Intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance and a slow-cycling state in bone marrow-disseminated tumor cells
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Takuya Nakamura1,*, Satoru Shinriki2,*, Hirofumi Jono3, Jianying Guo4, Mitsuharu Ueda4, Mitsuhiro Hayashi5, Satoshi Yamashita4, Andries Zijlstra6, Hideki Nakayama1, Akimitsu Hiraki1, Masanori Shinohara1 and Yukio Ando4
1 Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
2 Department of Laboratory Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
3 Department of Clinical Pharmaceutical Sciences, Graduate School of Pharmaceutical Sciences, Kumamoto University and Department of Pharmacy, Kumamoto University Hospital, Kumamoto, Japan
4 Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
5 Department of Breast and Endocrine Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
6 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
* These authors contributed equally to this work
Satoru Shinriki, email:
Hirofumi Jono, email:
Keywords: bone marrow, disseminated tumor cells, drug resistance, slow-cycling cells, TGF-β2, SDF-1-CXCR4 axis
Received: October 12, 2014 Accepted: November 24, 2014 Published: November 25, 2014
Dormant or slow-cycling disseminated tumor cells (DTCs) in bone marrow (BM) are resistant to conventional therapy in various cancers including head and neck squamous cell carcinoma (HNSCC), although the molecular mechanisms remain largely unknown. This study aimed to identify the intrinsic molecular mechanisms underlying drug resistance in BM-DTCs. We used in vivo selection of the human HNSCC cell line HEp3, which mimics non-proliferative BM-DTCs in mice, to establish BM-DTC-derived (BM-HEp3) and lung metastases-derived (Lu-HEp3) sublines. Both sublines had higher migration activity and shortened survival in a murine xenograft model compared with parental (P-HEp3) cells. Slow-cycling BM-HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly. The drug resistance and slow-cycling state of BM-HEp3 cells depended on enhanced positive feedback of the signaling axis of stromal cell-derived factor-1 (SDF-1)-C-X-C chemokine receptor-4 (CXCR4) via their overexpression. Interestingly, BM-DTCs highly expressed transforming growth factor-beta 2 (TGF-β2) to maintain SDF-1-CXCR4 overexpression. Inhibition of SDF-1-CXCR4 signaling by down-regulating TGF-β2 fully reversed the drug resistance of BM-HEp3 cells via reactivation of cell proliferation. These data suggest that the intrinsic TGF-β2-triggered SDF-1-CXCR4 signaling axis is crucial for drug resistance dependent on a slow-cycling state in BM-DTCs.
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