Adipose-derived stem cells enhance human breast cancer growth and cancer stem cell-like properties through adipsin
Adipose-derived stem cells enhance human breast cancer growth and cancer stem cell-like properties through adipsin
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DOI：
10.1038/s41388-018-0477-8
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发表时间：
2019-02-07
期刊：
影响因子：
8
通讯作者：
Minami, Hironobu
中科院分区：
文献类型：
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作者：
Goto, Hideaki;Shimono, Yohei;Minami, Hironobu
肿瘤微环境对肿瘤的发生、发展起着关键作用。尽管脂肪组织是乳腺组织基质的主要成分，并分泌各种细胞因子、趋化因子和生长因子，但脂肪细胞在乳腺癌中的作用仍有待阐明。在这项研究中，我们发现adipsin，一种从乳腺脂肪组织分泌的脂肪因子，增强了人乳腺癌患者来源的异种移植（PDX）细胞的增殖和癌症干细胞（CSC）样特性。Adipsin主要在乳腺癌患者手术标本的脂肪组织和从中分离的脂肪源性干细胞（ADSCs）中表达，并且其表达水平在肥胖患者中显著更高。ADSC显著增强了来自雌激素受体阳性和阴性乳腺癌PDX细胞的乳腺癌PDX细胞的球体形成能力。通过特异性抑制剂或ADSC中的adipsin敲低来抑制adipsin介导的信号传导显著降低了共培养的乳腺癌PDX细胞中的球体形成能力和CSC标志物的表达。乳腺癌PDX肿瘤的生长与ADSCs在体内的共同移植显着增强，当共同移植与adipsin敲低ADSCs减弱。这些结果表明，adipsin是一种重要的脂肪因子分泌的乳腺脂肪组织，作为一个组成部分的肿瘤微环境和CSC生态位在乳腺癌。
Tumor microenvironment plays a key role for tumor development and progression. Although adipose tissue is a predominant component of stroma in mammary tissues and secretes various cytokines, chemokines and growth factors, roles of adipocytes in breast cancers remain to be elucidated. In this study, we found that adipsin, an adipokine secreted from mammary adipose tissues, enhanced proliferation and cancer stem cell (CSC)-like properties of human breast cancer patient-derived xenograft (PDX) cells. Adipsin was predominantly expressed in both adipose tissues of the surgical specimens of breast cancer patients and adipose-derived stem cells (ADSCs) isolated from them, and its expression level was significantly higher in obese patients. ADSCs significantly enhanced the sphere-forming ability of breast cancer PDX cells derived from both estrogen receptor-positive and -negative breast cancer PDX cells. Suppression of adipsin-mediated signaling by a specific inhibitor or adipsin knockdown in ADSCs significantly decreased the sphere-forming ability and the expression of CSC markers in co-cultured breast cancer PDX cells. Growth of breast cancer PDX tumors was significantly enhanced by co-transplantation with ADSCs in vivo, and it was weakened when co-transplanted with the adipsin knocked-down ADSCs. These results suggest that adipsin is an important adipokine secreted from mammary adipose tissue that functions as a component of tumor microenvironment and a CSC niche in breast cancers.