Blockade of Fas Signaling in Breast Cancer Cells Suppresses Tumor Growth and Metastasis via Disruption of Fas Signaling-initiated Cancer-related Inflammation*
Blockade of Fas Signaling in Breast Cancer Cells Suppresses Tumor Growth and Metastasis via Disruption of Fas Signaling-initiated Cancer-related Inflammation*
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DOI：
10.1074/jbc.m113.525014
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发表时间：
2014-03
期刊：
影响因子：
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通讯作者：
Qiuyan Liu;Qinchun Tan;Yuanyuan Zheng;Kun Chen;C. Qian;Nan Li;Qingqing Wang;Xuetao Cao
中科院分区：
文献类型：
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作者：
Qiuyan Liu;Qinchun Tan;Yuanyuan Zheng;Kun Chen;C. Qian;Nan Li;Qingqing Wang;Xuetao Cao
背景：Fas信号的非凋亡功能已被提出在促进肿瘤进展中发挥重要作用。结果：Fas信号的阻断通过破坏Fas信号引发的癌症相关炎症来抑制肿瘤的生长和转移。结论：乳腺癌细胞中Fas信号引发的癌症相关炎症可能是癌症治疗的潜在靶点。意义：本研究为Fas信号在癌症相关炎症中的作用提供了机制见解。癌症相关炎症的机制仍有待充分阐明。Fas信号的非凋亡功能已被提出在促进肿瘤进展中发挥重要作用。目前还不清楚靶向Fas信号是否可以通过抑制癌症相关炎症来控制肿瘤进展。在目前的研究中，我们发现具有组成型Fas表达的乳腺癌细胞对激动性抗Fas抗体（Jo2）连接或Fas配体交联诱导的凋亡具有抗性。人类乳腺癌组织中Fas的高表达与乳腺癌患者预后差有显著相关性。为了确定阻断乳腺癌Fas信号通路是否能抑制肿瘤进展，我们用4T1乳腺癌细胞制备了原位异种移植小鼠模型，发现阻断4T1癌细胞Fas信号通路可显著降低肿瘤生长，体内抑制肿瘤转移，延长荷瘤小鼠的生存期。从机制上讲，阻断癌细胞中的Fas信号可显著减少体内髓源性抑制细胞（MDSCs）的全身或局部募集。此外，Fas信号通路的阻断通过损害p-p38和NFκB通路的活性，显著降低了乳腺癌细胞IL-6、前列腺素E2的产生。此外，给予COX-2抑制剂和抗il -6抗体可显著减少体内MDSC的积累。因此，阻断Fas信号可以通过抑制促炎细胞因子的产生和MDSC的积累来抑制乳腺癌的进展，这表明Fas信号在乳腺癌细胞中引发的癌症相关炎症可能是治疗乳腺癌的潜在靶点。
Background: The non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. Results: Blockade of Fas signaling suppresses tumor growth and metastasis via disruption of Fas signaling-initiated cancer-related inflammation. Conclusion: Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for cancer treatment. Significance: This study provides mechanistic insight into the role of Fas signaling in cancer-related inflammation. Mechanisms for cancer-related inflammation remain to be fully elucidated. Non-apoptotic functions of Fas signaling have been proposed to play an important role in promoting tumor progression. It has yet to be determined if targeting Fas signaling can control tumor progression through suppression of cancer-related inflammation. In the current study we found that breast cancer cells with constitutive Fas expression were resistant to apoptosis induction by agonistic anti-Fas antibody (Jo2) ligation or Fas ligand cross-linking. Higher expression of Fas in human breast cancer tissue has been significantly correlated with poorer prognosis in breast cancer patients. To determine whether blockade of Fas signaling in breast cancer could suppress tumor progression, we prepared an orthotopic xenograft mouse model with mammary cancer cells 4T1 and found that blockade of Fas signaling in 4T1 cancer cells markedly reduced tumor growth, inhibited tumor metastasis in vivo, and prolonged survival of tumor-bearing mice. Mechanistically, blockade of Fas signaling in cancer cells significantly decreased systemic or local recruitment of myeloid derived suppressor cells (MDSCs) in vivo. Furthermore, blockade of Fas signaling markedly reduced IL-6, prostaglandin E2 production from breast cancer cells by impairing p-p38, and activity of the NFκB pathway. In addition, administration of a COX-2 inhibitor and anti-IL-6 antibody significantly reduced MDSC accumulation in vivo. Therefore, blockade of Fas signaling can suppress breast cancer progression by inhibiting proinflammatory cytokine production and MDSC accumulation, indicating that Fas signaling-initiated cancer-related inflammation in breast cancer cells may be a potential target for treatment of breast cancer.