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.

Takuya Nakamura,Hirofumi Jono,Akimitsu Hiraki,Yukio Ando,Masanori Shinohara,Satoshi Yamashita,Jianying Guo,Mitsuharu Ueda,Mitsuhiro Hayashi,Hideki Nakayama,Andries Zijlstra,Satoru Shinriki

doi:10.18632/oncotarget.2826

Takuya Nakamura, Hirofumi Jono + Show 10 more

Open Access

https://doi.org/10.18632/oncotarget.2826

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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.

Highlights

Minimal residual disease caused by solitary disseminated tumor cells (DTCs) is often observed in bone marrow (BM) in patients with different types of cancer [1]
Using an in vivo selection approach, we demonstrated here that in BM-derived DTCs, but not in the primary cell population or in a lung metastatic derivative, autocrine TGF-β2 maintained the drug resistance and a slow-cycling state via enhancement of the stromal cell-derived factor-1 (SDF-1)-CXCR4 signaling axis
Our evidence suggests that DTCs lodged in the BM elicit this trait themselves, through an intrinsic mechanism: a positive feedback SDF-1-CXCR4 signaling loop, which is a frequently observed autocrine system [29] and, in this case, is likely to be initiated by CXCR4 overexpression

Summary

Introduction

Minimal residual disease caused by solitary disseminated tumor cells (DTCs) is often observed in bone marrow (BM) in patients with different types of cancer [1]. Most DTCs in BM aspirates are negative for proliferation markers [1,2], the abundance of these cells at the time of surgery or after treatment directly correlates www.impactjournals.com/oncotarget with reduced metastasis-free survival, even for cancers in which overt skeletal metastases, such as head and neck squamous cell carcinoma (HNSCC), are rare [1,3,4]. One most important obstacle to be overcome in cancer therapy is resistance of BM-DTCs to conventional chemotherapeutic agents [7,8] Their drug resistance may result from coordinated growth arrest and a survival scheme that allow longterm dormancy [9]. Understanding how these cells resist conventional therapy and persist in a viable state for prolonged periods is of fundamental clinical interest

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