脂肪干细胞促进三阴性乳腺癌复发

　　大多数三阴性乳腺癌患者新辅助化疗后缓解不彻底，导致化疗残余肿瘤细胞，引起肿瘤复发和患者死亡。因此，亟待消除化疗残余肿瘤细胞的方法。虽然基质细胞有助于肿瘤细胞的浸润作用，但是目前尚不明确其影响化疗残余肿瘤细胞的能力。

　　2018年12月29日，施普林格·自然旗下《乳腺癌研究与治疗》在线发表美国杜克大学的研究报告，首次探讨了脂肪干细胞与化疗残余三阴性乳腺癌细胞之间的相互影响、脂肪干细胞是否促进化疗残余肿瘤细胞增殖、是否影响肿瘤复发。

　　该研究通过体外浸润细胞迁移实验，检测脂肪干细胞向化疗残余三阴性乳腺癌细胞的迁移。利用中和抗体和小分子抑制剂，确定基质细胞衍生因子SDF-1α→趋化因子受体CXCR4信号转导轴的作用。通过培养肿瘤细胞±脂肪干细胞的条件培养基，分析脂肪干细胞影响肿瘤细胞增殖的能力，并测定细胞计数。通过免疫印迹法，分析化疗残余肿瘤细胞暴露于脂肪干细胞条件培养基后被激活的下游信号转导通路。利用成纤维细胞生长因子FGF2中和抗体，评定FGF2对促进增殖的作用。

　　结果发现，脂肪干细胞通过CXCR4→SDF-1α信号转导轴，向化疗残余三阴性乳腺癌细胞进行迁移。此外，脂肪干细胞条件培养基可以促进化疗残余肿瘤细胞的增殖和细胞外信号调节激酶的活性。反之，FGF2中和抗体可以抑制脂肪干细胞诱发的化疗残余肿瘤细胞增殖。

　　因此，该研究结果表明，脂肪干细胞通过SDF-1α→CXCR4信号转导，向化疗残余三阴性乳腺癌细胞进行迁移，并通过分泌FGF2和激活细胞外信号调节激酶，以旁分泌方式促进化疗残余肿瘤细胞增殖，该旁分泌信号转导有望成为防止肿瘤复发的新靶点。

Breast Cancer Res Treat. 2018 Dec 29.

Adipose stem cell crosstalk with chemo-residual breast cancer cells: implications for tumor recurrence.

Matthew A. Lyes, Sturgis Payne, Paul Ferrell, Salvatore V. Pizzo, Scott T. Hollenbeck, Robin E. Bachelder.

Duke University Medical Center, Durham, USA; Duke University Hospital, Durham, USA.

PURPOSE: Most triple-negative breast cancer (TNBC) patients exhibit an incomplete response to neoadjuvant chemotherapy, resulting in chemo-residual tumor cells that drive tumor recurrence and patient mortality. Accordingly, strategies for eliminating chemo-residual tumor cells are urgently needed. Although stromal cells contribute to tumor cell invasion, to date, their ability to influence chemo-residual tumor cell behavior has not been examined. Our study is the first to investigate cross-talk between adipose-derived stem cells (ASCs) and chemo-residual TNBC cells. We examine if ASCs promote chemo-residual tumor cell proliferation, having implications for tumor recurrence.

METHODS: ASC migration toward chemo-residual TNBC cells was tested in a transwell migration assay. Importance of the SDF-1α/CXCR4 axis was determined using neutralizing antibodies and a small molecule inhibitor. The ability of ASCs to drive tumor cell proliferation was analyzed by culturing tumor cells±ASC conditioned media (CM) and determining cell counts. Downstream signaling pathways activated in chemo-residual tumor cells following their exposure to ASC CM were studied by immunoblotting. Importance of FGF2 in promoting proliferation was assessed using an FGF2-neutralizing antibody.

RESULTS: ASCs migrated toward chemo-residual TNBC cells in a CXCR4/SDF-1α-dependent manner. Moreover, ASC CM increased chemo-residual tumor cell proliferation and activity of extracellular signal-regulated kinase (ERK). An FGF2-neutralizing antibody inhibited ASC-induced chemo-residual tumor cell proliferation.

CONCLUSIONS: ASCs migrate toward chemo-residual TNBC cells via SDF-1α/CXCR4 signaling, and drive chemo-residual tumor cell proliferation in a paracrine manner by secreting FGF2 and activating ERK. This paracrine signaling can potentially be targeted to prevent tumor recurrence.

KEYWORDS: Triple-negative breast cancer (TNBC) Adipose-derived stem cells (ASCs) Migration Proliferation Fibroblast growth factor 2 (FGF2) Recurrence

DOI: 10.1007/s10549-018-05103-w

以下广告内容与本微信公众号无关