Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.
Gut colonization with an obesity-associated enteropathogenic microbe modulates the premetastatic niches to promote breast cancer lung and liver metastasis.
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DOI：
10.3389/fimmu.2023.1194931
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发表时间：
2023
影响因子：
7.3
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中科院分区：
文献类型：
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肥胖是乳腺癌生长和转移进展的独立危险因素，也与肠道生态失调密切相关;肥胖状态和生态失调相互促进。肠道中脆弱拟杆菌的丰度与肥胖密切相关，我们最近发现了B的存在。恶性乳腺癌中的脆弱性。因为肠出血性B. fragilis或ETBF，其分泌B。脆性毒素（BFT）是乳腺癌的原癌微生物，有必要研究其对乳腺癌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肠道定殖的同基因乳腺导管内（MIND）模型来查询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阵列检查肿瘤微环境和远处转移部位中免疫网络和细胞因子/趋化因子的改变。ETBF感染引发全身性炎症，除了在富含骨髓细胞、巨噬细胞和T调节细胞的肝和肺中产生促转移免疫抑制环境之外，还通过增加促炎和促肿瘤细胞因子如IL 17 A、IL 17 E、IL 27 p28、IL 17 A/F、IL 6和IL 10来帮助在重要器官中建立转移前小生境形成。它通过免疫细胞和间质浸润、血管发生增加和EMT样反应诱导肿瘤微环境重塑，从而促进早期转移性播散，准备在乳腺肿瘤荷瘤小鼠的肝脏和肺中定植有利环境。在这项研究中，我们表明，肠道ETBF感染伴随诱导全身炎症，重塑肿瘤免疫微环境，并创造有利的转移壁龛，以加强早期传播和种植转移到肝和肺组织，与“种子和土壤假说”一致。我们的研究结果也支持ETBF诱导的转移的“平行模型”，该模型主张肿瘤细胞的早期传播，形成独立于原发肿瘤负荷的转移性病变。
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 Bacteroides fragilis is strongly linked with obesity, and we recently discovered the presence of B. fragilis in malignant breast cancer. Given that enterotoxigenic B. fragilis or ETBF, which secretes B. fragilis 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.
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影响因子：
4.6
作者：
Chan AA;Bashir M;Rivas MN;Duvall K;Sieling PA;Pieber TR;Vaishampayan PA;Love SM;Lee DJ
通讯作者：
Lee DJ
影响因子：
11.2
作者：
Benevides L;da Fonseca DM;Donate PB;Tiezzi DG;De Carvalho DD;de Andrade JM;Martins GA;Silva JS
通讯作者：
Silva JS
在自发的乳腺癌模型中，IL-15的过表达通过NK1.1+细胞促进肿瘤破坏。
影响因子：
3.8
作者：
Gillgrass AE;Chew MV;Krneta T;Ashkar AA
通讯作者：
Ashkar AA
影响因子：
3.8
作者：
Roy LD;Sahraei M;Schettini JL;Gruber HE;Besmer DM;Mukherjee P
通讯作者：
Mukherjee P
影响因子：
3.1
作者：
Ding, Song-Ze;Minohara, Yutaka;Crowe, Sheila E.
通讯作者：
Crowe, Sheila E.