肠道微生物组的致癌转化可能导致患乳腺癌的风险。最近的研究提供了证据,表明微生物组分泌抑制细胞增殖的代谢产物,运动,和癌细胞的转移形成。在这项研究中,我们表明吲哚丙酸(IPA),一种细菌色氨酸代谢产物,具有细胞抑制特性。IPA选择性靶向乳腺癌细胞,但它对非转化没有影响,原代成纤维细胞。在基于细胞和动物的实验中,我们发现,IPA的补充降低了肿瘤干细胞的比例和增殖,运动,和癌细胞的转移形成。这些是通过抑制上皮-间质转化来实现的,诱导氧化和亚硝化应激,增强抗肿瘤免疫反应。增加的氧化/亚硝化应激是由于IPA介导的核因子红系2相关因子2(NRF2)的下调,诱导型一氧化氮合酶(iNOS)的上调,和增强线粒体反应性物种的产生。增加的氧化/亚硝基应激导致细胞停滞和癌细胞干细胞减少。IPA通过芳烃受体(AHR)和孕烷X受体(PXR)受体发挥作用。PXR和AHR的较高表达支持人类乳腺癌患者的更好生存率,强调IPA诱导途径在乳腺癌细胞抑制中的重要性。此外,AHR激活和PXR表达与癌细胞增殖水平以及肿瘤的分期和分级呈负相关。在新诊断为乳腺癌的女性中,粪便微生物组的IPA生物合成能力受到抑制,尤其是阶段0。细菌吲哚生物合成与人类肿瘤的淋巴细胞浸润有关。一起来看,我们发现IPA是一种抑制细胞生长的细菌代谢产物,其产生在人类乳腺癌中被抑制。细菌代谢产物,其中,IPA,在调节疾病的进展中起着关键作用,而不是疾病的开始。
Oncobiotic transformation of the gut microbiome may contribute to the risk of breast cancer. Recent studies have provided evidence that the microbiome secretes cytostatic metabolites that inhibit the proliferation, movement, and metastasis formation of cancer cells. In this study, we show that indolepropionic acid (IPA), a bacterial tryptophan metabolite, has cytostatic properties. IPA selectively targeted breast cancer cells, but it had no effects on non-transformed, primary fibroblasts. In cell-based and animal experiments, we showed that IPA supplementation reduced the proportions of cancer stem cells and the proliferation, movement, and metastasis formation of cancer cells. These were achieved through inhibiting epithelial-to-mesenchymal transition, inducing oxidative and nitrosative stress, and boosting antitumor immune response. Increased oxidative/nitrosative stress was due to the IPA-mediated downregulation of nuclear factor erythroid 2-related factor 2 (NRF2), upregulation of inducible nitric oxide synthase (iNOS), and enhanced mitochondrial reactive species production. Increased oxidative/nitrosative stress led to cytostasis and reductions in cancer cell stem-ness. IPA exerted its effects through aryl hydrocarbon receptor (AHR) and pregnane X receptor (PXR) receptors. A higher expression of PXR and AHR supported better survival in human breast cancer patients, highlighting the importance of IPA-elicited pathways in cytostasis in breast cancer. Furthermore, AHR activation and PXR expression related inversely to cancer cell proliferation level and to the stage and grade of the tumor. The fecal microbiome\'s capacity for IPA biosynthesis was suppressed in women newly diagnosed with breast cancer, especially with stage 0. Bacterial indole biosynthesis showed correlation with lymphocyte infiltration to tumors in humans. Taken together, we found that IPA is a cytostatic bacterial metabolite, the production of which is suppressed in human breast cancer. Bacterial metabolites, among them, IPA, have a pivotal role in regulating the progression but not the initiation of the disease.