Adipose-derived stem cells (ADSCs) have been implicated in
tumor growth and
metastasis in
breast cancer. ADSCs exhibit
tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for
breast reconstruction. Although we have previously shown that a high level of the
adipocytokine visfatin in human
breast cancer tissues correlated with
tumor progression mediated by cAbl and STAT3, the effects of
visfatin in the tumor microenvironment are unclear. To understand how
visfatin modulates
breast cancer within the
tumor-stromal environment, we examined determinants of
breast cancer progression using a
visfatin-primed ADSCs-
tumor co-culture model. ADSCs were isolated from
tumor-free adipose tissue adjacent to
breast tumors. ADSCs were treated with or without
visfatin for 48 h and then collected for co-culture with
breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with
visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs).
Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture
conditioned medium, with GDF15
neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger
tumor mass than with uADSCs. Positive correlations were noted between
visfatin, GDF15, and phosphor-AKT expressions in human
breast cancer specimens. In conclusion,
visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate
breast cancer progression.