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

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.