Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017, Japan.
Division of Molecular and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Hyogo, 6500017, Japan.
Oncogene. 2019 Feb;38(6):767-779. doi: 10.1038/s41388-018-0477-8. Epub 2018 Sep 3.
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.
肿瘤微环境在肿瘤的发生和发展中起着关键作用。尽管脂肪组织是乳腺组织中基质的主要成分，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，我们发现脂肪因子 adipsin 可增强人源乳腺癌患者来源异种移植（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来源干细胞（ADSCs）中表达，并且在肥胖患者中的表达水平显著更高。ADSCs 可显著增强源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 敲低抑制 adipsin 介导的信号通路，可显著降低共培养的乳腺癌 PDX 细胞的球体形成能力和 CSC 标志物的表达。体内共移植 ADSCs 可显著增强乳腺癌 PDX 肿瘤的生长，而共移植 adipsin 敲低的 ADSCs 则可减弱其生长。这些结果表明，adipsin 是一种从乳腺脂肪组织分泌的重要脂肪因子，可作为肿瘤微环境的组成部分和乳腺癌中 CSC 生态位的组成部分发挥作用。
