Ledet Melissa M, Harman Rebecca M, Fan Jennifer C, Schmitt-Matzen Emily, Diaz-Rubio Maria Elena, Zhang Sheng, Van de Walle Gerlinde R
Baker Institute for Animal Health, College of Veterinary Medicine, Cornell University, 235 Hungerford Hill Road, Ithaca, NY, 14853, USA.
Proteomic and Metabolomics Facility, Cornell University, Ithaca, NY, 14853, USA.
Sci Rep. 2020 Nov 25;10(1):20580. doi: 10.1038/s41598-020-77639-1.
Determining mechanisms that naturally protect species from developing cancer is critical in order to prevent and treat cancer. Here, we describe a novel cancer-suppressing mechanism, via the secretion of bioactive factors by mammary cells, that is present in domesticated mammals with a low mammary cancer incidence. Specifically, these bioactive factors induced triple-negative breast cancer cell (TNBC) death in vitro and reduced tumorigenicity in a xenograft TNBC mouse model in vivo. RNA deep sequencing showed significant downregulation of genes associated with breast cancer progression in secretome-cultured TNBC cells. Further in-depth multi-omics analysis identified sphingomyelins as key secreted factors, and their role was confirmed via inhibition of the sphingomyelin signaling pathway. We speculate that secreted sphingomyelins in the mammary gland of mammals with a naturally low incidence of mammary cancer mediate the elimination of cancer cells. This study contributes to the growing list of protective mechanisms identified in cancer-proof species.
确定自然保护物种免受癌症侵害的机制对于预防和治疗癌症至关重要。在此，我们描述了一种新的癌症抑制机制，即通过乳腺细胞分泌生物活性因子，这种机制存在于乳腺癌发病率较低的家养哺乳动物中。具体而言，这些生物活性因子在体外诱导三阴性乳腺癌细胞（TNBC）死亡，并在体内异种移植TNBC小鼠模型中降低致瘤性。RNA深度测序显示，在分泌组培养的TNBC细胞中，与乳腺癌进展相关的基因显著下调。进一步深入的多组学分析确定鞘磷脂是关键的分泌因子，并通过抑制鞘磷脂信号通路证实了它们的作用。我们推测，在乳腺癌自然发病率较低的哺乳动物乳腺中分泌的鞘磷脂介导了癌细胞的清除。这项研究为在抗癌物种中发现的越来越多的保护机制增添了内容。
