Yang, Zheng-jie Yang, Ke Zeng, Ming-quan Qian, Gang Chen, Lei Shi & Guo-xing Zhu

  2. Division of Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University, Shanghai, People’s Republic of China

    Feng-xiang Liu

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  1. Xiao Yang
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  2. Zheng-jie Yang
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  3. Feng-xiang Liu
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  4. Ke Zeng
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  5. Ming-quan Qian
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  6. Gang Chen
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  7. Lei Shi
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  8. Guo-xing Zhu
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Corresponding author

Correspondence to Guo-xing Zhu.

Additional information

Xiao Yang and Zheng-jie Yang contributed equally.

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Yang, X., Yang, Zj., Liu, Fx. et al. Inhibition of mTOR and HIF pathways diminishes chondro-osteogenesis and cell proliferation in chondroblastoma. Tumor Biol. 34, 3111–3119 (2013). https://doi.org/10.1007/s13277-013-0879-8

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  • DOI: https://doi.org/10.1007/s13277-013-0879-8

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