Adipose-derived stem cells enhance the tumorigenic potential of pre-malignant breast epithelial cells through paracrine activation of PI3K-AKT pathway.

Abstract

Background: Adipose-derived stem cells (ADSCs)-assisted fat grafting has emerged as a widely used procedure for breast reconstruction post mastectomy and for aesthetic augmentation. Given the limited cases of breast cancer following grafting, the oncological safety of this procedure remains controversial.

Methods: The effects of ADSCs on the oncogenic features of premalignant MCF-10AT cells were investigated using co-culture and xenograft models. We further evaluated the malignancy-promoting effect of ADSCs in a 7,12-Dimethylbenz(a)anthracene (DMBA)-induced breast cancer model. RNA-sequencing was performed on ADSCs, MCF-10AT cells, and ADSC-co-cultured MCF-10AT cells. Protein changes in ADSC/MCF-10AT co-culture medium and MCF-10AT cells were determined by proteomic analysis. Pathway inhibitors were used to investigate signaling pathways involved in the ADSC-induced oncogenic changes of MCF-10AT cells.

Results: We found that ADSCs promoted the proliferation and migration of MCF-10AT cells, and co-injection of ADSCs increased the tumor incidence of MCF-10AT cells from 29% to 58% in nude mice. Additionally, grafted ADSCs significantly enhanced tumor incidence, growth, and distant metastasis in the DMBA-induced rats, while it could not induce tumorigenesis in normal breast tissues. Combined RNA-sequencing and proteomic analysis demonstrated that the paracrine factors secreted by ADSCs robustly activated the oncogenic PI3K-AKT signaling in MCF-10AT cells. We also revealed the auto-activated TGF-beta and Wnt pathways in co-cultured MCF-10AT cells, which may be synergistic in tumor formation and progression. As expected, blocking these pathways, especially the PI3K-AKT pathway, strongly diminished the promoting effects of ADSCs, suggesting their potential as therapeutic targets for ADSC grafting-associated breast tumors.

Conclusions: Our data illustrated the synergistic effect between ADSC paracrine factors and MCF-10AT auto-activated pathways in the carcinogenesis of MCF-10AT cells through activation of the oncogenic PI3K-AKT pathway. Based on these findings, we strongly recommend pre-operative examinations for breast cancer risk factors before ADSC-associated transplantation.