Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, United States.
Department of Oncology, Georgetown University, Baltimore, MD, United States.
Front Immunol. 2023 Jul 12;14:1194931. doi: 10.3389/fimmu.2023.1194931. eCollection 2023.
Obesity, an independent risk factor for breast cancer growth and metastatic progression, is also closely intertwined with gut dysbiosis; and both obese state and dysbiosis promote each other. Enteric abundance of is strongly linked with obesity, and we recently discovered the presence of in malignant breast cancer. Given that enterotoxigenic or ETBF, which secretes toxin (BFT), has been identified as a procarcinogenic microbe in breast cancer, it is necessary to examine its impact on distant metastasis and underlying systemic and localized alterations promoting metastatic progression of breast cancer.
We used syngeneic mammary intraductal (MIND) model harboring gut colonization with ETBF to query distant metastasis of breast cancer cells. Alterations in the immune network and cytokines/chemokines in the tumor microenvironment and distant metastatic sites were examined using flow cytometry, immunohistochemistry, and multiplex arrays.
ETBF infection initiates a systemic inflammation aiding in the establishment of the premetastatic niche formation in vital organs via increased proinflammatory and protumorigenic cytokines like IL17A, IL17E, IL27p28, IL17A/F, IL6, and IL10 in addition to creating a prometastatic immunosuppressive environment in the liver and lungs rich in myeloid cells, macrophages, and T regulatory cells. It induces remodeling of the tumor microenvironment via immune cell and stroma infiltration, increased vasculogenesis, and an EMT-like response, thereby encouraging early metastatic dissemination ready to colonize the conducive environment in liver and lungs of the breast tumor-bearing mice.
In this study, we show that enteric ETBF infection concomitantly induces systemic inflammation, reshapes the tumor immune microenvironment, and creates conducive metastatic niches to potentiate early dissemination and seeding of metastases to liver and lung tissues in agreement with the "seed and soil hypothesis." Our results also support the ETBF-induced "parallel model" of metastasis that advocates for an early dissemination of tumor cells that form metastatic lesions independent of the primary tumor load.
肥胖是乳腺癌生长和转移进展的独立危险因素，它也与肠道菌群失调密切相关；肥胖和菌群失调相互促进。 在肥胖状态下， 大量存在，而我们最近发现 存在于恶性乳腺癌中。鉴于产肠毒素 （ETBF） 分泌 毒素（BFT），已被确定为乳腺癌的致癌前微生物，有必要研究其对远处转移的影响，以及促进乳腺癌转移进展的潜在全身和局部改变。
我们使用带有 ETBF 肠道定植的同源乳腺管内（MIND）模型来研究乳腺癌细胞的远处转移。使用流式细胞术、免疫组织化学和多重分析检测肿瘤微环境和远处转移部位的免疫网络和细胞因子/趋化因子的改变。
ETBF 感染会引发全身性炎症，通过增加促炎和促肿瘤细胞因子（如 IL17A、IL17E、IL27p28、IL17A/F、IL6 和 IL10），帮助在重要器官中建立前转移龛形成，从而促进早期转移扩散，在富含髓样细胞、巨噬细胞和 T 调节细胞的肝脏和肺部中建立促转移免疫抑制环境。它通过免疫细胞和基质浸润、增加血管生成和 EMT 样反应来重塑肿瘤微环境，从而鼓励早期转移扩散，为乳腺癌荷瘤小鼠的肝脏和肺部有利环境中的定植做好准备。
在这项研究中，我们表明肠道 ETBF 感染同时诱导全身性炎症，重塑肿瘤免疫微环境，并创建有利的转移龛，以增强早期向肝脏和肺部的转移扩散和定植，这与“种子和土壤假说”一致。我们的结果还支持 ETBF 诱导的转移“平行模型”，该模型主张肿瘤细胞的早期扩散，形成独立于原发肿瘤负荷的转移性病变。
