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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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A proposed mechanism of drug resistance and the slow-cycling state in BM-DTCsThis scheme summarizes data from this and other studies and presents a model illustrating how cell-autonomous and BM microenvironment-mediated mechanisms may synergistically contribute to drug resistance and a slow-cycling state in DTCs. As demonstrated in our study, BM-DTCs overexpress TGF-β2 through a yet unknown mechanism. This cytokine maintains expression of CXCR4 and SDF-1, which results in drug resistance and a slow-cycling state in a cell-autonomous fashion. SDF-1 and TGF-β2 in the BM microenvironment may facilitate these signaling pathways, which may contribute to creating conditions that would allow DTCs to persist as dormant residual disease.
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Figure 5: A proposed mechanism of drug resistance and the slow-cycling state in BM-DTCsThis scheme summarizes data from this and other studies and presents a model illustrating how cell-autonomous and BM microenvironment-mediated mechanisms may synergistically contribute to drug resistance and a slow-cycling state in DTCs. As demonstrated in our study, BM-DTCs overexpress TGF-β2 through a yet unknown mechanism. This cytokine maintains expression of CXCR4 and SDF-1, which results in drug resistance and a slow-cycling state in a cell-autonomous fashion. SDF-1 and TGF-β2 in the BM microenvironment may facilitate these signaling pathways, which may contribute to creating conditions that would allow DTCs to persist as dormant residual disease.

Mentions: In addition, knockdown of TGF-β2 expression stimulated proliferation of only BM-HEp3 cells, in a similar manner as did CXCR4 inhibition (Figure 4C). Addition of TGF-β1 or TGF-β3 significantly increased proliferation of these cells (Figure 4D). Moreover, we found that knockdown of TGF-β2 completely abolished cisplatin resistance in BM-HEp3 cells, but we did not note any change in cisplatin sensitivity in P-HEp3 and Lu-HEp3 cells, which we did observe when CXCR4 was inhibited (Figure 4E). Taken together, our data demonstrate that TGF-β2 overexpression was responsible for an enhanced SDF-1-CXCR4 signaling axis and for the subsequent chemoresistance and slow-cycling state in BM-derived DTCs (Figure 5).


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)

A proposed mechanism of drug resistance and the slow-cycling state in BM-DTCsThis scheme summarizes data from this and other studies and presents a model illustrating how cell-autonomous and BM microenvironment-mediated mechanisms may synergistically contribute to drug resistance and a slow-cycling state in DTCs. As demonstrated in our study, BM-DTCs overexpress TGF-β2 through a yet unknown mechanism. This cytokine maintains expression of CXCR4 and SDF-1, which results in drug resistance and a slow-cycling state in a cell-autonomous fashion. SDF-1 and TGF-β2 in the BM microenvironment may facilitate these signaling pathways, which may contribute to creating conditions that would allow DTCs to persist as dormant residual disease.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 5: A proposed mechanism of drug resistance and the slow-cycling state in BM-DTCsThis scheme summarizes data from this and other studies and presents a model illustrating how cell-autonomous and BM microenvironment-mediated mechanisms may synergistically contribute to drug resistance and a slow-cycling state in DTCs. As demonstrated in our study, BM-DTCs overexpress TGF-β2 through a yet unknown mechanism. This cytokine maintains expression of CXCR4 and SDF-1, which results in drug resistance and a slow-cycling state in a cell-autonomous fashion. SDF-1 and TGF-β2 in the BM microenvironment may facilitate these signaling pathways, which may contribute to creating conditions that would allow DTCs to persist as dormant residual disease.
Mentions: In addition, knockdown of TGF-β2 expression stimulated proliferation of only BM-HEp3 cells, in a similar manner as did CXCR4 inhibition (Figure 4C). Addition of TGF-β1 or TGF-β3 significantly increased proliferation of these cells (Figure 4D). Moreover, we found that knockdown of TGF-β2 completely abolished cisplatin resistance in BM-HEp3 cells, but we did not note any change in cisplatin sensitivity in P-HEp3 and Lu-HEp3 cells, which we did observe when CXCR4 was inhibited (Figure 4E). Taken together, our data demonstrate that TGF-β2 overexpression was responsible for an enhanced SDF-1-CXCR4 signaling axis and for the subsequent chemoresistance and slow-cycling state in BM-derived DTCs (Figure 5).

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