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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.

Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, Yamashita S, Zijlstra A, Nakayama H, Hiraki A, Shinohara M, Ando Y - Oncotarget (2015)

Bottom Line: Slow-cycling BM-HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

ABSTRACT
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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Cell proliferation and cisplatin sensitivity of BM-derived and lung-derived DTCs(A) Proliferation rate of P-HEp3 (P), Lu-HEp3 (Lu), and BM-HEp3 (BM) cells. The number of cells in each subline was determined at the indicated time points after plating. *P < .05, †P < .01 compared with P-HEp3 cells. (B) Cells were serum-starved and then their survival was evaluated at the indicated time points. †P < .01 compared with P-HEp3 and Lu-HEp3 cells. (C) Cells were treated with cisplatin at the concentrations shown for 48 hours, after which cell numbers were determined. *P < .05, †P < .01,§P < .005. Values are means ± SEM of triplicate samples.
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Figure 2: Cell proliferation and cisplatin sensitivity of BM-derived and lung-derived DTCs(A) Proliferation rate of P-HEp3 (P), Lu-HEp3 (Lu), and BM-HEp3 (BM) cells. The number of cells in each subline was determined at the indicated time points after plating. *P < .05, †P < .01 compared with P-HEp3 cells. (B) Cells were serum-starved and then their survival was evaluated at the indicated time points. †P < .01 compared with P-HEp3 and Lu-HEp3 cells. (C) Cells were treated with cisplatin at the concentrations shown for 48 hours, after which cell numbers were determined. *P < .05, †P < .01,§P < .005. Values are means ± SEM of triplicate samples.

Mentions: We next investigated the proliferation and survival of each cell line in vitro. We found that BM-HEp3 cell proliferation was significantly slower than proliferation of P-HEp3 cells, whereas Lu-HEp3 cells proliferated rapidly (Figure 2A). Although survival of Lu-HEp3 and P-HEp3 cells under serum-free conditions did not appear to differ, the survival rate of BM-HEp3 cells was significantly higher than that of the other cell lines (Figure 2B).


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.

Nakamura T, Shinriki S, Jono H, Guo J, Ueda M, Hayashi M, Yamashita S, Zijlstra A, Nakayama H, Hiraki A, Shinohara M, Ando Y - Oncotarget (2015)

Cell proliferation and cisplatin sensitivity of BM-derived and lung-derived DTCs(A) Proliferation rate of P-HEp3 (P), Lu-HEp3 (Lu), and BM-HEp3 (BM) cells. The number of cells in each subline was determined at the indicated time points after plating. *P < .05, †P < .01 compared with P-HEp3 cells. (B) Cells were serum-starved and then their survival was evaluated at the indicated time points. †P < .01 compared with P-HEp3 and Lu-HEp3 cells. (C) Cells were treated with cisplatin at the concentrations shown for 48 hours, after which cell numbers were determined. *P < .05, †P < .01,§P < .005. Values are means ± SEM of triplicate samples.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359213&req=5

Figure 2: Cell proliferation and cisplatin sensitivity of BM-derived and lung-derived DTCs(A) Proliferation rate of P-HEp3 (P), Lu-HEp3 (Lu), and BM-HEp3 (BM) cells. The number of cells in each subline was determined at the indicated time points after plating. *P < .05, †P < .01 compared with P-HEp3 cells. (B) Cells were serum-starved and then their survival was evaluated at the indicated time points. †P < .01 compared with P-HEp3 and Lu-HEp3 cells. (C) Cells were treated with cisplatin at the concentrations shown for 48 hours, after which cell numbers were determined. *P < .05, †P < .01,§P < .005. Values are means ± SEM of triplicate samples.
Mentions: We next investigated the proliferation and survival of each cell line in vitro. We found that BM-HEp3 cell proliferation was significantly slower than proliferation of P-HEp3 cells, whereas Lu-HEp3 cells proliferated rapidly (Figure 2A). Although survival of Lu-HEp3 and P-HEp3 cells under serum-free conditions did not appear to differ, the survival rate of BM-HEp3 cells was significantly higher than that of the other cell lines (Figure 2B).

Bottom Line: Slow-cycling BM-HEp3 cells had intrinsically enhanced cisplatin resistance compared with Lu-HEp3 cells, which also manifested this resistance but proliferated rapidly.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral and Maxillofacial Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus