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CCR2 signaling in breast carcinoma cells promotes tumor growth and invasion by promoting CCL2 and suppressing CD154 effects on the angiogenic and immune microenvironments.
Oncogene ( IF 8 ) Pub Date : 2019-12-11 , DOI: 10.1038/s41388-019-1141-7
Gage Brummer 1 , Wei Fang 1 , Curtis Smart 1 , Brandon Zinda 1 , Nadia Alissa 2 , Cory Berkland 3 , David Miller 4 , Nikki Cheng 1, 2
Affiliation  

Breast cancer is the second leading cause of cancer-related deaths for women, due mainly to metastatic disease. Invasive tumors exhibit aberrations in recruitment and activity of immune cells, including decreased cytotoxic T cells. Restoring the levels and activity of cytotoxic T cells is a promising anticancer strategy; but its success is tumor type dependent. The mechanisms that coordinate recruitment and activity of immune cells and other stromal cells in breast cancer remain poorly understood. Using the MMTV-PyVmT/FVB mammary tumor model, we demonstrate a novel role for CCL2/CCR2 chemokine signaling in tumor progression by altering the microenvironment. Selective targeting of CCR2 in the PyVmT mammary epithelium inhibited tumor growth and invasion, elevated CD8+ T cells, decreased M2 macrophages and decreased angiogenesis. Co-culture models demonstrated these stromal cell responses were mediated by tumor-derived CCL2 and CCR2-mediated suppression of the T-cell activating cytokine, CD154. Coculture analysis indicated that CCR2-induced stromal reactivity was important for tumor cell proliferation and invasion. In breast tumor tissues, CD154 expression inversely correlated with CCR2 expression and correlated with relapse free survival. Targeting the CCL2/CCR2 signaling pathway may reprogram the immune angiogenic and microenvironments and enhance effectiveness of targeted and immunotherapies.

中文翻译:

乳腺癌细胞中的CCR2信号传导通过促进CCL2并抑制CD154对血管生成和免疫微环境的作用来促进肿瘤生长和侵袭。

乳腺癌是女性与癌症相关的死亡的第二大主要原因,主要是由于转移性疾病。侵袭性肿瘤在免疫细胞的募集和活性中表现出异常,包括细胞毒性T细胞减少。恢复细胞毒性T细胞的水平和活性是一种有前途的抗癌策略。但其成功取决于肿瘤类型。在乳腺癌中协调免疫细胞和其他基质细胞的募集和活性的机制仍然知之甚少。使用MMTV-PyVmT / FVB乳腺肿瘤模型,我们通过改变微环境证明了CCL2 / CCR2趋化因子信号传导在肿瘤进展中的新作用。PyVmT乳腺上皮细胞中CCR2的选择性靶向抑制了肿瘤的生长和侵袭,CD8 + T细胞升高,M2巨噬细胞减少,血管生成减少。共培养模型表明,这些基质细胞反应是由肿瘤来源的CCL2和CCR2介导的T细胞活化细胞因子CD154的抑制介导的。共培养分析表明,CCR2诱导的基质反应对于肿瘤细胞的增殖和侵袭很重要。在乳腺肿瘤组织中,CD154表达与CCR2表达呈反相关,与无复发生存相关。靶向CCL2 / CCR2信号通路可以重新编程免疫血管生成和微环境,并增强靶向和免疫疗法的有效性。在乳腺肿瘤组织中,CD154表达与CCR2表达呈反相关,与无复发生存相关。靶向CCL2 / CCR2信号通路可以重新编程免疫血管生成和微环境,并增强靶向和免疫疗法的有效性。在乳腺肿瘤组织中,CD154表达与CCR2表达呈反相关,与无复发生存相关。靶向CCL2 / CCR2信号通路可以重新编程免疫血管生成和微环境,并增强靶向和免疫疗法的有效性。
更新日期:2019-12-11
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