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.
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This work was supported by: (1) grants-in-aid from the Japan Society for the Promotion of Science (JSPS KAKENHI) 15K14381 and 18K07231 (to YS); (2) Japan-Belgium Research Cooperative Program from the Japan Society for the Promotion of Science (to YS); (3) a grant from the Japan Foundation for Applied Enzymology (to YS); (4) a grant from the Itoh-Chubei Foundation (to YS); (5) an extramural collaborative research grant of Cancer Research Institute, Kanazawa University (to YS); (6) a grant from the Princess Takamatsu Cancer Research Fund (to YS). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.
Study concept and design: HG, YS, YF, YI, TM and HM. Acquisition of data: HG, YS, YF, YI and SK. Analysis and interpretation of data: HG, YS, YF, YI, MT, NK, ST, TM and HM.
Conflict of interest
YS, HG and HM are listed as co-inventors on a Japanese patent application that describes the use of adipsin as therapeutic targeting of cancer and CSCs (2018-027603). The remaining authors declare that they have no conflict of interest.
Primary human breast cancer specimens were obtained from the consented patients who were admitted to Kobe University Hospital. All participants provided written informed consent for this investigation. The investigation was approved by the Institutional Review Board at Kobe University (permission number: 1299). All animal experiments were performed under the approval of the Kobe University Animal Care and Use Committee (permission number: P150802)
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Goto, H., Shimono, Y., Funakoshi, Y. et al. Adipose-derived stem cells enhance human breast cancer growth and cancer stem cell-like properties through adipsin. Oncogene 38, 767–779 (2019). https://doi.org/10.1038/s41388-018-0477-8
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