Wu Qifeng, He Jinguang, Herrler Tanja, Yu Baofu, Zhou Qimin, Zheng Danning, Chen Xiaoxue, Yan Yangxuanyu, Dai Chuanchang, Liu Kai, Zou Gangming, Ge Shengfang, Qiao Yunbo, Li Qingfeng, Wei Jiao
Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai JiaoTong University School of Medicine, Shanghai, 200125, China.
Berufsgenossenschaftliche Unfallklinik Murnau, Murnau, Germany.
Breast Cancer. 2025 May;32(3):552-565. doi: 10.1007/s12282-025-01686-7. Epub 2025 Feb 28.
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.
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.
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.
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.
脂肪来源干细胞（ADSCs）辅助脂肪移植已成为乳房切除术后乳房重建及美容隆乳广泛应用的一种手术方式。鉴于移植后乳腺癌病例有限，该手术的肿瘤学安全性仍存在争议。
使用共培养和异种移植模型研究ADSCs对癌前MCF - 10AT细胞致癌特性的影响。我们进一步在7,12 - 二甲基苯并(a)蒽（DMBA）诱导的乳腺癌模型中评估ADSCs的促恶性作用。对ADSCs、MCF - 10AT细胞以及与ADSCs共培养的MCF - 10AT细胞进行RNA测序。通过蛋白质组学分析确定ADSC/MCF - 10AT共培养基和MCF - 10AT细胞中的蛋白质变化。使用通路抑制剂研究参与ADSCs诱导的MCF - 10AT细胞致癌变化的信号通路。
我们发现ADSCs促进MCF - 10AT细胞的增殖和迁移，并且在裸鼠中共注射ADSCs使MCF - 10AT细胞的肿瘤发生率从29%增加到58%。此外，移植的ADSCs显著提高了DMBA诱导的大鼠的肿瘤发生率、生长和远处转移，而它在正常乳腺组织中不能诱导肿瘤发生。联合RNA测序和蛋白质组学分析表明，ADSCs分泌的旁分泌因子强烈激活了MCF - 10AT细胞中的致癌PI3K - AKT信号。我们还揭示了共培养的MCF - 10AT细胞中自激活的TGF - β和Wnt通路，这可能在肿瘤形成和进展中具有协同作用。正如预期的那样，阻断这些通路，尤其是PI3K - AKT通路，强烈减弱了ADSCs的促进作用，表明它们作为ADSC移植相关乳腺肿瘤治疗靶点的潜力。
我们的数据说明了ADSC旁分泌因子与MCF - 10AT自激活通路在通过激活致癌PI3K - AKT通路导致MCF - 10AT细胞癌变过程中的协同作用。基于这些发现，我们强烈建议在与ADSC相关的移植术前进行乳腺癌风险因素的术前检查。
