Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction

SIMPLE SUMMARY: Obesity, which is characterized by the excess of adipose tissue, is associated with an increased risk of multiple cancers. We have previously reported that adipsin, a secreted factor from adipocytes, enhances cancer cell proliferation and stem cell properties. In this study, we found that adipsin affected adipocytes themselves and enhanced their secretion of hepatocyte growth factor (HGF). We found that HGF enhanced the adipocyte-cancer cell interactions as a downstream effector of adipsin. Understanding the adipocyte-cancer cell interaction will provide a novel strategy to treat cancers whose initiation, invasion, and metastatic progression are associated with adipose tissues. ABSTRACT: Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.